Immune system

The Immune system is a network of biological processes that protects an organism from diseases.

Quotes

 * To our knowledge, though preliminarily, this is the first time differentially expressed gene networks specific for the immune system are shown to correlate with global alteration of miRNA expression in the PBMCs of PTSD patients. Furthermore, we correlated the expression of several differentially expressed genes with altered DNA methylations at the corresponding CpG sites of the promoter of the respective genes. Functional enrichment of the differentially expressed genes indicated probable alteration of Th cell differentiation pathway. This pathway was one of the major pathways with three genes (STAT4, TBX21, and HLA-DQA1) present from the significant set of genes. STAT4 and TBX21 have crucial roles in regulating T cell functions. For example, TBX21 is the main transcription factor for the expression of interferon gamma, a pro-inflammatory gene and already reported by our group (Bam et al.) to be elevated in PTSD. This observation is important because the fate of Th cells decides the outcome of immune cell functions whether to be pro- or anti-inflammatory in nature. It also further supports the report on differential expression of T cell produced pro-inflammatory cytokine(s) in PTSD6. Therefore, we conclude that an alteration in the T cell biology is possibly one of the root causes for the underlying inflammation seen during PTSD. Altogether, our observation corroborates well with previous PTSD reports employing RNA-Seq technique with RNA obtained from peripheral blood leukocytes. The authors reported that several genes involved in the innate immune system network were differentially expressed in PTSD. Similarly, in the present study, the top canonical pathways with differentially expressed genes were from the innate immune system in addition to some disease specific pathways. For example, the top canonical pathway with the largest number of differentially expressed genes from our dataset was ‘agranulocyte/granulocyte adhesion and diapedesis’. This pathway describes the stages involved in the movement or migration of leukocytes out of the circulatory system to the site of tissue damage or infection during an inflammatory response. Chemotactic molecules (chemokines) like those secreted by monocytes, macrophages and other immune cells play an important role during this process35,36. Function of chemokines is mainly to bring about migration (homing) of leukocytes in the respective sites during homeostasis and inflammatory processes. Other functions of chemokines are seen during different processes like maturation, activation and differentiation for different types of leukocytes. We observed that expression of many of the chemokines and their receptors (CCL4, CCL5, CXCL1, CXCL2, CXCL3, CXCL6, CXCL8, CXCR1, and CXCR2) were altered in PTSD patients. Chemokines like CCL4, CCL5, CXCL1, CXCL2, CXCL3, CXCL6 and CXCL8 are considered to be pro-inflammatory in their function41. Another example of a canonical pathway with several differentially expressed genes from our dataset was “dendritic cell maturation”, which plays a critical role in antigen processing and presentation.
 * Marpe Bam, Xiaoming Yang, Elizabeth E. Zumbrun, Yin Zhong, Juhua Zhou, Jay P. Ginsberg, Quinne Leyden, Jiajia Zhang, Prakash S. Nagarkatti & Mitzi Nagarkatti; “Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation”, Scientific Reports, volume 6, Article number: 31209 (11 August 2016)


 * In summary, the present work has identified differentially expressed genes and miRNAs and the related canonical immune system pathways in the PBMCs of PTSD inflicted war veterans. Furthermore, we provide evidence that many genes have altered DNA methylation at their CpG islands and the expression of the associated genes inversely correlate in PTSD patients. Taken together, the present and previous reports from our lab, and from other research groups, clearly indicate that miRNAs and DNA methylation play a critical role in the modulation of the immune system, with a special emphasis on chronic inflammation seen in PTSD. Most importantly, our findings, although preliminary, open future directions for studies in a pathway specific manner and targeting specific gene regulators to develop novel management strategies and therapies to control the inflammatory response seen during PTSD in war return veterans and the general population.
 * Marpe Bam, Xiaoming Yang, Elizabeth E. Zumbrun, Yin Zhong, Juhua Zhou, Jay P. Ginsberg, Quinne Leyden, Jiajia Zhang, Prakash S. Nagarkatti & Mitzi Nagarkatti; “Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation”, Scientific Reports, volume 6, Article number: 31209 (11 August 2016)


 * While families are taking steps to prevent the spread of COVID-19, it may be the right time to educate children on healthy eating and routines... some foods and habits that can help strengthen your kid’s immune system 1. Add foods high in vitamin C... 2. Make chicken soup a year-round option... 3. Lower sugar intake... 4. Incorporate essential oils... 5. Make sure they get enough sleep... 6. Encourage daily exercise... 7. Teach proper handwashing...
 * Gisselle Bances, "7 tips to help strengthen your child’s immune system", Yahoo Life, (7 July 2020)


 * The present study aimed to assess the effect of Sambucol products on the healthy immune system - namely, its effect on cytokine production. The production of inflammatory cytokines was tested using blood - derived monocytes from 12 healthy human donors. Adherent monocytes were separated from PBL and incubated with different Sambucol preparations i.e., Sambucol Elderberry Extract, Sambucol Black Elderberry Syrup, Sambucol Immune System and Sambucol for Kids. Production of inflammatory cytokines (IL-1 beta, TNF-alpha, IL-6, IL-8) was significantly increased, mostly by the Sambucol Black Elderberry Extract (2-45 fold), as compared to LPS, a known monocyte activator (3.6-10.7 fold). The most striking increase was noted in TNF-alpha production (44.9 fold). We conclude from this study that, in addition to its antiviral properties, Sambucol Elderberry Extract and its formulations activate the healthy immune system by increasing inflammatory cytokine production. Sambucol might therefore be beneficial to the immune system activation and in the inflammatory process in healthy individuals or in patients with various diseases. Sambucol could also have an immunoprotective or immunostimulatory effect when administered to cancer or AIDS patients, in conjunction with chemotherapeutic or other treatments. In view of the increasing popularity of botanical supplements, such studies and investigations in vitro, in vivo and in clinical trials need to be developed.
 * V Barak, T Halperin, I Kalickman, “The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines”. Eur Cytokine Netw. Apr-Jun 2001;12(2):290-6.],


 * The three Sambucol formulations activate the healthy immune system by increasing inflammatory and anti-inflammatory cytokines production, while the effect of Protec and Chizukit N is much less. Sambucol could therefore have immunostimulatory properties when administered to patients suffering from influenza (as shown before), or immunodepressed cancer or AIDS patients who are receiving chemotherapy or other treatments.
 * Vivian Barak, Shlomo Birkenfeld, Tal Halperin, Inna Kalickman, “The effect of herbal remedies on the production of human inflammatory and anti-inflammatory cytokines”, Isr Med Assoc J. 2002 Nov;4(11 Suppl):919-22.


 * For the longest time, scientists thought that the brain was totally separate from the body’s immune system—recent work has shown that’s not so. In the membranes that cover the brain and spinal cord, there are lymphatic vessels that can drain fluid and immune cells from the cerebrospinal fluid into the deep cervical lymph nodes, which are located in the neck. Researchers identified these vessels first in mice, then found a “potentially similar structure” in humans.
 * Julie Beck, “How the Immune System Controls Social Behavior”, The Atlantic, (July 21, 2016)


 * [A] new study has shown that the immune system’s connections with the central nervous system may actually affect how animals behave socially. The key is a molecule called interferon-gamma. T-cells, a type of white blood cell, in those vessels emit interferon-gamma (let’s just call it I-G, not to be confused with Instagram) into the brain. Once there, it inhibits neurons in the prefrontal cortex. This is normal—without I-G, that region can become overactive. And researchers have found that in mice, when the prefrontal cortex becomes overactive, they get asocial. Why would more brain activity make an animal less social? “I like the example of traffic,” says Vladimir Litvak, a professor at the University of Massachusetts Medical School, and an author on the study. “Too much traffic actually causes the stop of traffic. The system is unable to process all these signals.” The researchers looked at several kinds of animals—rats, mice, zebrafish, and fruit flies—and found that when they gathered together, certain genes would activate and this I-G response would flare up. (Except the flies, who don’t actually have I-G, but they do have similar genes that activate.)
 * Julie Beck, “How the Immune System Controls Social Behavior”, The Atlantic, (July 21, 2016)


 * Immune system dysfunction is linked to several diseases that involve social dysfunction—dementia, schizophrenia, and autism spectrum disorder among them. It could be that I-G is the link that explains this connection. “We were really fascinated by why this antipathogen molecule would have a prosocial function—that doesn't really make sense,” says Anthony Filiano, a postdoctoral researcher at the University of Virgnia, and lead author on the study. Socializing helps animals in tons of ways, sure, but gathering in groups makes diseases more likely to spread. Why, evolutionarily speaking, is that something the immune system would want to promote? On this, the researchers can only speculate. “Naturally if individuals tend to spread diseases, that could easily result in extinction of the whole colony,” Litvak says. “So you have to have a very strong immune response.” Maybe the immune system activates when animals are socializing to protect them against the increased risk of getting a disease. Fililano suggests the possibility of a more complicated co-evolution between animals and the pathogens that infect them. It could be that viruses evolved to try to trigger this response, so animals would be more social, and spread the viruses further. And then, the animals in turn evolved so the immune system would protect them even when they were being social.
 * Julie Beck, “How the Immune System Controls Social Behavior”, The Atlantic, (July 21, 2016)


 * Many of the botanical "immunomodulators", a class of herbal medicines widely recognized in traditional medical systems such as Chinese Medicine (TCM) and Ayurvedic Medicine, alter immune function and may offer clinically relevant therapeutics or leads to therapeutics. Many of these traditional remedies are prepared from combinations of medicinal plants which may influence numerous molecular pathways. These effects may differ from the sum of effects from the individual plants and therefore, research demonstrating the effects of the formula is crucial for insights into the effects of traditional remedies. In this review we surveyed the primary literature for research that focused on combinations of medicinal plants and effects on cytokine activity. The results demonstrate that many extracts of herb mixtures have effects on at least one cytokine. The most commonly studies cytokines were IL-4, IL-6, IL-10, TNF and IFN-γ. The majority of the formulas researched derived from TCM. The following formulas had activity on at least three cytokines; Chizukit N, CKBM, Daeganghwal-tang, Food Allergy Formula, Gamcho-Sasim-Tang, Hachimi-jio-gan, Herbkines, Hochuekki, Immune System Formula, Jeo-Dang-Tang, Juzen-taiho-to, Kakkon-to, Kan jang, Mao-Bushi-Saishin-to, MSSM-002, Ninjin-youei-to, PG201, Protec, Qing-huo-bai-du-yin, Qingfu Guanjieshu, Sambucol Active Defense, Seng-fu-tang, Shin-Xiao-Xiang, Tien Hsien, Thuja formula, Unkei-to, Vigconic, Wheeze-relief-formula, Xia-Bai-San, Yangyuk-Sanhwa-Tang, Yi-fey Ruenn-hou, and Yuldahansotang. Of the western based combinations, formulas with Echinacea spp. were common and showed multiple activities. Numerous formulas demonstrated activity on both gene and protein expression. The research demonstrates that the reviewed botanical formulas modulate cytokine activity, although the bulk of the research is in vitro. Therapeutic success using these formulas may be partially due to their effects on cytokines. Further study of phytotherapy on cytokine related diseases/syndromes is necessary.
 * J J Burns, Lijun Zhao, Ethan Will Taylor, Kevin Spelman; “The influence of traditional herbal formulas on cytokine activity”, Toxicology, 2010 Nov 28;278(1):140-59.


 * The immune response was assessed in 13 competitive bodybuilders self-administering anabolic-androgenic steroids and ten competitive bodybuilders not administering these drugs. Laboratory assessment included the number and relative distribution of T-cells, T-helper/inducer cells, T-cytotoxic/suppressor cells, activated T-cells, lymphocyte transformation to the mitogens, pokeweed mitogen (PWM), phytohemagglutinin (PHA), Concanavalin-A (CON-A), Staphylococcus aureus Cowan strain I (SAC), serum immunoglobulins, and natural killer (NK) activity. There were no significant differences in T-cell subsets among steroid users and non-users, but lymphocyte transformation studies revealed that the anabolic-androgenic steroid-using group had enhanced proliferative ability to the B-cell mitogen, SAC, in comparison to non-bodybuilding controls. NK activity was significantly (P less than 0.05) augmented in the anabolic-androgenic steroid users but not in the non-using bodybuilders. Serum immunoglobulin levels, in particular IgA, were significantly (P less than 0.017) lower in the steroid-using group. Four of 13 steroid users and three of eight non-steroid-using bodybuilders had detectable antinuclear antibodies. These studies indicate that 1) anabolic-androgenic steroid use as practiced by contemporary athletes is a potent modulator of immune responsiveness and 2) autoantibodies are prevalent in strength-trained men even in the absence of anabolic steroid use.
 * L H Calabrese 1, S M Kleiner, B P Barna, C I Skibinski, D T Kirkendall, R G Lahita, J A Lombardo; “The effects of anabolic steroids and strength training on the human immune response”, Med Sci Sports Exerc. 1989 Aug;21(4):386-92.


 * Humanity has repeatedly faced epidemics of known and novel pathogens and the immune system has adapted to survive.
 * Rita Carsetti, Concetta Quintarelli, Isabella Quinti, Eva Piano Mortari, Alimuddin Zumla, Giuseppe Ippolito, et al.; “The immune system of children: the key to understanding SARS-CoV-2 susceptibility?”, The Lancet, Volume 4, ISSUE 6, P414-416, (June 01, 2020)


 * During the first months of life, maternal antibodies protect the child from the microorganisms that the mother has encountered previously. Although water sanitation and hygiene practices have reduced epidemics and vaccines have been developed to prevent potentially lethal diseases, all microorganisms are new for the child. The frequent infections occurring in the first years of life serve to build the pool of memory T and B cells that will prevent reinfection or development of disease by commonly encountered pathogens. Thus, the paediatric immune system is prepared and fit to react to novelty, a function that might be diminished in adults and ineffective in elderly people aged 70 years or older. Although innate immunity and T cells play a crucial role in the defense against infection, antibodies also play an important role. In the SARS, Ebola, and H1N1 epidemics, convalescent plasma containing antibodies from patients who had recovered from viral infections was used for treatment at the early stage of disease. Human monoclonal antibodies obtained from cloned B cells of a convalescent SARS-Cov-2 might become candidate therapeutics. In most cases, viral load peaks in the first week of infection and patients generate a primary immune response by days 10–14, followed by virus clearance through the action of high-affinity antibodies and T cells. The response of naive B cells to any novel infection or vaccine occurs through the germinal centre reaction and takes 2 weeks. This is a reasonable time for the response to a vaccine, but it is much too long for the response to infection. In the germinal centre, B cells modify their antibodies through the introduction of somatic mutations in the antigen-binding site of the immunoglobulin variable heavy chain genes. Only modified B cells that express high-affinity antibodies are selected to become memory B cells (MBCs) and plasma cells.
 * Rita Carsetti, Concetta Quintarelli, Isabella Quinti, Eva Piano Mortari, Alimuddin Zumla, Giuseppe Ippolito, et al.; “The immune system of children: the key to understanding SARS-CoV-2 susceptibility?”, The Lancet, Volume 4, ISSUE 6, P414-416, (June 01, 2020)


 * Evolution has endowed a survival advantage to children to combat known and unknown pathogens. The adult is also well protected by the balance of cells with high and low specificity. With ageing, malnutrition, immunosuppression, and co-morbid states, our immune system loses the ability to adapt to novelty. Although vaccines are the way forward, in emergency situations such as the COVID-19 pandemic, the investigation and use of immune tools that nature has endowed to children might improve management outcomes.
 * Rita Carsetti, Concetta Quintarelli, Isabella Quinti, Eva Piano Mortari, Alimuddin Zumla, Giuseppe Ippolito, et al.; “The immune system of children: the key to understanding SARS-CoV-2 susceptibility?”, The Lancet, Volume 4, ISSUE 6, P414-416, (June 01, 2020)


 * How many times have you heard or said: "Don't kiss me. I have a cold." It makes sense. Close contact spreads colds, so avoiding physical intimacy with cold sufferers should be a sensible way to avoid humanity's most common illness. But a study at Wilkes-Barre University in Pennsylvania shows the opposite, that the close contact of lovemaking reduces risk of colds.
 * Michael Castleman M.A., “Want to Prevent Colds? Have Sex Weekly”, Psychology Today, (Jun 01, 2009)


 * Why would frequent sex in a happy, long-term relationship help prevent colds? It's counterintuitive. Close contact should increase the likelihood of cold transmission--unless interpersonal closeness provides benefits that override the risk of physical proximity. Indeed, a happy, sexually active relationship provides two significant immunological benefits--relaxation and social support.
 * Michael Castleman M.A., “Want to Prevent Colds? Have Sex Weekly”, Psychology Today, (Jun 01, 2009)


 * Many studies show that deep relaxation, the kind that results from meditation or visualization/guided imagery, stimulates the immune system. Psychologists at Washington State University took blood samples from 65 people and counted their number of infection-fighting white blood cells. Then the group watched a video that described the immune system. One-third of them did nothing else. Another third was taught to meditate, and practiced twice a day. The final third learned to visualize their immune systems growing stronger, and practiced that visualization twice a day. A week later, the researchers obtained new blood samples. The control group experienced no increase in white cells. But both the meditation and visualization groups did.
 * Michael Castleman M.A., “Want to Prevent Colds? Have Sex Weekly”, Psychology Today, (Jun 01, 2009)


 * Many studies show that social support revs up the immune system, and helps prevent colds. At the University of Pittsburgh, psychologist Sheldon Cohen, Ph.D., studied 276 healthy volunteers, who completed a survey of their social ties-to lovers, friends, family, and organizations-and then had live cold virus squirted up their noses. Those with the most social support were least likely to catch the cold.
 * Michael Castleman M.A., “Want to Prevent Colds? Have Sex Weekly”, Psychology Today, (Jun 01, 2009)


 * 112 college students reported the frequency of their sexual encounters and were divided into four categories: none, infrequent (less than once a week), frequent (one to two times per week), and very frequent (three or more times per week). Participants also described their overall sexual satisfaction. Saliva samples were collected and assayed for salivary immunoglobulin A (IgA). Individuals in the frequent group showed significantly higher levels of IgA than the other three groups, which were comparable. Data on length of relationship and sexual satisfaction were not related to the group differences.
 * Carl J Charnetski, Francis X Brennan; “Sexual frequency and salivary immunoglobulin A (IgA)” Psychol Rep. 2004 Jun;94(3 Pt 1):839-44.


 * “Theoretically,” said Dye, “massage allows for faster recovery due to increased circulation of the lymph and blood vascular systems,” said Dye. “The findings can guide clinicians or midwives in providing aromatherapy massage to women throughout the pregnancy,” the study’s authors wrote. “Massage is popular in America, with almost 9% of adults receiving at least one massage within the past year,” said Mark Rapaport, MD, chairman of the Department of Psychiatry and Behavioral Neurosciences and lead study author, said in a statement.
 * George Citroner, “This is How Massage Helps Build a Healthy Immune System”, Massage Magazine, (April 8, 2020)


 * “There is still so much unknown about the coronavirus, but having a healthy, functioning immune system will always be helpful in reducing the effects of the virus, if contracted, and, could possibly be helpful in prevention of even contracting the virus at all,” said Vicky Karr, LMT, a CE provider and owner of Spa Success. “Because massage therapy aids in improving the immune system, it is generally assumed that it could help reduce the risk of coronavirus infection,” she added. However, according to Karr, because of the close bodily proximity between “a massage therapist and their client,” all of us should be following the “social distancing” guidelines that have been put into place, and not seek massage therapy until the pandemic has subsided.
 * George Citroner, “This is How Massage Helps Build a Healthy Immune System”, Massage Magazine, (April 8, 2020)


 * In humans, surgical procedures (Andersen et al., 1998; Pollock et al., 1992) as well as other major stressors (Cohen and Herbert, 1996) have been reported to suppress NKA and other immune functions for several days. The biological significance of such immune suppression is suggested by the well‐established relationship between surgical procedures and the outbreak of dormant infectious diseases known to be under immune surveillance, such as tuberculosis, herpes or cytomegalovirus (Glaser et al., 1987; Holzheimer et al., 1997). Whether such immune‐suppressive effects of surgery also impact tumor development in the clinical setting remains unknown. However, many patients undergo surgery for the excision of a neoplasm with metastatic potential at the time of surgery, as evidenced by the presence of positive lymph nodes or the detection of metastases. If our findings in rats can be generalized to such clinical settings, then suppression of NKA or other immune functions under such circumstances may increase the susceptibility to tumor metastasis during or shortly after surgery. In conclusion, based on the findings of this and other studies, we suggest that under specific circumstances various stressors, including surgical stress, can enhance metastasis by suppressing the cytotoxic activity of NK cells. Because surgical procedures are life‐saving and, thus, cannot be wit held, prophylactic measures against their potential immune‐suppressive and metastasis‐enhancing effects should be considered.
 * Sheldon Cohen, Denise Janicki-Deverts, William J Doyle, Gregory E Miller, Ellen Frank, Bruce S Rabin, Ronald B Turner; “Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk”, Proc Natl Acad Sci U S A . 2012 Apr 17;109(16):5995-9.


 * DNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-κB/Rel transcription factors (p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways. These data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.
 * Steve W Cole, Louise C Hawkley, Jesusa M Arevalo, Caroline Y Sung, Robert M Rose & John T Cacioppo; “Social regulation of gene expression in human leukocytes”, Genome Biology, volume 8, (13 September 2007)


 * This study provides the first systematic analysis of genome-wide transcriptional alterations as a potential mechanism of social-epidemiological influences on human health. Individuals who experience themselves as chronically isolated from others have an increased risk of several inflammation-related diseases, and the broad pattern of leukocyte transcriptional alterations identified in this study provides a framework for understanding that risk at the molecular level. Immune cells from people who report consistently high levels of subjective social isolation (loneliness) showed increased expression of genes controlling basic cellular transcription processes, cell cycle progression, pro-inflammatory cytokine signaling, and prostaglandin synthesis. Against this generalized backdrop of immunological activation, however, several functionally distinct subsets of immune response genes showed selective under-expression, including type I interferon response genes involved in innate antiviral resistance, and genes supporting antibody production and mature B lymphocyte function. These leukocyte transcriptional dynamics are consistent with clinical data indicating a complex pattern of host resistance alterations in social isolates, including increased risk of inflammation-mediated disease, accompanied by decreased resistance to viral infection and impaired humoral immune response. In addition to providing a molecular framework for understanding the biological mechanisms of social epidemiology, the present results provide a functional genomic target for the rational selection of biological interventions to remediate those effects. The transcriptional fingerprint of loneliness identified here may also provide a novel genomic biomarker for assessing the impact of such interventions prior to the onset of clinical disease.
 * Steve W Cole, Louise C Hawkley, Jesusa M Arevalo, Caroline Y Sung, Robert M Rose & John T Cacioppo; “Social regulation of gene expression in human leukocytes”, Genome Biology, volume 8, (13 September 2007)


 * These data identify a distinct transcriptional fingerprint of subjective social isolation in human leukocytes, which involves increased basal expression of inflammatory and immune response genes. Bioinformatic analysis of differentially expressed promoters suggests that these effects may be shaped by reduced activity of the anti-inflammatory glucocorticoid transcription control pathway and a complementary increase in activity of the pro-inflammatory NF-κB/Rel pathway. These data provide the first evidence that social-environmental risk factors are linked to global alterations in human gene transcription, and they establish a molecular context for understanding the increased risk of inflammatory disease observed in human beings who experience a chronic sense of subjective social isolation (loneliness). Dissociation between stable circulating cortisol levels and impaired glucocorticoid receptor-mediated transcription highlights the need to analyze social environmental risk at the level of the functional genomic dynamics that ultimately drive the expression of disease.
 * Steve W Cole, Louise C Hawkley, Jesusa M Arevalo, Caroline Y Sung, Robert M Rose & John T Cacioppo; “Social regulation of gene expression in human leukocytes”, Genome Biology, volume 8, (13 September 2007)


 * The normal immune system has local and systemic components which are influenced by a variety of alterations. Impaired host immunity is associated with neoplasia, protein calorie malnutrition, and the administration of immunosuppressive drugs. It is well accepted that protein calorie malnutrition impairs host immunity with particular detrimental effects on the T-cell system, resulting in increased opportunistic infection and increased morbidity and mortality in hospitalized patients. Individual nutrient substrates may also have a major influence on the immune system. Individual amino acids are often described as essential, based on requirements for optimal growth and maintenance of positive N balance. Arginine has been demonstrated to be essential to the traumatized host and may have tissue-specific properties which influence components of the immune system. Thus, arginine may be of value in clinical situations where the immune system is compromised. In a series of experiments in normal animals, arginine was demonstrated to enhance cellular immune mechanisms, in particular T-cell function. It also has a marked immunopreserving effect in the face of immunosuppression induced by protein malnutrition and increases in tumor burden. In postoperative surgical patients, arginine supplementation results in enhanced T-lymphocyte response and augmented T-helper cell numbers, with a rapid return to normal of T-cell function postoperatively compared with control patients. These data suggest that arginine supplementation may enhance or preserve immune function in high-risk surgical patients and theoretically improve the host's capacity to resist infection.
 * J M Daly, J Reynolds, R K Sigal, J Shou, M D Liberman; “Effect of dietary protein and amino acids on immune function”, Crit Care Med. 1990 Feb;18(2 Suppl):S86-93.


 * Normally, there are very small numbers of viable white cells in most units of blood transfused today. People with normal immune systems can reject transfused donor lymphocytes, which is a good thing. If transfused lymphocytes are not rejected there can be problems. Very sensitive tests for donor white cells have shown that they may persist in the recipients blood for one or two weeks after transfusion before they are rejected. It is possible for transfused lymphocytes to survive and proliferate, however. Small numbers of donor lymphocytes have been found in some patients months or years after transfusion. This results in a state of microchimerism, in which a little of the patients immune system is genetically foreign. We do not know the full implications of microchimerism, but it most likely causes some abnormalities in immune responses. In the most severe case, transfused lymphocytes can not only survive, but also react against the patients tissues. This causes graft-versus-host disease, which is usually fatal. Patients with markedly impaired cellular immunity are at risk of transfusion-associated graft-versus-host disease. Blood for such patients is routinely gamma irradiated to prevent this rare but very serious reaction.
 * Robertson D. Davenport, “Why are blood transfusions from strangers not rejected, like transplanted organs can be?”, Scientific American, (November 3, 2003)


 * Stress and surgery have been suggested to compromise host resistance to infectious and malignant diseases in experimental and clinical settings. Because stress affects numerous physiological systems, the role of the immune system in mediating such effects is unclear. In the current study, we assessed the degree to which stress-induced alterations in natural killer (NK) cell activity underlie increased susceptibility to tumor development in F344 rats. Two stress paradigms were used: forced swim and abdominal surgery. Host resistance to tumor development was studied using 3 tumor models syngeneic to inbred F344 rats: CRNK-16 leukemia and the MADB106 mammary adenocarcinoma, both sensitive to NK activity, and the NK-insensitive C4047 colon cancer. Swim stress increased CRNK-16-associated mortality and metastatic development of MADB106 but not metastasis of C4047 cells. In both stress paradigms, stress suppressed NK activity (NKA) for a duration that paralleled its metastasis-enhancing effects on the MADB106 tumor. In vivo depletion of large granular lymphocyte/NK cells abolished the metastasis-enhancing effects of swim stress but not of surgical stress. Our findings indicate that stress-induced suppression of NKA is sufficient to cause enhanced tumor development. Under certain stressful conditions, suppression of NKA is the primary mediator of the tumor-enhancing effects of stress, while under other conditions, additional factors play a significant role. Clinical circumstances in which surgical stress may induce enhanced metastatic growth are discussed.
 * S Ben-Eliyahu 1, G G Page, R Yirmiya, G Shakhar; “Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity”, Int J Cancer. 1999 Mar 15;80(6):880-8.


 * This study was designed to investigate changes in the immune system of elite swimmers compared with well-conditioned age- and sex-matched controls in relation to a competition swim (field study). Furthermore, the aim was to reveal possible differences in immune system changes depending on the type of sport performed by comparing with an earlier study of similar design, from the same laboratory that tested elite runners in relation to a competition run. The swimmers were tested before, immediately after and 2 h and 24 h after a competition swim. Lymphocyte subsets (CD5, CD3, HLA-DR, CD4, CD8, CD19, CD3/CD16+56, CD57, CD18, CD16/CD122) all increased after the run, decreased to normal or subnormal levels after 2 h, and returned to normal after 24 h (absolute numbers). The findings were identical for the swimmers and the age- and sex-matched control group. No change in polymorphonuclear granulocyte migration was found. The lymphocyte proliferative responses decreased 2 h after the exercise. No changes were seen in plasma cytokine levels (interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) in relation to exercise, but significantly lower baseline values for IL-6 were observed in the swimmers. An increase in total natural killer cell activity immediately after exercise, followed after 2 h by a decrease, was seen in both swimmers and controls. Finally, no complement activation was detected. Compared with an earlier study of elite runners, differences were seen in granulocyte chemotactic response, TNF-alpha plasma activity and the lymphocyte proliferative response to mitogen. These differences might be explained by the degree of immune system activation following muscle damage during exercise, inducing an increase in cytokines, which are known to activate and modulate both lymphocytes and granulocyte function. Our findings demonstrate identical exercise-induced, immune system changes in elite swimmers and well conditioned controls, and furthermore, the findings suggest that different types of sport performed at maximum intensity induce different immune system changes.
 * G T Espersen, A Elbaek, S Schmidt-Olsen, E Ejlersen, K Varming, N Grunnet; “Short-term changes in the immune system of elite swimmers under competition conditions. Different immunomodulation induced by various types of sport”, Scand J Med Sci Sports. 1996 Jun;6(3):156-63.


 * Yoga is an ancient mind-body practice that is increasingly recognized to have health benefits in a variety of clinical and non-clinical conditions. This systematic review summarizes the findings of randomized controlled trials examining the effects of yoga on immune system functioning which is imperative to justify its application in the clinic. Fifteen RCTs were eligible for the review. Even though the existing evidence is not entirely consistent, a general pattern emerged suggesting that yoga can downregulate pro-inflammatory markers. In particular, the qualitative evaluation of RCTs revealed decreases in IL-1beta, as well as indications for reductions in IL-6 and TNF-alpha. These results imply that yoga may be implemented as a complementary intervention for populations at risk or already suffering from diseases with an inflammatory component. Beyond this, yoga practice may exert further beneficial effects by enhancing cell-mediated and mucosal immunity. It is hypothesized that longer time spans of yoga practice are required to achieve consistent effects especially on circulating inflammatory markers. Overall, this field of investigation is still young, hence the current body of evidence is small and for most immune parameters, more research is required to draw distinct conclusions.
 * Falkenberg RI, Eising C, & Peters ML; “Yoga and immune system functioning: a systematic review of randomized controlled trials”, J Behav Med. 2018 Feb 10.


 * There has been a growing interest over the past decade into the health benefits of music, in particular examining its psychological and neurological effects. Yet this is the first attempt to systematically review publications on the psychoneuroimmunology of music. Of the selected sixty three studies published over the past twenty-two years, a range of effects of music on neurotransmitters, hormones, cytokines, lymphocytes, vital signs and immunoglobulins as well as psychological assessments are cataloged. Research so far points to the pivotal role of stress pathways in linking music to an immune response. However, several challenges to this research are noted: 1) there is very little discussion on the possible mechanisms by which music is achieving its neurological and immunological impact; 2) the studies tend to examine biomarkers in isolation, without taking into consideration the interaction of the biomarkers in question with other physiological or metabolic activities of the body, leading to an unclear understanding of the impact that music may be having; 3) terms are not being defined clearly enough, such as distinctions not being made between different kinds of stress and 'music' being used to encompass a broad spectrum of activities without determining which aspects of musical engagement are responsible for alterations in biomarkers, In light of this, a new model is presented which provides a framework for developing a taxonomy of musical and stress-related variables in research design, and tracing the broad pathways that are involved in its influence on the body.
 * Daisy Fancourt, Adam Ockelford, Abi Abebech Belai; “The Psychoneuroimmunological Effects of Music: A Systematic Review and A New Model”, Brain Behavior and Immunity, 36, (October 2013), p.15


 * Research into the health beneﬁts of music has rapidly expanded over the last decade, driven both by a desire to understand more about the inner workings of music on the brain and body and in order to see how music can be better applied in community, educational and, in particular, healthcare settings (MacDonald et al., 2012). The scientiﬁc study of music has gradually probed deeper into the mechanisms underlying the perception and processing of music, exploring the psychology of music (Hallam et al., 2008) and the cognitive neuroscience of music, sometimes referred to as ‘neuromusicology’ (Peretz and Zatorre, 2003). This depth of enquiry has included the neurological basis for music-induced emotions (e.g. Trainor and Schmidt, 2003; Juslin, 2009), the neurobiology of certain aspects of music such as harmony (e.g. Tramo et al., 2003) and the neuroanatomy of music performance (Parsons, 2003). And breadth of study has ranged from the perception of folk songs inside the womb (Lemos et al., 2011), to the performance of opera on concert platforms (Kenny et al., 2004), and the use of pop music in operating theatres (Pluyter et al., 2010). Recently, there has been interest in the chemical and biological effects music, summarized in two reviews. Chanda and Levitin (2013) presented an overview of the neurochemical effects of music, in which they made reference to immunological changes. Their research has gained attention in the popular press as apparent evidence that music can boost the immune system and hold the key to wellbeing. However, their overview was not systematic and due to the focus speciﬁcally on neurochemical responses, it only reviewed half the studies pertaining to the psychoneuroimmunology of music and referred to a third of the immune biomarkers that have been tested with respect to music. A second recent article, (Kreutz et al., 2012), overviewed the psychoneuroendocrinological effects of music in order to test the assumption ‘that psychological processes associated with musical experiences lead to changes in the hormonal systems of brain and body’ (Kreutz et al., 2012, p. 457); something they label as ‘perhaps one of the most fascinating areas of future research’ (Kreutz et al., 2012, p. 471). But as with the study by Chanda and Levitin (2013), their overview was not systematic and examines the impact of music on just ﬁve biomarkers (cortisol, oxytocin, testosterone, beta-endorphin and immunoglobulin A). And neither study discussed parallel physiological or psychological ﬁndings. This led Kreutz et al. (2012, p. 471) to conclude that ‘much more research efforts should be undertaken to ascertain the emerging patterns of changes that were reported in the available literature’. Consequently, a comprehensive systematic review into music and psychoneuroimmunology is timely. This would aim to consolidate key ﬁndings to date, compare theories concerning the mechanisms behind music’s effect, and highlight gaps in current knowledge, helping to guide the focus of future studies. In particular, a systematic review could identify any challenges currently hindering the progress of research and, by presenting a new model, help overcome these obstacles.
 * Daisy Fancourt, Adam Ockelford, Abi Abebech Belai; “The Psychoneuroimmunological Effects of Music: A Systematic Review and A New Model”, Brain Behavior and Immunity, 36, (October 2013), pp.15-16


 * Six studies examined the effect of music on leukocytes [see Table 3a]. Bittman et al. (2001) found that natural killer cells increased, which was accompanied by an endocrine response (see Section 3.4) when participants took part in stimulating group drumming sessions. In contrast, Leardi et al. (2007) found that for relaxing recorded music, natural killer cell levels decreased, with the most marked results noted when patients selected their own music. Cai et al. (2001) found that participatory music therapy sessions prevented levels of natural killer cells along with CD4+ T cells, CD3, and the ratio of CD4 to CD8 cells from dropping.
 * Daisy Fancourt, Adam Ockelford, Abi Abebech Belai; “The Psychoneuroimmunological Effects of Music: A Systematic Review and A New Model”, Brain Behavior and Immunity, 36, (October 2013), p.19


 * If PTSD is causally associated with disruption of the immune system, interventions that directly target inflammatory markers might result in improved psychological and biomedical outcomes. Many people with PTSD are treated with psychotropic medications, but to date, there have been only a few attempts to develop novel pharmacotherapeutic agents for PTSD. FDA-approved SSRIs are associated with reduced inflammation and may have both direct and indirect benefits for patients with PTSD.
 * Janine D. Flory, Rachel Yehuda; “Is PTSD a Systemic Disorder?”, Psychiatric Times, Vol 35 No 4, Volume 35, Issue 4, (April 29, 2018)


 * The link between PTSD and chronic illness has been established but the potential role of immune system markers in mediating this association is only beginning to be examined. As new psychotherapeutic and pharmacological treatments are developed, there is an opportunity to examine the relationships between inflammatory markers and symptoms as they change over time. Future research should examine how and whether psychotherapy affects inflammatory markers, and also to determine the extent to which inflammation is reduced by medications that alleviate PTSD symptoms. It is possible that the growing interest in alternative therapies for PTSD such as meditation, yoga, acupuncture, and other interventions that increase physical activity or alter dietary intake may provide benefits through their anti-inflammatory effects. It is also important to examine whether the association between PTSD and immune markers is part of a broader association between mental illness and poor health or whether there is specificity between trauma exposure and particular markers and disease outcomes. Moreover, it is important to identify the contributions of trauma type, sex, race, and ethnicity to these associations.
 * Janine D. Flory, Rachel Yehuda; “Is PTSD a Systemic Disorder?”, Psychiatric Times, Vol 35 No 4, Volume 35, Issue 4, (April 29, 2018)


 * Intense exercise is frequently associated with postexercise alterations in percentage and number of blood lymphocyte phenotypes and suppression of natural killer cell activity and lymphocyte proliferative responses to mitogen. Because suppression is most often observed after intense or prolonged endurance exercise, we hypothesized that high-intensity resistance exercise might elicit similar responses in elderly exercisers. Postresistance exercise suppression of NCMC has been reported previously by two groups of investigators using young males as subjects. Because the elderly are reported to have impaired cellular immune function, we were concerned about the potential of an acute bout of resistance exercise to negatively impact the immune system. There have been few studies completed to date that have examined the immune responses to endurance training in elderly subjects, and these findings have been equivocal. Therefore, a second purpose of this investigation was to examine whether 10 wk of resistance training would elicit changes in resting immune function, as measured by phenotypic and functional tests. In summary, acute resistance exercise did not negatively affect immune function either before or after a 10-wk period of resistance training. Additionally, 10 wk of resistance training, while eliciting substantial increases in muscular strength, did not positively influence the immune system in these elderly women compared with inactive controls.
 * M. G. Flynn, M. Fahlman, W. A. Braun, C. P. Lambert, L. E. Bouillon, P. G. Brolinson, and C. W. Armstrong; ”Effects of resistance training on selected indexes of immune function in elderly women”, Journal of Applied Physiology, (01 Jun 1999)


 * In conclusion, immune function in 67- to 84-yr-old women was not suppressed during the recovery period from a single bout of resistance exercise. In addition, a 10-wk resistance training program did not significantly alter resting indexes of immune function in these women, and the exercise-induced immune responses were similar before and after resistance training. The present data lead us to suggest that women aged 69–84 yr can substantially improve strength with chronic resistance training without either detrimental or positive effects on selected indexes of immune system function.
 * M. G. Flynn, M. Fahlman, W. A. Braun, C. P. Lambert, L. E. Bouillon, P. G. Brolinson, and C. W. Armstrong; ”Effects of resistance training on selected indexes of immune function in elderly women”, Medicine & Science in Sports & Exercise, (01 Jun 1999)


 * A new University of Illinois study touts the benefits of soluble fiber -- found in oats, apples, and nuts, for starters -- saying that it reduces the inflammation associated with obesity-related diseases and strengthens the immune system. "Soluble fiber changes the personality of immune cells -- they go from being pro-inflammatory, angry cells to anti-inflammatory, healing cells that help us recover faster from infection," said Gregory Freund, a professor in the U of I's College of Medicine and a faculty member in the College of Agriculture, Consumer and Environmental Sciences' Division of Nutritional Sciences.
 * Gregory Freund as quoted in “An apple a day? Study shows soluble fiber boosts immune system”, Science Daily, (March 17, 2010)


 * Humans evolved on a planet with a 24-hour cycle of light and dark, and our bodies are set up to work in partnership with sunlight. One of the most obvious examples of this is the production of vitamin D in the skin in response to UVB exposure. This daily dose of vitamin D can help to strengthen our bones and teeth, but it also has an effect on our immune cells.  Vitamin D enables the macrophages in our lungs – a first line of defence against respiratory infections – to spew out an antimicrobial peptide called cathelicidin, killing bacteria and viruses directly. It also tweaks the activity of other immune cells, such as B and T cells, which orchestrate longer-term responses. People with low levels of vitamin D are at greater risk of viral respiratory tract infections such as influenza.
 * Linda Geddes, "How staying indoors affects your immune system", by BBC, (21 May 2020)


 * Some of the main things are over-sterilizing their environment, keeping their children from ever getting dirty. So going out into the backyard and playing in the mud, and then as soon as they're filthy, bringing them in and sterilizing their hands with antiseptic wipes, and then making sure that none of the dirt gets near their faces. Also, keeping them away from animals. The dogs and cats, sure, but also, other animals. It's fine to wash their hands if there's a cold or a flu virus around, but if they're interacting with a dog, and the dog licks their face, that's not a bad thing. In fact that could be extremely beneficial for the child's health.
 * Jack Gilbert as quoted by Lulu Garcia-Navarro in “'Dirt Is Good': Why Kids Need Exposure To Germs”, NPR, (July 16, 2017)


 * In the past, we would have eaten a lot more fermented foods, which contain bacteria. We would have allowed our children to be exposed to animals and plants and soil on a much more regular basis. Now we live indoors. We sterilize our surfaces. Their immune systems then become hyper-sensitized. You have these little soldier cells in your body called neutrophils, and when they spend too long going around looking for something to do, they become grumpy and pro-inflammatory. And so when they finally see something that's foreign, like a piece of pollen, they become explosively inflammatory. They go crazy. That's what triggers asthma and eczema and often times, food allergies.
 * Jack Gilbert as quoted by Lulu Garcia-Navarro in “'Dirt Is Good': Why Kids Need Exposure To Germs”, NPR, (July 16, 2017)


 * We experience stress when the brain senses danger and triggers the “fight or flight” mode, preparing the muscles, heart and lungs to get you out of harm’s way. “Stress works to increase certain hormones, particularly cortisol, which ask the immune system to stand down so they can do the temporary job of addressing the existential threat,” explains Dr. Rachel Franklin... But when stress is chronic, it hurts immunity. “If allowed to circulate, stress hormones make the immune system sluggish when faced with a challenge,” Franklin says.
 * Heidi Godman, "7 Best Immunity Boosters "Focus on a healthy lifestyle to optimize your immunity", US News and World Report] (7 July 2020)


 * Obesity increases inflammation. Chronic inflammation and chronic disease make the immune response less effective,” says Dr. Heidi Zapata... Smoking and heavy drinking are very harmful to immunity. “Excessive alcohol consumption that leads to liver issues will affect the immune system. In people with cirrhosis and liver disease, I’d in many ways consider them immunocompromised,” “There’s nothing worse you could do for your immune system than smoke... While your immune system should be on patrol looking for something it needs to fight, you’ve instead sent it to your lungs, sinus passages, mouth and throat to fight the poison you just ingested. Your immune system can’t fight battles on multiple fronts and do it effectively,” Franklin says.  Changing these habits are among the best immune boosters.
 * Heidi Godman, "7 Best Immunity Boosters "Focus on a healthy lifestyle to optimize your immunity", US News and World Report] (7 July 2020)


 * CORVALLIS, Ore. - In an analysis of 446 compounds for their the ability to boost the innate immune system in humans, researchers in the Linus Pauling Institute at Oregon State University discovered just two that stood out from the crowd - the resveratrol found in red grapes and a compound called pterostilbene from blueberries.
 * Adrian Gombart, “Red grapes, blueberries may enhance immune function”, Oregon State University, (September 13, 2013)


 * "Out of a study of hundreds of compounds, just these two popped right out," said Adrian Gombart, an LPI principal investigator and associate professor in the OSU College of Science. "Their synergy with vitamin D to increase CAMP gene expression was significant and intriguing. It's a pretty interesting interaction."
 * Adrian Gombart, “Red grapes, blueberries may enhance immune function”, Oregon State University, (September 13, 2013)


 * Berries are generally considered beneficial to health. This health-promoting potential has mainly been ascribed to berries' phytochemical and vitamin content, and little attention has been paid to the potential benefits of berries for the digestive tract, despite this being the first point of contact. In vivo studies that described the health effects of berries on individual parts of the digestive tract (ie, the mouth, esophagus, stomach, small and large intestine, microbiome, and immune system) were reviewed. Immune effects were included because a large part of the immune system is located in the intestine. Beneficial health effects were mainly observed for whole berry extracts, not individual berry components. These effects ranged from support of the immune system and beneficial microbiota to reduction in the number and size of premalignant and malignant lesions. These results demonstrate the potency of berries and suggest berries can serve as a strong adjuvant to established treatments or therapies for a variety of gastrointestinal and immune-related illnesses.
 * Coen Govers, Muzeyyen Berkel Kasikci, Addie A van der Sluis, Jurriaan J Mes “Review of the health effects of berries and their phytochemicals on the digestive and immune systems”, Nutr Rev. 2018 Jan 1;76(1):29-46.


 * Medicinal mushrooms have been proposed as a novel therapy that may improve cancer treatment and patients’ survival. They have been used medicinally since at least 3000 bce. Mushrooms are reported to have antimicrobial, anti-inflammatory, cardiovascular-protective, antidiabetic, hepatoprotective, and anticancer properties. It is well-established that mushrooms are adept at immune modulation and affect hematopoietic stem cells, lymphocytes, macrophages, T cells, dendritic cells (DCs), and natural killer (NK) cells.1 Extensive research over the last 40 years has demonstrated that mushrooms have potent antineoplastic properties that slow growth of tumors, regulate tumor genes, decrease tumoral angioneogenesis, and increase malignant-cell phagocytosis. Additionally, evidence suggests that medicinal mushrooms may safely boost chemotherapeutic efficacy and simultaneously protect against bone marrow suppression.
 * Alena G. Guggenheim, Kirsten M. Wright, and Heather L. Zwickey, “Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology”, Integr Med (Encinitas). 2014 Feb; 13(1): 32–44.


 * The mushrooms discussed in this review elicit effects on cytokine production. The authors know that immune stimulation during cancer can be beneficial in terms of tumor regression and patients’ survival. Upon diagnosis, most patients are treated with antineoplastic therapy and are immunosuppressed. Emerging evidence suggests that mushrooms may reverse myelosuppression, which makes them a promising adjunct therapy to optimize overall treatment outcomes. Anytime an adjunct therapy is added to a conventional therapy, drug-botanical interaction must be addressed. Interestingly, mushrooms appear to increase the effects of chemotherapy. This important finding must be considered when patients are using mushrooms for myelosuppression or other symptoms. While the immunological findings are promising, ultimately this information must be applied to patients and clinical outcomes, as the goal when working with any patient with cancer is to improve quality of life and ultimately improve survival. To that end, the meta-analysis of turkey tail by Eliza et al demonstrated an increased rate of survival for cancer patients who took this mushroom, especially participants with breast, gastric, and colorectal cancers. The articles examined in this meta-analysis did not obtain immunologic outcomes and were thus not included in the current article. Similarly, a retrospective case series of patients who were treated for hepatocellular carcinoma with a combination of 11 different integrative therapies, which included Cordyceps and β-glucan from Agaricus, showed a significant correlation between the number of treatments used and survival. Patients given ≥4 agents had a survival of 40.2 vs 6.4 months for those given ≤3 agents (P < .001). Of these individuals, participants whose combination therapy included Cordyceps had the longest survival.
 * Alena G. Guggenheim, Kirsten M. Wright, and Heather L. Zwickey, “Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology”, Integr Med (Encinitas). 2014 Feb; 13(1): 32–44.


 * Sixty years after the pioneering tolerance studies of Medawar and his colleagues (Billingham et al. 1953), immune rejection continues to be a dreaded complication. The emergence of novel agents with efficacy not only against the cellular, but also the humoral arms of the immune response may improve the management of transplant recipients. A one-size-fits-all approach remains the clinical norm despite serious toxicities. A personalized immunosuppressive drug therapy based on mechanistic biomarkers remains an unmet objective and worthy of pursuit.
 * Choli Hartono, Thangamani Muthukumar, and Manikkam Suthanthiran, “Immunosuppressive Drug Therapy”, Cold Spring Harb Perspect Med. 2013 Sep; 3(9): a015487.


 * The idea of boosting your immunity is enticing, but the ability to do so has proved elusive for several reasons. The immune system is precisely that — a system, not a single entity. To function well, it requires balance and harmony. There is still much that researchers don't know about the intricacies and interconnectedness of the immune response. For now, there are no scientifically proven direct links between lifestyle and enhanced immune function. But that doesn't mean the effects of lifestyle on the immune system aren't intriguing and shouldn't be studied. Researchers are exploring the effects of diet, exercise, age, psychological stress, and other factors on the immune response, both in animals and in humans. In the meantime, general healthy-living strategies are a good way to start giving your immune system the upper hand.
 * “How to boost your immune system“, Harvard Health Publishing, (Updated: April 6, 2020; Published: September, 2014)


 * Many products on store shelves claim to boost or support immunity. But the concept of boosting immunity actually makes little sense scientifically. In fact, boosting the number of cells in your body — immune cells or others — is not necessarily a good thing. For example, athletes who engage in "blood doping" — pumping blood into their systems to boost their number of blood cells and enhance their performance — run the risk of strokes. Attempting to boost the cells of your immune system is especially complicated because there are so many different kinds of cells in the immune system that respond to so many different microbes in so many ways. Which cells should you boost, and to what number? So far, scientists do not know the answer. What is known is that the body is continually generating immune cells. Certainly, it produces many more lymphocytes than it can possibly use. The extra cells remove themselves through a natural process of cell death called apoptosis — some before they see any action, some after the battle is won. No one knows how many cells or what the best mix of cells the immune system needs to function at its optimum level.
 * “How to boost your immune system“, Harvard Health Publishing, (Updated: April 6, 2020; Published: September, 2014)


 * Like any fighting force, the immune system army marches on its stomach. Healthy immune system warriors need good, regular nourishment. Scientists have long recognized that people who live in poverty and are malnourished are more vulnerable to infectious diseases. Whether the increased rate of disease is caused by malnutrition's effect on the immune system, however, is not certain. There are still relatively few studies of the effects of nutrition on the immune system of humans.
 * “How to boost your immune system“, Harvard Health Publishing, (Updated: April 6, 2020; Published: September, 2014)


 * Move Your Body. Movement is a key component of your overall health, including your immune system. When you get your heart pumping, even briefly, your circulatory system brings more blood to your muscles, of course, but it can also help in delivering more white cells throughout the body, which detect pathogens and fight infection.... Get Enough Sleep... Getting enough of it is vital for a well-functioning immune system. Sleep seems to enhance a specific white blood cell response in the body, mainly the T cells, and this helps fight off infection in the body... Practice Mindfulness... stress suppresses your immune system... it’s been shown that meditation and mindfulness can improve one’s response to stress, and, in turn, promote immune function... Spend Time in Nature.  We all know that going out in the sun and getting some of that Vitamin D is good for us. Being outside and in nature is also helpful for a variety of reasons beyond that... Vote I really believe voting is crucial to our health... failures of political leadership helped accelerate the early spread of coronavirus. Doing your civic duty and electing competent, thoughtful leaders is one of the best ways to protect yourself and others from preventable illness
 * Joe Holder, "Boost Your Immune System With These Five Practices", Gentlemen's Quarterly,, (19 June 2020)

“Breast cancer patients have improved immune and neuroendocrine functions following massage therapy”, Journal of Psychosomatic Research, Volume 57, Issue 1, July 2004, Pages 45-52
 * Women with breast cancer are at risk for elevated depression, anxiety, and decreased natural killer (NK) cell number. Stress has been linked to increased tumor development by decreasing NK cell activity. The objectives of this study included examining massage therapy for women with breast cancer for (1) improving mood and biological measures associated with mood enhancement (serotonin, dopamine), (2) reducing stress and stress hormone levels, and (3) boosting immune measures. Methods: Thirty-four women (M age=53) diagnosed with Stage 1 or 2 breast cancer were randomly assigned postsurgery to a massage therapy group (to receive 30-min massages three times per week for 5 weeks) or a control group. The massage consisted of stroking, squeezing, and stretching techniques to the head, arms, legs/feet, and back. On the first and last day of the study, the women were assessed on (1) immediate effects measures of anxiety, depressed mood, and vigor and (2) longer term effects on depression, anxiety and hostility, functioning, body image, and avoidant versus intrusive coping style, in addition to urinary catecholamines (norepinephrine, epinephrine, and dopamine) and serotonin levels. A subset of 27 women (n=15 massage) had blood drawn to assay immune measures. Results: The immediate massage therapy effects included reduced anxiety, depressed mood, and anger. The longer term massage effects included reduced depression and hostility and increased urinary dopamine, serotonin values, NK cell number, and lymphocytes. Conclusions: Women with Stage 1 and 2 breast cancer may benefit from thrice-weekly massage therapy for reducing depressed mood, anxiety, and anger and for enhancing dopamine, serotonin, and NK cell number and lymphocytes.
 * Gail Ironson, TiffanyField, JudithHurley, GaliaKatz, MiguelDiego, SharleneWeiss, Mary AnnFletcher,SaulSchanberg, CynthiaKuhn, IrisBurman;


 * Could early consumption of human breast milk also provide long-term benefits by protecting individuals from chronic diseases later in life? We examined the literature for evidence of long-term benefits of breastfeeding that may influence autoimmunity. While the evidence is not conclusive, there is enough evidence to suggest that breastfeeding may significantly alter the immune system of the suckling infant. Clues to this early influence are seen in the effects of breastfeeding on thymic size, the antibody response to vaccination, and increased tolerance to breast milk leukocyte antigens. Fundamental changes in the infant's immune system as a result of premature cessation of breastfeeding could lay the groundwork for later dysfunction in the immunologic controls necessary to prevent autoimmune disease or hypersensitivity reactions.
 * Kelly M. Jackson, PhD; Andrea M. Nazar, DO; “Breastfeeding, the Immune Response, and Long-term Health”, The Journal of the American Osteopathic Association, April 2006, Vol. 106, 203-207.


 * Massage is a common conservative intervention used to treat myalgia. Although subjective reports have supported the premise that massage decreases pain, few studies have systematically investigated the dose response characteristics of massage relative to a control group. The purpose of this study was to perform a double-blinded, randomized controlled trial of the effects of massage on mechanical hyperalgesia (pressure pain thresholds, PPT) and perceived pain using delayed onset muscle soreness (DOMS) as an endogenous model of myalgia. Participants were randomly assigned to a no-treatment control, superficial touch, or deep-tissue massage group. Eccentric wrist extension exercises were performed at visit 1 to induce DOMS 48 hours later at visit 2. Pain, assessed using visual analog scales (VAS), and PPTs were measured at baseline, after exercise, before treatment, and after treatment. Deep massage decreased pain (48.4% DOMS reversal) during muscle stretch. Mechanical hyperalgesia was reduced (27.5% reversal) after both the deep massage and superficial touch groups relative to control (increased hyperalgesia by 38.4%). Resting pain did not vary between treatment groups. Perspective: This randomized, controlled trial suggests that massage is capable of reducing myalgia symptoms by approximately 25% to 50%, varying with assessment technique. Thus, potential analgesia may depend on the pain assessment used. This information may assist clinicians in determining conservative treatment options for patients with myalgia.
 * Laura A Frey Law 1, Stephanie Evans, Jill Knudtson, Steven Nus, Kerri Scholl, Kathleen A Sluka; “Massage reduces pain perception and hyperalgesia in experimental muscle pain: a randomized, controlled trial”, J Pain. 2008 Aug;9(8):714-21.


 * We should have known better. One of the most fundamental aspects of immune defense, fever, is well known to affect both our mood and behavior, things that are seated squarely in the brain. When you are running a fever, you just feel different. You lose appetite, energy, and even enthusiasm for things that you normally enjoy. You feel terrible. This is no accident and it is not due to the elevated body temperature itself. Strenuous exercise on a hot day can raise body temperature even more than fever usually does, yet it does not cause lethargy. We don't often think of it this way, but the feelings associated with fever are psychological symptoms. It changes our mood and our subjective inner feelings, but it also alters our behavior. We are less likely to leave the house, do any work, or even socialize. We just want to lay in bed and rest. The evolutionary value of this is obvious. By nudging us toward rest, we conserve valuable energy for the immune fight. The psychological symptoms of fever have probably saved many human and animal lives. There may also be a social aspect to fever. By knocking us off our feet, fever may act to reduce our interactions with others. This would be clever indeed because, if the infection is contagious, this could help reduce its spread to other members of our group. In most cases, among the people we interact most with are our close biological relatives.
 * Nathan H. Lents, “New Study Reveals How Immune System Affects Social Behavior”, Psychology Today, (Aug 08, 2016)


 * A deficiency of dietary protein or amino acids has long been known to impair immune function and increase the susceptibility of animals and humans to infectious disease. However, only in the past 15 years have the underlying cellular and molecular mechanisms begun to unfold. Protein malnutrition reduces concentrations of most amino acids in plasma. Findings from recent studies indicate an important role for amino acids in immune responses by regulating: (1) the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; (2) cellular redox state, gene expression and lymphocyte proliferation; and (3) the production of antibodies, cytokines and other cytotoxic substances. Increasing evidence shows that dietary supplementation of specific amino acids to animals and humans with malnutrition and infectious disease enhances the immune status, thereby reducing morbidity and mortality. Arginine, glutamine and cysteine precursors are the best prototypes. Because of a negative impact of imbalance and antagonism among amino acids on nutrient intake and utilisation, care should be exercised in developing effective strategies of enteral or parenteral provision for maximum health benefits. Such measures should be based on knowledge about the biochemistry and physiology of amino acids, their roles in immune responses, nutritional and pathological states of individuals and expected treatment outcomes. New knowledge about the metabolism of amino acids in leucocytes is critical for the development of effective means to prevent and treat immunodeficient diseases. These nutrients hold great promise in improving health and preventing infectious diseases in animals and humans.
 * Peng Li, Yu-Long Yin, Defa Li, Sung Woo Kim, Guoyao Wu; “Amino acids and immune function”, Br J Nutr. 2007 Aug;98(2):237-52.


 * In the adaptive system, B cells are involved in humoral immune response, whereas T cells contribute to cellular immune response. Immunopotentiating drugs are used to restore the immune system to normal and to reduce reoccurring and life-threatening infections. Immunosuppressive drugs are applied to control autoimmune disorders and inflammation when excessive tissue damage occurs, as well as to prevent transplant rejection after an organ transplant (Taylor, Watson, and Bradley 2005). Increasing evidence shows that cordyceps is a bidirectional modulator with both potentiating and suppressive effects on the immune system through regulating innate and adaptive immunity (Li and Tsim 2004; Ng and Wang 2005; Feng, Yang, and Li 2008; (Zhou et al. 2009a).
 * Bao-qin Lin and Shao-ping Li, “Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition”, “Cordyceps as an Herbal Drug”, (2011)


 * Doing everything you can to keep your immune system strong can feel like a lot of work. Committing to an exercise routine, good sleep habits, taking supplements, stress management and good nutrition is no small feat, but well worth your time and effort when it comes to staying well. But what if all your valiant efforts could be undone... just by eating one certain food? ...According to nutrition studies and health experts, you might want to rethink your sugar habit.
 * Doctors warn that sugar can temporarily weaken your immune system, Mercey Livingston, CNET, (9 June 2020)


 * Clifford Lowell, an immunologist at the University of California at San Francisco, thinks the high levels of IgA in volunteers who had moderately frequent sex are easy to understand. “Sexually active people may be exposed to many more infectious agents than sexually non-active people,” Lowell says. “The immune system would respond to these foreign antigens by producing and releasing more IgA.” This could give them better protection against colds and flu. Why there was no IgA rise in the most sexually active group is less clear. “My feeling is that the people in the very-frequent-sex group may be in obsessive or poor relationships that are causing them a lot of anxiety,” speculates Charnetski. “We know that stress and anxiety make IgA go down.”
 * Clifford Lowell as quoted in “Can regular sex ward off colds and flu?”, Diane Urbani, New Scientist, issue 2182, (17 April 1999)


 * Karate is a Japanese martial arts system with potential physical and psychological benefits. However, karate has been scarcely investigated from a psychobiological perspective, and its effects on the immune system remain virtually unknown. We designed the present study with the aim of analyzing the effects of karate practice on immunological parameters. 27 healthy male volunteer subjects participated in the study, 15 in the experimental group and 12 in the control. Experimental subjects were all karate players who had practiced this martial art for a minimum of three years attending regular lessons at a karate training center, in the evening, two to three days per week. Blood samples for the quantification of immunological parameters (total leukocytes, neutrophils, monocytes, eosinophils, basophils, lymphocytes, IgG, IgA, and IgM) were taken in both groups. A t-test for independent groups was performed in each dependent variable; a value of p<0.05 was considered to be significant. Karate practitioners exhibited a significantly higher number of total leukocytes (p<0.02), monocytes (p<0.01), and lymphocytes (p<0.01), a higher percentage of monocytes (p<0.01), and greater serum concentrations of IgG (p<0.02) and IgM (p<0.01). Our findings show that long-term karate practice is related to a broad modulation of immune parameters, including total and specific leukocyte counts, as well as immunoglobulin concentrations. This peculiar immunomodulatory profile, apart from its psychobiological relevance, may have noteworthy clinical implications.
 * Juan M. Manzaneque, Francisca M. Vera,  Gabriel A. Carranque,  Francisco M. Rodríguez-Peña,  Federico Navajas,  and María J. Blanca; “Immunological Modulation in Long-Term Karate Practitioners”, Evid Based Complement Alternat Med. 2018; 2018: 1654148.


 * The larger number of lymphocytes associated with the karate group is also an interesting result from our research. While karate has never been reported to be associated with changes of lymphocyte counts, training in Taekwondo, a Korean martial art similar to karate, has been said to be related to elevations of specific lymphocyte subpopulations. Likewise, a recent investigation of immunoendocrine changes following Marine Corps martial arts training revealed that this program also induced an elevation of lymphocytes. The changes of lymphocyte count induced by martial arts training are a remarkable effect that confirms martial arts can exert a noteworthy action on the immune system reaching even cell components of the adaptive immune response.
 * Juan M. Manzaneque, Francisca M. Vera,  Gabriel A. Carranque,  Francisco M. Rodríguez-Peña,  Federico Navajas,  and María J. Blanca; “Immunological Modulation in Long-Term Karate Practitioners”, Evid Based Complement Alternat Med. 2018; 2018: 1654148.


 * A possible way of immunomodulation of the maternal immune system before pregnancy would be exposure to paternal antigens via seminal fluid to oral mucosa. We hypothesized that women with recurrent miscarriage have had less oral sex compared to women with uneventful pregnancy. In a matched case control study, 97 women with at least three unexplained consecutive miscarriages prior to the 20th week of gestation with the same partner were included. Cases were younger than 36 years at time of the third miscarriage. The control group included 137 matched women with an uneventful pregnancy. The association between oral sex and recurrent miscarriage was assessed with conditional logistic regression, odds ratios (ORs) were estimated. Missing data were imputed using Imputation by Chained Equations. In the matched analysis, 41 out of 72 women with recurrent miscarriage had have oral sex, whereas 70 out of 96 matched controls answered positive to this question (56.9% vs. 72.9%, OR 0.50 95%CI 0.25−0.97, p = 0.04). After imputation of missing exposure data (51.7%), the association became weaker (OR 0.67, 95%CI 0.36–1.24, p = 0.21). In conclusion, this study suggests a possible protective role of oral sex in the occurrence of recurrent miscarriage in a proportion of the cases. Future studies in women with recurrent miscarriage explained by immune abnormalities should reveal whether oral exposure to seminal plasma indeed modifies the maternal immune system, resulting in more live births.
 * T.Meuleman, N.BadenaG.W.HaasnootbM.M.WagneraO.M.DekkerscS.le CessiecdC.PicaveteJ.M.M.van LithaF.H.J.ClaasbK.W.M.Bloemenkampaf; “Oral sex is associated with reduced incidence of recurrent miscarriage”; Journal of Reproductive Immunology, Volume 133, June 2019, Pages 1-6


 * Psychological stress has been linked empirically with dysregulation of facets of the human immune system, yet these effects are not the same in every situation or population. Recent research has made strides towards understanding risk factors for immune dysregulation as well as why these risks occur. This review discusses mechanisms and mediators underlying the stress-immune relation, the role of context in determining whether an immunologic responses to stress is adaptive versus maladaptive, and the stress-immune relation in populations including children exposed to early adversity, older adults, and individuals with clinical diagnoses. The reviewed work holds great promise for further elucidating the circumstances under which psychological stress has immunological consequences, and provides new directions for work in this field.
 * Jennifer N. Morey, Ian A. Boggero, April B. Scott, and Suzanne C. Segerstrom, “Current Directions in Stress and Human Immune Function”, Curr Opin Psychol. 2015 October 1; 5: p.13


 * In the last two decades, numerous scientists have highlighted the interactions between bone and immune cells as well as their overlapping regulatory mechanisms. For example, osteoclasts, the bone-resorbing cells, are derived from the same myeloid precursor cells that give rise to macrophages and myeloid dendritic cells. On the other hand, osteoblasts, the bone-forming cells, regulate hematopoietic stem cell niches from which all blood and immune cells are derived. Furthermore, many of the soluble mediators of immune cells, including cytokines and growth factors, regulate the activities of osteoblasts and osteoclasts. This increased recognition of the complex interactions between the immune system and bone led to the development of the interdisciplinary osteoimmunology field. Research in this field has great potential to provide a better understanding of the pathogenesis of several diseases affecting both the bone and immune systems, thus providing the molecular basis for novel therapeutic strategies. In these review, we reported the latest findings about the reciprocal regulation of bone and immune cells.
 * Giorgio Mori, Patrizia D'Amelio, Roberta Faccio, and Giacomina Brunetti; “The Interplay between the Bone and the Immune System”, (14 July 2013)


 * Over the past two decades extraordinary advancement has been done in understanding the crosstalk between the bone and immune system in physiological and pathological conditions. Although numerous data arise from animal models, exciting data from human studies are emerging and as a consequence the first biological drugs targeting cytokines released from immune cells are emerging as alternative therapeutic management for inflammatory bone disease, such as arthritis and osteoporosis. However, despite the advancement made, further studies needed to elucidate the cross-talk between the bone and immune system.
 * Giorgio Mori, Patrizia D'Amelio, Roberta Faccio, and Giacomina Brunetti; “The Interplay between the Bone and the Immune System”, (14 July 2013)


 * Based on available literature, this review suggests that hydrotherapy was widely used to improve immunity and for the management of pain, CHF, MI, chronic obstructive pulmonary diseases, asthma, PD, AS, RA, OAK, FMS, anorectal disorders, fatigue, anxiety, obesity, hypercholesterolemia, hyperthermia, labor, etc. It produces different effects on various systems of the body depending on the temperature of water and though these effects are scientifically evidence based, there is lack of evidences for the mechanism on how hydrotherapy improves these diseases, which is one of the limitations of hydrotherapy, and further studies are required to find the mechanism of hydrotherapy on various diseases.
 * A Mooventhan and L Nivethitha; “Scientific Evidence-Based Effects of Hydrotherapy on Various Systems of the Body”, N Am J Med Sci. 2014 May; 6(5): 199–209.


 * “The link between diesel exhaust and asthma could simply have been that the particulates were irritating the lungs,” said Nadeau. “What we found is that the problems are more systemic. This is one of the few papers to have linked from A to Z the increased exposure to ambient air pollution with suppressed Treg cell levels, changes in a key gene and increased severity of asthma symptoms.” The researchers noted that Treg cells are important for other autoimmune disorders, so the implications of this study could go beyond asthma.
 * Kari Nadeau as quoted by Sarah Yang, ”Air pollution alters immune function, worsens asthma symptoms”, Berkeley News, UC Berkeley, (October 5, 2010)


 * The immune system can distinguish between normal, healthy cells and unhealthy cells by recognizing a variety of "danger" cues called danger-associated molecular patterns (DAMPs). Cells may be unhealthy because of infection or because of cellular damage caused by non-infectious agents like sunburn or cancer. Infectious microbes such as viruses and bacteria release another set of signals recognized by the immune system called pathogen-associated molecular patterns (PAMPs). When the immune system first recognizes these signals, it responds to address the problem. If an immune response cannot be activated when there is sufficient need, problems arise, like infection. On the other hand, when an immune response is activated without a real threat or is not turned off once the danger passes, different problems arise, such as allergic reactions and autoimmune disease.
 * National Institute of Allergy and Infectious Diseases, “Overview of the Immune System “, (December 30, 2013)


 * Immunity in newborn babies is only temporary and starts to decrease after the first few weeks or months. Breast milk also contains antibodies, which means that babies who are breastfed have passive immunity for longer.  The thick yellowish milk (colostrum) produced for the first few days following birth is particularly rich in antibodies. Premature babies are at higher risk of developing an illness because their immune systems aren't as strong and they haven't had as many antibodies passed to them. As newborn immunity is only temporary, it's important to begin childhood immunisations when your baby is 2 months old. This applies to babies who are either premature or full-term.
 * NHS, ”How long do babies carry their mother's immunity?”


 * As a new parent, Jack Gilbert got a lot of different advice on how to properly look after his child: when to give him antibiotics or how often he should sterilize his pacifier, for example. After the birth of his second child, Gilbert, a scientist who studies microbial ecosystems at the University of Chicago, decided to find out what's actually known about the risks involved when modern-day children come in contact with germs. "It turned out that most of the exposures were actually beneficial," Gilbert says. "So that dirty pacifier that fell on the floor — if you just stick it in your mouth and lick it, and then pop it back in little Tommy's mouth, it's actually going to stimulate their immune system. Their immune system's going to become stronger because of it."
 * Lulu Garcia-Navarro, “'Dirt Is Good': Why Kids Need Exposure To Germs”, NPR, (July 16, 2017)


 * The effects of music on the immune system and cancer development were evaluated in rodents subjected to sound stress. Animals were exposed daily to broad band noise around midnight and/or music for 5 hours on the following morning. Thymus and spleen cellularity, peripheral T lymphocyte population, the proliferative response of spleen cells to mitogen concanavalin A and natural killer cell activity were calculated in BALB/c mice. Sprague Dawley rats were injected i.v. with Walker 256 carcinosarcoma cells; 8 days later the rats were sacrificed and the number of metastatic nodules on the surface of the lungs was calculated macroscopically. Music reduced the suppressive effects of stress on immune parameters in mice and decreased the enhancing effects of stress on the development of lung metastases provoked by carcinosarcoma cells. Music enhanced the immune parameters and the anti-tumor response in unstressed rodents. Our data at present demonstrates that music can effectively reverse adverse effects of stress on the number and capacities of lymphocytes that are required for an optimal immunological response against cancer in rodents.
 * María J Núñez, Paula Mañá, David Liñares, María P Riveiro, José Balboa, Juan Suárez-Quintanilla, Mónica Maracchi, Manuel Rey Méndez, José M López, Manuel Freire-Garabal “Music, immunity and cancer”, Life Sci. 2002 Jul 19;71(9):1047-57.


 * Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal—but not adult—GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.
 * Torsten Olszak, Dingding An, Sebastian Zeissig, Miguel Pinilla Vera, Julia Richter, Andre Franke, Jonathan N. Glickman, Reiner Sieber, Rebecca M. Baron, Dennis L. Kasper, Richard S. Blumberg; “Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function”, Science, 27 Apr 2012: Vol. 336, Issue 6080, pp.489-493


 * Background. T cell-mediated immune responses contribute to the hepatocellular injury during autoimmune hepatitis, viral infection, and hepatotoxins. Pharmacological compounds regulating immune responses are suitable candidates for prevention/treatment of this pathology. Therefore, the main aim of this study was to define the effects of antioxidant, anti-inflammatory mixture of citrus peel extract (CPE) on the immune-mediated liver injury. Methods. The influence of CPE on liver injury was determined by the activity of transaminases in plasma and the histological changes. Anti-inflammatory and antioxidant effects were studied by measuring frequency of T regulatory cells (Tregs), cytokines (TNF-α, IL-10, and IFN-γ), and nitric oxide levels. Results. The CPE application notably prevents development of liver injury through decreasing levels of both cytokines (TNF-alpha, INF) and regulatory T cells and increasing levels of IL-10. CPE injection also diminished the serum NO, which in turn resulted in evident reduction of the liver damage. Conclusion. Our findings represent the primary preclinical data indicating that the CPE in vivo could ameliorate Con A induced hepatitis. The low dose of CPE most likely can be used for the treatment of the T cell-mediated liver injury as in autoimmune hepatitis, alcoholic hepatitis, and chronic viral hepatitis.
 * Ia Pantsulaia, Manana Iobadze, Nato Pantsulaia, and Tinatin Chikovani; “The Effect of Citrus Peel Extracts on Cytokines Levels and T Regulatory Cells in Acute Liver Injury”, Biomed Res Int. 2014; 2014: 127879.


 * The practice of physical exercise, both in its acute form and in its chronic form, significantly alters the immune system. Studies indicate that the modulation of the immune response related to exercise depends on factors such as regularity, intensity, duration and type of effort applied. Moderate-intensity physical exercises stimulate cellular immunity, while prolonged or high-intensity practices without appropriate rest can trigger decreased cellular immunity, increasing the propensity for infectious diseases. According to the International Society for Exercise and Immunology (ISEI), the immunological decrease occurs after the practice of prolonged physical exercise, that is, after 90 min of moderate- to high-intensity physical activity.
 * Matheus Pelinski da Silveira, Kimberly Kamila da Silva Fagundes, Matheus Ribeiro Bizuti, Édina Starck, Renata Calciolari Rossi, and Débora Tavares de Resende e Silva, “Physical exercise as a tool to help the immune system against COVID-19: an integrative review of the current literature”, Clin Exp Med. 2020 Jul 29 : 1–14.


 * Conclusion: The effects of dehydration/rehydration did not negatively influence simulated 2000-m rowing race performance in lightweight oarswomen but did produce a higher tympanic temperature and had a differential effect on blood leukocyte, neutrophil, and natural killer (CD3-/16+) cell concentrations after exercise compared with the euhydrated state.
 * Michael A Penkman, Catherine J Field, Christopher M Sellar, Vicki J Harber, Gordon J Bell; “Effect of hydration status on high-intensity rowing performance and immune function”, Int J Sports Physiol Perform. 2008 Dec;3(4):531-46.


 * The use of nanoparticles in vaccinology is inspired by the fact that most pathogens have a dimension within the nano-size range and therefore can be processed efficiently by the immune system, which leads to a potent immune response.
 * Ngoc Bich Pham, Thuong Thi Ho, Giang Thu Nguyen, Thuy Thi Le, Ngoc Thu Le, Huan-Cheng Chang, Minh Dinh Pham, Udo Conrad & Ha Hoang Chu; “Nanodiamond enhances immune responses in mice against recombinant HA/H7N9 protein”, Journal of Nanobiotechnology volume 15, Article number: 69 (2017)


 * When I attended medical school in the mid-1980s, no one imagined that the immune system had anything to do with the brain. When I became a researcher in 2000, we were convinced that inflammation would only be relevant to patients with medical illnesses that might account for their immune activation. Now, in 2018 I find myself amazed that inflammation is frequently named as the root cause of all psychiatric conditions- the sine qua non of all mental illness.
 * Charles Raison, “Introduction: The Inflammation Connection”, Psychiatric Times, (April 29, 2018)


 * The effects of 12 wk of progressive resistance strength training on in vivo and in vitro immune parameters were evaluated in a controlled study of eight subjects with rheumatoid arthritis (RA), eight healthy young (22-30 yr), and eight healthy elderly (65-80 yr) individuals. Six healthy elderly (65-80 yr) nontraining control subjects were also evaluated to account for seasonal and psychosocial effects. Training subjects exercised at 80% of their one-repetition maximum and performed eight repetitions per set, three sets per session on a twice weekly basis. Peripheral blood mononuclear cell (PBMC) subpopulations, cytokine and prostaglandin (PG) E2 production, proliferative response, and delayed type hypersensitivity (DTH) skin response were measured before and after 12 wk of training. Training did not induce changes in PBMC subsets, interleukin (IL)-1 beta, tumor necrosis factor-alpha (TNF), IL-6, IL-2, or PGE2 production, lymphocyte proliferation, or DTH response in any of the training groups, compared with control subjects. These data suggest that 12 wk of high-intensity progressive resistance strength training does not affect immune function in young or elderly healthy individuals or subjects with RA.
 * L C Rall, R Roubenoff, J G Cannon, L W Abad, C A Dinarello, S N Meydani; “Effects of progressive resistance training on immune response in aging and chronic inflammation”, Med Sci Sports Exerc. 1996 Nov;28(11):1356-65.


 * Few studies have included subjects of different age groups to examine the age-related differences in immune response after exercise training. Several of the same immune parameters that are transiently affected by acute exercise are also those that are altered during aging. An age-associated decline in T-cell mediated immune parameters is well recognized and is characterized by a reduced lymphocyte proliferative response, decreased frequency and size of delayed type hypersensitivity responses, decreased IL-2 production by T cells, and alterations in T-cell subsets. The effects of exercise training on these already diminished immune parameters is unknown. Recently, there has been increasing emphasis on the benefits of strength-training exercises among elderly individuals in terms of improved muscle strength and function, increased muscle mass, and weight control. Undoubtedly, there are many positive effects of strength training for the elderly. However, given the complex series of changes in many physiological systems that occur as a result of exercise training, the ultimate impact on the immune system is difficult to predict. Therefore, given the age-related declines in immunity, understanding the impact of strength training (which is being increasingly recommended to these individuals) in terms of the immune response is critically important. Even less is known about the effect of exercise in patients with autoimmune disorders in whom the immune system is inappropriately activated. Like the elderly, individuals with the chronic inflammatory condition rheumatoid arthritis (RA) demonstrate reduced physical performance capacity, and it has been increasingly recognized that exercise of varying types leads to improvements in physical performance capacity, cardiorespiratory fitness, muscle strength, and activities of daily living without exacerbating clinical disease progression or joint damage. However, subjects with RA also exhibit an altered resting cytokine profile with increased IL-1 and TNF production by PBMC. The effects of an exercise training regimen on the activated immune system of these subjects, compared with healthy individuals, remain to be elucidated.
 * L C Rall, R Roubenoff, J G Cannon, L W Abad, C A Dinarello, S N Meydani; “Effects of progressive resistance training on immune response in aging and chronic inflammation”, Med Sci Sports Exerc. 1996 Nov;28(11):1356-65.


 * In conclusion, the pilot data suggest that there are sustained cumulative biologic effects of repeated massage and light touch on neuroendocrine and immune parameters in healthy volunteers, but these differ by dosage. Weekly massage increased circulating phenotypic lymphochyte markers and decreased mitogen-stimulated cytokine production with a minimal effect on HPA function. Twice-weekly massage appears to potentiate neuroendocrine differences. These findings suggest that further investigation of “dosage,” as well as length of treatment and deconstructing the massage technique, are needed.
 * Mark H. Rapaport, Pamela Schettler,and Catherine Bresee, MS; “A Preliminary Study of the Effects of Repeated Massage on Hypothalamic–Pituitary–Adrenal and Immune Function in Healthy Individuals: A Study of Mechanisms of Action and Dosage”, J Altern Complement Med. 2012 Aug; 18(8): 789–797.


 * Autoimmune diseases occur when the immune system attacks and destroys the organs and tissues of its own host. Autoimmunity is the third most common type of disease in the United States. Because there is no cure for autoimmunity, it is extremely important to study the mechanisms that trigger these diseases. Most autoimmune diseases predominantly affect females, indicating a strong sex bias. Various factors, including sex hormones, the presence or absence of a second X chromosome, and sex-specific gut microbiota can influence gene expression in a sex-specific way. These changes in gene expression may, in turn, lead to susceptibility or protection from autoimmunity, creating a sex bias for autoimmune diseases.
 * Kira Rubtsova, Philippa Marrack, Anatoly V Rubtsov, “Sexual dimorphism in autoimmunity”, J Clin Invest. 2015 Jun; 125(6):2187-93.


 * Banana lectin (BanLec) is a dimeric protein occurring in fruit pulp that modulates immune cell functioning in vitro. In order to assess the immune response in vivo, BanLec from ripe banana (Musa acuminata) fruit was purified and orally given to mice for seven days. The analysis of cytokines in the mice peripheral blood revealed increased IL-10, IL-17 and TNFα, and a reduction of IFNγ and IL-6. In the thymus, an increase of CD4+ and a decrease of CD8+ T-cells were observed after oral administration of BanLec. The modulation of pro- and anti-inflammatory cytokines and T-cells in the peripheral blood and thymus of mice demonstrated the immunomodulatory properties of natural BanLec in vivo. This research brings new data on a protein from a fresh fruit consumed worldwide that may act as an immunomodulator, potentially affecting the host response to infections, immune diseases and cancer.
 * Ana Claudia Miranda Brito Sansone, Marcelo Sansone, Carlos Tadeu Dos Santos Dias, João Roberto Oliveira do Nascimento; “Oral administration of banana lectin modulates cytokine profile and abundance of T-cell populations in mice”, Int J Biol Macromol. 2016 Aug;89:19-24. doi: 10.1016/j.ijbiomac.2016.04.049. Epub 2016 Apr 20.


 * Lymphocytes are not required for the initiation of wound healing, but an intact cellular immune response is essential for a normal outcome of tissue repair. Injury affects lymphocyte immune mechanisms leading to generalized immunosuppression which, in turn, increases host susceptibility to infection and sepsis. Although the exact origin of post-traumatic immunosuppression remains unknown, stress hormones and immunosuppressive factors, such as inflammatory cytokines, prostaglandin E2 and nitric oxide, affect lymphocyte function adversely. Post-traumatic impairment of T lymphocyte immune function is reflected in decreased lymphocyte numbers, as well as altered T cell phenotype and activity. Antibody-producing B lymphocytes are variably affected by injury, probably secondary to alterations of T lymphocyte function, as a result of their close interaction with helper T cells. Therapeutic modulation of the host immune response may include non-specific and specific interventions to improve overall defence mechanisms. Conclusion: Early resuscitation to restore lymphocyte function after injury is important for tissue repair and the prevention of immunosuppression.
 * M Schäffer, A Barbul; “Lymphocyte function in wound healing and following injury”, Br J Surg. 1998 Apr;85(4):444-60.


 * Many people have heard of the “hygiene hypothesis” — the idea that individuals who are exposed to a variety of microbes (i.e., germs) in childhood build better immunity. In fact, there is evidence that young children who have early exposure to different types of germs are less likely to develop allergies and autoimmune disorders such as hay fever, asthma, or inflammatory bowel disease. However, by the time you are an adult, you have already spent years being exposed to many types of bacteria and viruses. You’ve created a robust immune system that can respond to these microbes. Your immune system “remembers” viral and bacterial markers, and as soon as one of these markers shows up, your body starts making antibodies to destroy that intruder. Of course, SARS-CoV-2, the virus that causes the COVID-19 illness, is a new virus. Before its initial appearance in humans at the end of 2019, no human had been exposed to the virus or had opportunity to build immunity against that particular pathogen. But while your immune system won’t have any specific “memory” of the virus, it will mount an immune response if you are infected — because that’s how your immune system works. Coming into contact with germs spurs an immune response, but it doesn’t do anything to make your immune system stronger. And this current period of contact with fewer germs does nothing to weaken the immune response you will be able to mount, as needed, in the future. But that doesn’t mean social distancing will have no effect on your immune system. The psychological effects of social isolation can affect your immune system. The culprits are loneliness and stress.
 * Kim Schive, “Is all this social distancing weakening our immune systems?”, MIT Medical, (May 26, 2020)


 * Modulation of cytokine secretion may offer novel approaches in the treatment of a variety of diseases. One strategy in the modulation of cytokine expression may be through the use of herbal medicines. A class of herbal medicines, known as immunomodulators, alters the activity of immune function through the dynamic regulation of informational molecules such as cytokines. This may offer an explanation of the effects of herbs on the immune system and other tissues. For this informal review, the authors surveyed the primary literature on medicinal plants and their effects on cytokine expression, taking special care to analyze research that utilized the multi-component extracts equivalent to or similar to what are used in traditional medicine, clinical phytotherapy, or in the marketplace.
 * Kevin Spelman, Jj Burns, Douglas Nichols, Nasha Winters, Steve Ottersberg, Mark Tenborg, “Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators”, Altern Med Rev. 2006 Jun;11(2):128-50.


 * The in vitro and in vivo research demonstrates that the reviewed botanical medicines modulate the secretion of multiple cytokines. The reported therapeutic success of these plants by traditional cultures and modern clinicians may be partially due to their effects on cytokines. Phytotherapy offers a potential therapeutic modality for the treatment of many differing conditions involving cytokines. Given the activity demonstrated by many of the reviewed herbal medicines and the increasing awareness of the broad-spectrum effects of cytokines on autoimmune conditions and chronic degenerative processes, further study of phytotherapy for cytokine-related diseases and syndromes is warranted.
 * Kevin Spelman, Jj Burns, Douglas Nichols, Nasha Winters, Steve Ottersberg, Mark Tenborg, “Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators”, Altern Med Rev. 2006 Jun;11(2):128-50.


 * It is well established that the intestine is an important site responsible for the local immune system. It is speculated that people suffering from constipation and carrying fecal residues in the intestine may have a decreased function of this immune system. In this study, colon irrigation, which is cleansing of the colon using a simple hydrotherapy instrument, was performed in 10 subjects with or without the disease. The number of leukocytes and their demarcation were then evaluated. The number and ratio of lymphocytes increased significantly after irrigation. This result suggested that colon irrigation might induce lymphocyte transmigration from gut-associated lymphatic tissues into the circulation, which may improve colon and immune system function.
 * Yoko Uchiyama-Tanaka, “Colon irrigation causes lymphocyte movement from gut-associated lymphatic tissues to peripheral blood”, Biomed Res. 2009 Oct;30(5):311-4.


 * Exposure to germs in childhood is thought to help strengthen the immune system and protect children from developing allergies and asthma, but the pathways by which this occurs have been unclear. Now, researchers have identified a mechanism in mice that may explain the role of exposure to microbes in the development of asthma and ulcerative colitis, a common form of inflammatory bowel disease.
 * Helen Thompson, “Early exposure to germs has lasting benefits”, Nature, (22 March 2012)


 * The Hygiene Hypothesis was proposed more than twenty years ago by Strachan1 to explain the dramatic increase in the prevalence of allergic diseases and asthma that has occurred over the past two to three decades. What Strachan observed was that the younger children in large families had less asthma and allergy, presumably due to increased exposure to infections that passed around in such large families. Later, the Hygiene Hypothesis was extended to explain the great increase in the prevalence of inflammatory bowel disease that occurred over the same time period. However, the exact scientific underpinnings for the Hygiene Hypothesis, e.g., the specific infections and the mechanisms by which infections affect the immune system to prevent disease, have remained a puzzle over the years for both scientists and clinicians. A clear biological explanation for the Hygiene Hypothesis though, may be at hand, as proposed in an article recently published in Science, using mouse models2. Blumberg and his colleagues showed that mice raised under sterile, germ free conditions were more likely to develop experimental colitis, called oxazolone-induced colitis, and more likely to develop an experimental form of allergic asthma. Importantly, reestablishment of the intestinal commensal bacteria, collectively known as microbiota, in the germ-free mice with standard mouse colony bacteria prevented their predisposition to severe colitis or asthma. However, the beneficial effects from the microbiota developed only when very young mice were exposed to the bacteria, whereas exposure of adult germ-free mice to the microbiota did not reduce the predisposition to colitis or asthma. Thus, exposure of pregnant germ-free mice to the microbiota, which then affected the pups when they were born, prevented the later predisposition of the pups as adults to colitis and asthma, consistent with the idea that exposure of young children to germs prevents asthma and allergy.
 * Dale T Umetsu, “Early exposure to germs and the Hygiene Hypothesis”, Cell Res. 2012 Aug; 22(8): 1210–1211.


 * The idea that mice growing up in “germless” environments develop an expansion of iNKT cells, which then predispose them to the development of colitis and allergic asthma, may be very relevant to humans. Epidemiological studies have already shown that birth by Caesarian section, which may limit early exposure to microbiota from the mothers' vaginal tracts, or extensive use of antibiotics in young children, which may also reduce the intestinal microbiota, also predisposes to the development of asthma and allergy. On the other hand, living on a farm in Western Europe, or having multiple pets, which may increase the early exposure to a more diverse community of microbiota, in some way prevents the development of asthma and allergy. Thus, early events in young children related to microbial exposures appear to have lasting effects on the innate and adaptive immune systems, and as proposed by the Blumberg study, on iNKT cells. The striking effects of commensal microbiota on the development iNKT cells are in line with other recent studies showing that specific strains of intestinal bacteria in mice, such as segmented filamentous bacteria, and clostridia are required for the development of Th17 cells and regulatory T cells, respectively. Thus, it is becoming clear that a symbiotic relationship exists between bacteria and our immune system. As we understand this relationship better, perhaps in the future we could see the development of therapies that mimic the beneficial effects of “infection”, for example, encouraging early exposure of infants to a “standard” disease-preventing collection of germs.
 * Dale T Umetsu, “Early exposure to germs and the Hygiene Hypothesis”, Cell Res. 2012 Aug; 22(8): 1210–1211.


 * The earliest documented examples of micronutrients’ influencing immunity date from the nineteenth century. Such work indicated previously unappreciated links with immunity and made a strong case that infections did not cause observed disorders and pathologies but were secondary to deficiency in micronutrients. Supported by clinical and epidemiological studies, which show a substantial negative correlation of nutritional deficiencies with immunocompetence and the reverse correlation with the risk of infection and related pathologies, is the idea that nutrition is an important determinant of immunity is now generally well accepted (Fig. 1). Nevertheless, the impact of dietary elements in immune system–related processes is still often dismissed, even when substantial amounts of data correlate diet with immune system–related related disorders.
 * Marc Veldhoen and Henrique Veiga-Fernandes, “Feeding immunity: skepticism, delicacies and delights”, Nat Immunol. 2015 Mar; 16(3): 215–219.


 * There is an emergent interest in understanding how the ‘Western diet’ affects immunity. Many people across the globe have adopted this diet, and epidemiological studies have revealed that it correlates with a high incidence of chronic inflammatory disorders, including diabetes, multiple sclerosis and asthma. Nevertheless, because the Western diet includes a large proportion of red meat, sugars, fats and refined carbohydrates and relatively small amounts of vegetables, fruits and fish, it is likely that the causative component of its associated pathologies is not a single entity but a complex array of unbalanced abundance of micronutrients in the diet. However, epidemiological studies have highlighted roles for specific micronutrients in immunity. For example, mounting evidence correlates vitamin A deficiency, which is still highly prevalent among children and pregnant women in several African and Asian countries with a high risk of intestinal and respiratory infections. These observations were substantiated by experimental data as early as 1925, when rats on a diet deficient in vitamin A were found to develop thymic atrophy. It is now understood that different processes require different amounts of micronutrients, with the immune system generally the largest consumer. In view of this, the World Health Organization established a vitamin A–supplementation program, which had a positive effect on morbidity and mortality rates of infectious diseases in deprived children. Interestingly, low vitamin A levels are also associated with reduced efficacy of vaccination protocols, but the benefits of vitamin A supplementation during vaccination are still a matter of controversy.
 * Marc Veldhoen and Henrique Veiga-Fernandes, “Feeding immunity: skepticism, delicacies and delights”, Nat Immunol. 2015 Mar; 16(3): 215–219.
 * Malnutrition is the most common cause of immunodeficiency worldwide, and the impaired immunocompetence that results from it may exist for many years.
 * Marc Veldhoen and Henrique Veiga-Fernandes, “Feeding immunity: skepticism, delicacies and delights”, Nat Immunol. 2015 Mar; 16(3): 215–219.


 * Where does ‘nutritional immunology’ stand? The historical collection of casuistic discoveries, epidemiology studies and more recent mechanistic work indicates that the challenges ahead lie in defining the molecular links between nutrients and cells of the immune system that form the basis of protective immunity. Novel high-throughput technology platforms offer real opportunities to shed light on new nutritional delights for the immune system. However, although opportunities are there for the taking, this will occur only if the research community is alert and open to the ever-growing evidence that nutrients shape and define immunity.
 * Marc Veldhoen and Henrique Veiga-Fernandes, “Feeding immunity: skepticism, delicacies and delights”, Nat Immunol. 2015 Mar; 16(3): 215–219.


 * “The link between PTSD and chronic illness has been established but the potential role of immune system markers in mediating this association is only beginning to be examined,” wrote VA clinician-researchers Drs. Janine Flory and Rachel Yehuda in a special report in Psychiatric Times in April 2018.
 * “Tackling trauma, depression via the immune system”, Office of Research & Development, VA.gov


 * In the same issue of Psychiatric Times Dr. Charles Raison, with the University of Wisconsin-Madison, offered further perspective on the topic. He wrote that his time in medical school in the 1980s was like the “dark ages,” with respect to understanding the brain-immune connection. “We now know the immune system and the brain have everything to do with each other; really, they are best understood as part of one larger system with causal influences that move in both directions. Brain states that produce mental illness also tend to activate inflammation. And inflammation is equally capable of producing depression, anxiety, fatigue, and social withdrawal.” He added that environmental insults—for example, toxic exposures—can hike inflammation and “likely increase the risk of mental illness through this mechanism.” Tonelli shares that view. He points out that military PTSD may be different in its complexity than other forms of the disorder—for example, like that seen in cases of sexual or child abuse—because war can mean not only severe emotional trauma, but also bodily injury, exposure to extreme heat or cold, sleep deprivation, and other physical assaults on the human organism. “We need to incorporate physical trauma to the pathophysiology of PTSD,” he says. “Getting hurt physically in any way is an important mechanistic process leading to PTSD in which the immune system and inflammation play crucial roles.”
 * “Tackling trauma, depression via the immune system”, Office of Research & Development, VA.gov


 * The immune system is made up of special organs, cells and chemicals that fight infection (microbes). The main parts of the immune system are: white blood cells, antibodies, the complement system, the lymphatic system, the spleen, the thymus, and the bone marrow. These are the parts of your immune system that actively fight infection.
 * Victoria State Health Program, Better Health Channel, ”Immune system explained“, (December 2017)


 * The immune system keeps a record of every microbe it has ever defeated, in types of white blood cells (B- and T-lymphocytes) known as memory cells. This means it can recognise and destroy the microbe quickly if it enters the body again, before it can multiply and make you feel sick. Some infections, like the flu and the common cold, have to be fought many times because so many different viruses or strains of the same type of virus can cause these illnesses. Catching a cold or flu from one virus does not give you immunity against the others.
 * Victoria State Health Program, Better Health Channel, ”Immune system explained“, (December 2017)


 * The human immune system is mind-bendingly complex, and ageing affects nearly every component. Some types of immune cell become depleted: for example, older adults have fewer naive T cells that respond to new invaders, and fewer B cells, which produce antibodies that latch on to invading pathogens and target them for destruction. Older people also tend to experience chronic, low-grade inflammation, a phenomenon known as inflammageing (see ‘Depleted defences’). Although some inflammation is a key part of a healthy immune response, this constant buzz of internal activation makes the immune system less responsive to external insults. “This overarching, chronic inflammatory state is what’s driving much of the immune dysfunction that we see,” says Kaeberlein. The upshot is a poorer reaction to infections and a dulled response to vaccines, which work by priming the immune system to fight off a pathogen without actually causing disease.
 * Cassandra Willyard quoting Matt Kaeberlein, “How anti-ageing drugs could boost COVID vaccines in older people”, Nature, 586, (14 October 2020), pp.352-354


 * One promising class of anti-ageing drug acts on pathways involved in cell growth. These drugs inhibit a protein known as mTOR. In the laboratory, inhibiting mTOR lengthens lifespan in animals from fruit flies to mice. “mTOR is one of probably multiple biologic mechanisms that contribute to why we age and why our organ systems start to decline,” says Joan Mannick, co-founder and chief medical officer of resTORbio, a biotech company based in Boston, Massachusetts, that aims to develop anti-ageing therapies. mTOR is a classic anti-ageing target, but it’s far from the only one. In fact, many anti-ageing pathways seem to be linked, says James Kirkland, who studies cellular ageing and disease at the Mayo Clinic in Rochester, Minnesota. “That is, if you target one, you tend to affect all the rest,” he says. Many of the immune changes that come with ageing lead to the same result: inflammation. So researchers are looking at drugs that will calm this symptom. Arne Akbar, an immunologist at University College London, has shown that the anti-inflammatory drug losmapimod, which is being developed as a therapy for muscular dystrophy, might help boost immunity. In a 2018 study, the researchers injected chickenpox virus into the skin of elderly adults7. Although these people had already been exposed to chickenpox, their immune response was lacklustre, hampered by excess inflammation. When the team gave the study participants losmapimod, it ratcheted down inflammation by about 70% and improved their immune responses.
 * Cassandra Willyard, “How anti-ageing drugs could boost COVID vaccines in older people”, Nature, 586, (14 October 2020), pp.352-354


 * A team led by vaccinologist Ofer Levy at Boston Children’s Hospital in Massachusetts is working on a COVID-19 vaccine specifically for older adults, using an in-vitro screening system to identify the best adjuvants. “Vaccines were typically developed as one-size-fits-all,” he says. But a lot of features — age, sex, and even the season — affect vaccine responses, Levy says. The best combinations of adjuvant and vaccine they find will be tested in mice and then in humans. But, in general, developing medications to improve immune function seems like a much smarter strategy than creating vaccines specifically for elderly people, says Claire Chougnet, an immunologist at Cincinnati Children’s Hospital Medical Center in Ohio, who is studying inflammation in aged mice. Vaccine development is costly and time-intensive. “In the case of an emerging virus, when you want a quick response, that makes things even more complicated if you have to do two types of vaccine,” she says. Plus, individual vaccines target specific pathogens, but an immune-boosting medication could be used with any vaccine. “That could work for flu, that could work for COVID-19. That would work for COVID-25,” she says. The approach is “extremely versatile”.
 * Cassandra Willyard, “How anti-ageing drugs could boost COVID vaccines in older people”, Nature, 586, (14 October 2020), pp.352-354


 * Adequate intakes of vitamins and trace elements are required for the immune system to function efficiently. Micronutrient deficiency suppresses immune functions by affecting the innate T-cell-mediated immune response and adaptive antibody response, and leads to dysregulation of the balanced host response. This increases the susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (both active and passive), in individuals with chronic alcohol abuse, in patients with certain diseases, during pregnancy and lactation, and in the elderly. With aging a variety of changes are observed in the immune system, which translate into less effective innate and adaptive immune responses and increased susceptibility to infections. Antioxidant vitamins and trace elements (vitamins C, E, selenium, copper, and zinc) counteract potential damage caused by reactive oxygen species to cellular tissues and modulate immune cell function through regulation of redox-sensitive transcription factors and affect production of cytokines and prostaglandins. Adequate intake of vitamins B, folate, B, C, E, and of selenium, zinc, copper, and iron supports a Th1 cytokine-mediated immune response with sufficient production of proinflammatory cytokines, which maintains an effective immune response and avoids a shift to an anti-inflammatory Th2 cell-mediated immune response and an increased risk of extracellular infections. Supplementation with these micronutrients reverses the Th2 cell-mediated immune response to a proinflammatory Th1 cytokine-regulated response with enhanced innate immunity. Vitamins A and D play important roles in both cell-mediated and humoral antibody response and support a Th2-mediated anti-inflammatory cytokine profile. Vitamin A deficiency impairs both innate immunity (mucosal epithelial regeneration) and adaptive immune response to infection resulting in an impaired ability to counteract extracellular pathogens. Vitamin D deficiency is correlated with a higher susceptibility to infections due to impaired localized innate immunity and defects in antigen-specific cellular immune response. Overall, inadequate intake and status of these vitamins and minerals may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition.
 * Eva S Wintergerst, Silvia Maggini, Dietrich H Hornig, “Contribution of selected vitamins and trace elements to immune function”, Ann Nutr Metab. 2007;51(4):301-23.


 * Immunosuppressive agents are commonly used in the nephrologist’s practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist.
 * Alexander C. Wiseman, “Immunosuppressive Medications”, Clin J Am Soc Nephrol, v.11(2); 2016 Feb 5


 * Immunosuppressive agents have a long history, with a recent acceleration in growth in number. After the discovery by Nobel Prize awardee Philip Hench that the corticosteroid cortisone had significant anti-inflammatory effects in patients with rheumatoid arthritis (RA) in 1949 (1) and the independent discoveries by Calne et al. (2), Murray et al. (3), and Zukoski et al. (4) that azathioprine (AZA) was an effective immunosuppressive agent in the prevention of kidney allograft rejection in the early 1960s (2–4), many of the mechanisms of the immune response remained opaque. The 1960s and 1970s were marked by a borrowing of cyclophosphamide from the developing field of cancer chemotherapy for use in immune diseases and transplantation, whereas the use of antilymphocyte serum as a lymphocyte-depleting agent gained favor in the developing field of kidney transplantation. The late 1970s and early 1980s brought revolutionary changes in drug development and discovery; two key developments were the technology to develop monoclonal antibodies (mAbs) for human therapeutic use and the discovery of the immunosuppressive effects of cyclosporin A from fermentation extracts of the fungal species Tolypocladium inflatum (5,6). The 1990s were a period of significant immunosuppressive drug development, because increased insight into B and T cell development, activation, and proliferation, cytokine and chemokine signaling, and complement activation led to targeted therapeutics, particularly mAbs that could later be humanized (Figure 1). In reciprocal fashion, drug discovery often led to further understanding of the mechanisms of the immune response. Similar to cyclosporin A, sirolimus (previously called rapamycin) was discovered and developed as an antifungal, but it was found to have antineoplastic and immunosuppressive properties, the mechanisms of which were only later appreciated and described as mammalian target of rapamycin (mTOR) pathways (7,8).
 * Alexander C. Wiseman, “Immunosuppressive Medications”, Clin J Am Soc Nephrol, v.11(2); 2016 Feb 5


 * Back in the 2000s, we performed a series of studies in mice and people to understand how individual bouts of exercise and exercise training affect influenza infection and vaccination, respectively. In our animal studies, we found that moderate endurance exercise (30 min/day) could protect mice from death due to influenza. Mice that exercised for longer durations (∼2.5 h/day) exhibited an increase in some illness symptoms, but there was no statistically significant difference in mortality when compared to sedentary mice. We concluded that moderate exercise could be beneficial and that prolonged exercise could be detrimental to influenza-infected mice. For obvious reasons, we have not performed this experiment in people. We also did a large study to determine whether 10 months of regular endurance exercise could improve influenza vaccination responses in older adults, a group that is at risk for infectious disease due to immunosenescence. We found that regular, moderate cardiovascular exercise could extend the protective effect of the annual influenza vaccination so that it maintained protective levels of antibodies throughout the entire influenza season (i.e., into March and April in the northern hemisphere). We concluded that regular moderate endurance exercise might be one way to boost the protective effect of annual influenza vaccination. It is very important for all people to receive the annual influenza vaccine.
 * Jeffrey A. Woods, as quoted by Weimo Zhu in “Should, and how can, exercise be done during a coronavirus outbreak? An interview with Dr. Jeffrey A. Woods”, J Sport Health Sci. (2020 Mar Published online 2020 Feb 4); 9(2): 105–107.
 * The researchers found that air pollution exposure suppressed the immune system’s regulatory T cells (Treg), and that the decreased level of Treg function was linked to greater severity of asthma symptoms and lower lung capacity. Treg cells are responsible for putting the brakes on the immune system so that it doesn’t react to non-pathogenic substances in the body that are associated with allergy and asthma. When Treg function is low, the cells fail to block the inflammatory responses that are the hallmark of asthma symptoms.
 * Sarah Yang, ”Air pollution alters immune function, worsens asthma symptoms”, Berkeley News, UC Berkeley, (October 5, 2010)
 * A standard test at the time—and now—is LAL, which stands for limulus amebocyte lysate. Limulus refers to Limulus polyphemus, the species of horseshoe crab native to the Atlantic coast of North America. Amebocyte refers to cells in the crab’s blood. And lysate is the material freed from the cells once they have been “lysed” or broken. This is the stuff exquisitely sensitive to bacterial toxins. The first person to figure this out about LAL was Frederik Bang. Thirty years before Ding—and 9,000 miles away on Cape Cod—he too was collecting horseshoe crabs on the shore. (For reasons not entirely understood, horseshoe crabs are only found around the eastern coasts of North America and Asia.) Bang, a pathologist, was interested in the creature’s primitive immune system. He settled on a protocol of injecting bacteria from seawater directly into horseshoe crabs, which cause their blood to clump into “stringy masses.” Bang suspected this clotting had a purpose. It immobilized the bacteria, sealing off the rest of the horseshoe crab’s body from an invading pathogen. Intriguingly, their blood turned to gel even if he boiled the bacteria injection for five or 10 minutes first. This should have killed the bacteria and sterilized the injected solution. Bang realized the blood was sensitive not just to live bacteria but to bacterial toxins that persist even after sterilization. The human immune system may be much more sophisticated than a horseshoe crab’s, but it too reacts to these toxins. Doctors first realized this in the late 19th century, where patients given sterile shots nevertheless came down with “injection fever” or “saline fever.” In the worst cases, the toxins can cause septic shock and even death.
 * Sarah Zhang, “The Last Days of the Blue-Blood Harvest“, The Atlantic, (May 9, 2018)


 * We matched 267 847 pairs of individuals. Six months after the index date, the incidence of SARS-CoV-2 infection was significantly higher in vaccine recipients (6.7%) than the previously infected (2.9%). All-cause mortality in the vaccinated, however, was 37% lower than that of the previously infected. The rates of all-cause ED visits and hospitalizations were 24% and 37% lower in the vaccinated than in the previously infected.
 * SARS-CoV-2 Infection, Hospitalization, and Death in Vaccinated and Infected Individuals by Age Groups in Indiana, 2021‒2022, Wanzhu Tu PhD, Pengyue Zhang PhD, Anna Roberts MS, Katie S. Allen BS, Jennifer Williams MPH, Peter Embi MD, and Shaun Grannis MD, MS

“Sleep and immune function” (Jan 2012)
Luciana Besedovsky, Tanja Lange,and Jan Born; “Sleep and immune function”, Pflugers Arch. 2012 Jan; 463(1): 121–137.
 * Sleep and the circadian system exert a strong regulatory influence on immune functions. Investigations of the normal sleep–wake cycle showed that immune parameters like numbers of undifferentiated naïve T cells and the production of pro-inflammatory cytokines exhibit peaks during early nocturnal sleep whereas circulating numbers of immune cells with immediate effector functions, like cytotoxic natural killer cells, as well as anti-inflammatory cytokine activity peak during daytime wakefulness. Although it is difficult to entirely dissect the influence of sleep from that of the circadian rhythm, comparisons of the effects of nocturnal sleep with those of 24-h periods of wakefulness suggest that sleep facilitates the extravasation of T cells and their possible redistribution to lymph nodes. Moreover, such studies revealed a selectively enhancing influence of sleep on cytokines promoting the interaction between antigen presenting cells and T helper cells, like interleukin-12. Sleep on the night after experimental vaccinations against hepatitis A produced a strong and persistent increase in the number of antigen-specific Th cells and antibody titres. Together these findings indicate a specific role of sleep in the formation of immunological memory. This role appears to be associated in particular with the stage of slow wave sleep and the accompanying pro-inflammatory endocrine milieu that is hallmarked by high growth hormone and prolactin levels and low cortisol and catecholamine concentrations.
 * Over the last 15 years, research following a systems approach of neuroimmunology has accumulated surprisingly strong evidence that sleep enhances immune defence, in agreement with the popular wisdom that ‘sleep helps healing’. Although the communication between sleep regulatory networks in the central nervous system and the cells and tissues of the immune system is basically bidirectional, in this review, we will focus on the role of sleep for proper functioning of the immune system. First, we will give a short overview of the signals which mediate the communication between the nervous and immune system and thus provide the basis for the influence of sleep on immune processes. Because normally sleep is embedded in the circadian sleep–wake rhythm, we will then review studies that examined immune changes associated with the sleep (or rest) phase of this rhythm, without attempting to isolate the effects of sleep per se from those of circadian rhythm. Thereafter, we will concentrate on studies that aimed at disentangling the immuno-supporting effects of sleep from those of the circadian system. Results from these studies, many of them comparing the effects of sleep during the normal rest phase with 24 h of continuous waking, support the view that sleep is particularly important for initiating effective adaptive immune responses that eventually produce long-lasting immunological memory. We will close with some remarks about the detrimental effects of prolonged sleep loss on immune functions showing the importance of proper sleep for general health.
 * Comparing the immune and the central nervous system (CNS), both systems share a basic feature, i.e. they both respond to external stimuli and generate memory in a multi-step process that involves cell to cell contacts (synapses). The different stages of memory operations in the CNS are usually divided into an encoding phase, a consolidation phase in which the information is transferred from a short-term to a long-term store (with both stores represented by different neuronal networks) and a recall phase. This division might in its basic features also hold true for the different stages of immunological memory: According to this proposition, the encoding phase would in the immunological context be represented by the uptake of the antigen (the information which is to be remembered) by APC. The consolidation phase, in which, in the CNS, the crucial information of the newly encoded memory is transferred from its temporary storage site to neuronal networks serving as long-term store, might be represented by the formation of the ‘immunological synapse’ between APC and T cell, during which the antigenic information is forwarded from a short-term (APC) to a long-term (T cell) store. Finally, the recall phase would be represented by the facilitated response of the immune system upon re-encounter of the antigen (Fig. 1). It is clear that this is a pure conceptual view and that there are apparent differences between the two systems (cells of the immune system are migratory and act in special compartments and their proliferative capacity clearly outnumbers that of neurons). Nevertheless, the comparison with concepts of neurobehavioural memory formation which is well known to benefit from sleep might also help in understanding how sleep regulates memory formation during adaptive immune responses. Since sleep specifically enhances the consolidation of neurobehavioural memories whereas encoding and recall usually take place during waking, the transfer of this concept to the immune system would implicate that it is also the consolidation phase of immunological memory formation (that is, the formation of the immunological synapse) which mostly benefits from sleep. Indeed, as outlined in the section ‘Sleep enhances the formation of immunological memory’, this effectively seems to be the case.
 * The nocturnal sleep period in humans is characterised by a profound down-regulation of the two stress systems, the hypothalamus–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), with a concomitant drop in blood levels of cortisol, epinephrine and norepinephrine. In contrast, mediators serving cell growth, differentiation and restoration like the pituitary growth hormone (GH) and prolactin and (in day-active humans) the pineal hormone melatonin show a steep increase in their blood levels during sleep. In parallel, increases of leptin that is released by adipocytes are assumed to prevent sleep-disturbing feelings of hunger during this time. Despite their very different cellular sources, GH, prolactin, melatonin and leptin exert remarkably synergistic actions on the immune system. They are pro-inflammatory signals that support immune cell activation, proliferation, differentiation and the production of pro-inflammatory cytokines like interleukin (IL)-1, IL-12, tumour necrosis factor (TNF)-α and of Th1 cytokines like interferon (IFN)-γ. In contrast, cortisol and catecholamines generally suppress these immune functions in an anti-inflammatory manner, although some specific aspects of immunity may be supported by these signals. Of course, when experimentally administered, the effects of these hormones essentially depend on dosage and timing, and here only acute actions of these hormones within physiological ranges are of relevance. On this background, numerous experiments have shown a consistent and intriguing pattern of endocrine and immune rhythms reflecting an ‘inflammatory peak’ during nocturnal sleep whereas wakefulness is associated with prevalent anti-inflammatory activity.
 * In addition to the effects of hormones and danger signals, immune rhythms are regulated by intrinsic cellular clocks that have been demonstrated in peritoneal and splenic macrophages as well as peripheral Th cells and are capable of maintaining periodic changes in pro-inflammatory cytokine production for several days in vitro (Bollinger et al., under revision). Clock genes control up to 8% of the transcriptome in immune cells, amongst others, components involved in antigen presentation, phagocytosis and LPS, HSP and NFκB signalling (Bollinger et al., under revision). Accordingly, various other indices of immune function, like phagocytosis, activity of natural regulatory T cells as well as spontaneous and stimulated cell proliferation in peripheral blood, lymph nodes and spleen, have been revealed to display diurnal rhythms, also peaking during the rest period. Interestingly, in the latter study, blood levels of GH and prolactin correlated positively with unstimulated IFN-γ production and with the stimulated mitogenic response in rat lymph nodes suggesting an active contribution of these pro-inflammatory hormones to the rhythm in immune function. On the other hand, low sympathetic activity (as assessed by tyrosine hydroxylase activity) seemed to contribute to the high spontaneous T cell proliferation in lymph nodes.
 * Taken together, neuroendocrine rhythms with the prevalent release of pro-inflammatory hormones and a suppression of anti-inflammatory hormones particularly during the early SWS-rich portion of the rest period in combination with an accumulation of endogenous and exogenous danger signals across the active wake period and the intrinsic clock gene activity synergistically impact immune and non-immune cells to boost immune activation during the rest period. This pro-inflammatory function of sleep can be beneficial. Thus, sleep after vaccination can enhance the subsequent adaptive immune response like an adjuvant (see below). On the other hand, the pro-inflammatory surge during sleep can also be detrimental as evidenced by peak mortality rates in mice when LPS is injected during the sleep period (83%) in comparison with injection during the active period (10%), a pattern that is similarly observed for mortality rates in septic patients.
 * Immune cells migrate. New cells are constantly released from the bone marrow into the circulation. T and B cells circulate for up to years until they encounter their cognate antigen in secondary lymphatic tissues, whereas other cells, like macrophages, DC and neutrophils, extravasate to peripheral tissues already after a few hours or days. In humans, recirculating T cells, mainly naïve and central memory T cells, through a mechanism involving CD62L, leave the blood via high endothelial venules (HEV) to enter the lymph nodes and then return to the blood via efferent lymphatics and the thoracic duct. In peripheral blood, these cells show a pronounced circadian rhythm with a peak during the early rest period. A closely comparable rhythm is observed for lymphocytes, T cells and Th cells in lymph nodes, indicating that there is a fast equilibrium between the blood and this lymphatic compartment. In addition, there is evidence pointing to an accumulation of lymphocytes in lymph nodes during nocturnal sleep. In humans, rhythms of T cells in blood are coupled to the rhythm of cortisol such that the peak in cortisol in the beginning of the wake period precedes a decrease in blood T cell number by about 3 h. This coupling presumably reflects the cortisol-mediated redirection of T cells to the sheltering bone marrow during the active period via enhanced expression of CXCR4 (Fig. 2). In fact, the corresponding ligand in bone marrow, i.e. CXCL12, is likewise rhythmically produced with a parallel peak during the active period. However, this rhythm seems to be mainly governed by clock genes and the SNS. CXCR4 is not only expressed on mature T cells at early stages of differentiation, but also by hematopoietic stem cells that—like naïve and central memory T cells—show the highest numbers in peripheral blood in the beginning of the rest period in animals and humans. The decrease in HPA and cortisol activity during the rest period releases CXCR4+ T cells from the bone marrow, presumably to enable their subsequent distribution to other sites of action, for example to the lymph nodes where they can initiate adaptive immune responses. Low levels of cortisol could likewise facilitate the extravasation of T cells from the blood to lymph nodes, as glucocorticoids are known to impair lymphocyte migration across HEV presumably via effects on the endothelium. However, discrepant findings in animal studies suggest the presence of species-specific differences in the regulation of immune cell rhythms in lymph nodes. In addition to nadir glucocorticoid levels, other factors like high levels of GH and low SNS activity could contribute to the accumulation of lymphocytes in lymph nodes during early sleep.
 * Collectively, these findings provide strong evidence for the notion that processes of immune activation and proliferation involving pro-inflammatory signals, APC, naïve and central memory T cells in lymph nodes are timed to the resting period. The reason for this timing is not clear. However, inflammation, if present during waking, causes malaise, fatigue, immobility, pain and other aspects of sickness behaviour that are incompatible with the demands of mental and physical activity required for effectively coping with environmental challenges. Hence, confining it to sleep time seems reasonable. In addition, immune activation, especially protein synthesis and cell proliferation, needs energy, and the endocrine changes during sleep allow for the allocation of energy-rich fuels like glucose from insulin-dependent tissues (e.g. muscle) to the immune system. Finally, inflammation leads to oxidative stress and cell injury that are efficiently counteracted by melatonin scavenging free radicals and by hematopoietic stem cells providing cellular supply. These may be just some reasons favouring the sleep period as suitable time for initiating adaptive immune responses and associated pro-inflammatory activity. Nevertheless, pathogen encounter takes place mainly during the active period. So, why should the immune system wait for several hours before being activated? In the next section, we will outline that the wake period is associated with a completely different type of immune defence that acutely wards off any challenges in peripheral tissues and spleen, before the aforementioned slower, long-term processes of adaptive immunity develop in the lymph nodes.
 * Amongst the studies focussing on the effects of sleep on cytokine activity, there are some seemingly discrepant findings. However, these are probably due to differences in the assessment of cytokine activity. For example, IL-1β and TNF-α levels when measured after stimulation of whole blood samples are decreased by nocturnal sleep [13]. Yet, this effect completely vanishes when the changes in IL-1β and TNF-α activity are related to the number of monocytes producing these cytokines, as the number of these cells circulating in the blood are likewise reduced by sleep. Such observations underline the importance to measure immune cell functions, like the production of cytokines, in blood samples on a per cell basis. Indeed, identifying the percentage of monocytes producing TNF-α showed that sleep even enhanced the production of this cytokine, whereas the percentage of TNF-α producing CTL was decreased [31]. Differences in the procedure of cytokine measurement probably account also for some of the conflicting data concerning IL-2, which critically supports the development, proliferation and differentiation of T cells. Whereas IL-2 activity was found to be enhanced by sleep when the cytokine was determined after mitogen stimulation of whole blood samples (for example [13]), this finding was not replicated by others determining IL-2 production specifically for Th cells [8, 31]. The use of whole blood vs. isolated cells, assessment of stimulated vs. unstimulated cytokine production, relation to the numbers of cytokine-producing cells vs. absolute cytokine levels, the type of antigen used for stimulation and even the use of different anticoagulants can be all factors producing discrepant results. Nevertheless, despite the variety in the procedures used for assessing cytokine activity, the overall picture arising from these studies speaks for an enhancing influence of sleep preferentially on pro-inflammatory cytokine production specifically by immune cells contributing to the development of adaptive immune responses.
 * In sum, research during the past years has accumulated evidence that sleep affects a wide variety of immune functions, including the numbers of specific leukocyte subsets in circulating blood, the cell-specific production of cytokines and further immune cell functions. The effect of sleep is selective influencing some components of the immune system but not others. Sleep appears to preferentially promote the pro-inflammatory cytokine production important for the mounting of adaptive immune responses, and this action might primarily affect less differentiated immune cells, although the cell subset-specific production of cytokines needs to be further explored in this context. The pro-inflammatory actions of sleep mainly originate from the early SWS-rich part of nocturnal sleep. However, excessive pro-inflammatory activity becomes counter-regulated in the course of sleep as indicated, for example, by the concurrent upregulation of nTreg activity and a predominance of Th2 activity during late sleep. The enhancement of IL-12 production by important precursors of APC, together with a shift towards Th1 cytokines and a reduction of blood lymphocyte counts possibly reflecting a redistribution of these cells to secondary lymphoid organs, point to a supportive role of sleep in the initiation of an adaptive immune response, eventually leading to immunological memory.
 * Chronic sleep loss is not only associated with an increase in inflammatory markers but also with immunodeficiency. The immune response to vaccination against influenza virus was diminished after 6 days of restricted sleep [109]. There is also evidence for an enhanced susceptibility to the common cold with poor sleep efficiency [24]. Similar signs of an impaired immune defence were revealed in studies in rats subjected to excessive sleep deprivation. Although prolonged sleep withdrawal resulted in an enhanced pro-inflammatory state and a general immune activation, the activated immune system was not able to successfully combat invading bacteria and toxins, and rats eventually died from bacteraemia. In summary, chronic sleep deprivation can be seen as an unspecific state of chronic stress, which per se impacts immune functions and general health [27, 82, 83]. The adverse effects of chronic sleep deprivation comprise an enhanced risk for various diseases as a consequence of a persistent low-grade systemic inflammation on the one hand, as well as a manifest immunodeficiency characterised by an enhanced susceptibility to infections and a reduced immune response to vaccination on the other hand.
 * Sleep and the circadian system are strong regulators of immunological processes. The basis of this influence is a bidirectional communication between the central nervous and immune system which is mediated by shared signals (neurotransmitters, hormones and cytokines) and direct innervations of the immune system by the autonomic nervous system. Many immune functions display prominent rhythms in synchrony with the regular 24-h sleep–wake cycle, reflecting the synergistic actions of sleep and the circadian system on these parameters. Differentiated immune cells with immediate effector functions, like cytotoxic NK cells and terminally differentiated CTL, peak during the wake period thus allowing an efficient and fast combat of intruding antigens and reparation of tissue damage, which are more likely to occur during the active phase of the organism. In contrast, undifferentiated or less differentiated cells like naïve and central memory T cells peak during the night, when the more slowly evolving adaptive immune response is initiated. Nocturnal sleep, and especially SWS prevalent during the early night, promotes the release of GH and prolactin, while anti-inflammatory actions of cortisol and catecholamines are at the lowest levels. The endocrine milieu during early sleep critically supports (1) the interaction between APC and T cells, as evidenced by an enhanced production of IL-12, (2) a shift of the Th1/Th2 cytokine balance towards Th1 cytokines and (3) an increase in Th cell proliferation and (4) probably also facilitates the migration of naïve T cells to lymph nodes. Thereby, the endocrine milieu during early sleep likely promotes the initiation of Th1 immune responses that eventually supports the formation of long-lasting immunological memories. Prolonged sleep curtailment and the accompanying stress response invoke a persistent unspecific production of pro-inflammatory cytokines, best described as chronic low-grade inflammation, and also produce immunodeficiency, which both have detrimental effects on health.

”Bone and the Innate Immune System” (2014)
Julia F. Charles, and Mary C. Nakamura, ”Bone and the Innate Immune System”, Curr Osteoporos Rep. 2014 Mar; 12(1): 1–8.
 * The immune system and bone are intimately linked with significant physical and functionally related interactions. The innate immune system functions as an immediate response system to initiate protections against local challenges such as pathogens and cellular damage. Bone is a very specific microenvironment in which infectious attack is less common but repair and regeneration are ongoing and important functions. Thus in the bone the primary goal of innate immune and bone interactions is to maintain tissue integrity. Innate immune signals are critical for removal of damaged and apoptotic cells and to stimulate normal tissue repair and regeneration.
 * The recognition that immune cell function directly influences bone remodeling with reciprocal support and influence over immune cells by bone cells has led to the active research field of osteoimmunology. In addition to providing a structural support for the body and a reservoir for calcium, bone encases the bone marrow, a primary site for hematopoiesis and immune system development. Immune system influences on bone are diverse and have been the topic of several recent reviews, which have highlighted the effects of activation of the adaptive immune system on bone in the setting of infection, osteoporosis, cancer and autoimmunity.
 * Autophagy is thought to be a primordial form of innate immune pathogen elimination that has acquired a function in cellular homeostasis by enabling cells to survive stress or nutrient deprivation through the self-consumption of damaged cellular organelles. Autophagy is also important for the clearance of protein aggregates, targeting them for degradation. The process of autophagy initiates autophagosome formation and proteolytic degradation of cellular organelles and protein aggregates by lysosomes, freeing energy that can be used by the cell. Autophagy is also thought to regulate apoptosis, thus autophagy has both pro-survival and pro-death functions. Recent studies examining autophagy in bone cells and the requirement for autophagic components in osteoclast function have highlighted the interactions between these pathways, as discussed below.
 * Innate immune mechanisms are required for maintenance of bone homeostasis which requires clearance of apoptotic cells, utilization of autophagy and resolution of inflammation in response to cellular damage. Likely due to their common goals, bone and immune cells utilize multiple shared pathways and precursors. These interactions are necessary for normal bone development, turnover and remodeling. Dysregulation of innate immune homeostatic pathways has been implicated in a wide variety of disease states such as autoimmunity, aging and atherosclerosis and the recognition of their importance should be extended to include multiple types of pathological bone loss.

“Marriage, Divorce, and the Immune System” (Dec. 2018)
Janice K. Kiecolt-Glaser, “Marriage, Divorce, and the Immune System”, Am Psychol. 2018 Dec; 73(9): 1098–1108.
 * This paper reviews evidence from several lines of work to describe how marriage and divorce can provoke health-relevant immune alterations, including ways that marital closeness can be perilous for health and divorce can be beneficial. The multiple stresses of a troubled relationship are depressogenic, and the development of a mood disorder sets the stage for psychological and biological vulnerability. Depression provides a central pathway to immune dysregulation, inflammation, and poor health; gender-related differences in depression and inflammation can heighten risk for women compared to men. Sleep and obesity can simultaneously feed off depression as they promote it. In addition, spousal similarities in health behaviors, gene expression, immune profiles and the gut microbiota offer new ways to consider the health advantages and risks of marriage and divorce, providing new perspectives on couples’ interdependence, as well as new directions for research.
 * Cortisol, ACTH, epinephrine, and norepinephrine impact the immune response (Glaser & Kiecolt-Glaser, 2005), and thus it was not surprising that newlyweds’ hostile conflict behaviors had immunological correlates as well. In the blood samples obtained at the start and finish of their 24-hour visits, more hostile newlyweds demonstrated greater maladaptive change across multiple immune assays from one morning to the next relative to their less hostile counterparts, and women showed greater immune dysregulation than men (Kiecolt-Glaser et al., 1993). Furthermore, when these couples were followed up two years later, spouses in distressed marriages had larger declines on immune assays than those in happy marriages (Jaremka, Glaser, Malarkey, & Kiecolt-Glaser, 2013). In summary, despite the fact that these were very happy newlyweds, hostile behaviors during marital conflict produced persistent alterations in endocrine and immune function (Kiecolt-Glaser et al., 1993; Kiecolt-Glaser et al., 1996; Malarkey et al., 1994). Women showed greater endocrine and immune change than men during and after marital conflict. These patterns were especially notable because of couples’ high levels of marital satisfaction, and the newlyweds’ pristine physical and mental health.
 * The newlywed study illustrated key pathways through which marital behavior could alter the immune response, and, ultimately, health; nevertheless, the findings could have underestimated a troubled marriage’s real cost, because these healthy young newlyweds would be at low risk for any actual health consequences. Additionally, marital conflict occurs less frequently and is less intense in very early marriage (Storaasli & Markman, 1990), and thus could have muted endocrine and immune responses. Alternatively, the relative novelty of such conflicts for these newlyweds might have provoked larger responses; in this scenario, older couples’ responses to conflict might be muted, because of their greater familiarity with such disagreements in their long-term marriages (Birditt, Brown, Orbuch, & McIlvane, 2010). Accordingly, endocrine and immune responses to marital problem discussions were assessed in older couples (mean age = 67) who had been together for 42 years, on average (Kiecolt-Glaser et al., 1997). Among women, intensification of hostile conflict behaviors and lower marital satisfaction accounted for 16% to 21% of the variance in the increased cortisol, ACTH, and norepinephrine during the conflict discussion. However, men’s changes in these hormones were not associated with hostile behavior or marital satisfaction. Both men and women who had poorer immune responses across several immune markers were more hostile during the problem-solving task; in addition, they described their typical marital arguments as more hostile than those who had better immune response data. This study illustrated how hostile marital discussions can alter immune and endocrine function even among older couples in longer-term relationships, consistent with the evidence that stressors can continue to raise stress hormones even after repeated exposures (Miller et al., 2007). What is more, the risks can be substantially heightened by the age-related increases in inflammation discussed below.
 * Much remains to be learned. For example, the absence of immune data from same-sex couples reflects the broader hetero-normative perspective throughout the relationship literature, an important limitation. However, the fact that same-sex couples have greater health behavior concordance than different-sex couples (Holway, Umberson, & Donnelly, 2017) leads to interesting questions about same-sex couples’ similarities in gene expression, immune profiles, and gut microbiota. Greater health behavior concordance might also reflect greater risk when one partner is stressed or depressed. As is true for same-sex couples, the literature addressing both marriage and immune function is largely silent with regard to socioeconomic (SES) differences. Certainly, the link between low SES and poorer health is well-documented, and dovetails with the evidence that the chronic stress of low SES degrades marital quality (Neff & Karney, 2017). For example, the health of low SES people suffered more from marital conflict and benefited less from marital bliss than those of higher SES (Choi & Marks, 2013). Thus SES could interact with marital quality to affect health in multiple ways.
 * Partners influence each other’s mood and health behaviors, producing both direct and indirect downstream effects on the immune system, and these changes can create longer-term risks and benefits, resonating through autonomic, endocrine, gut microbiome, and immune system pathways. The potential long-term persistence of these changes suggests there may be new layers of meaning in the phrase “Till death do us part.”

“Immune systems of healthy adults 'remember' germs to which they’ve never been exposed, Stanford study finds” (Feb. 7, 2013)
Bruce Goldman, “Immune systems of healthy adults 'remember' germs to which they’ve never been exposed, Stanford study finds”, Stanford Medicine, (Feb. 7, 2013)
 * In a path-breaking study published online Feb. 7 in Immunity, the investigators found that over the course of our lives, CD4 cells — key players circulating in blood and lymph whose ability to kick-start the immune response to viral, bacterial, protozoan and fungal pathogens can spell the difference between life and death — somehow acquire memory of microbes that have never entered our bodies. Several implications flow from this discovery, said the study’s senior author, Mark Davis, PhD, professor of microbiology and immunology and director of Stanford’s Institute for Immunity, Transplantation and Infection. In the study, newborns’ blood showed no signs of this enhanced memory, which could explain why young children are so much more vulnerable to infectious diseases than adults. Moreover, the findings suggest a possible reason why vaccination against a single pathogen, measles, appears to have reduced overall mortality among African children more than can be attributed to the drop in measles deaths alone. And researchers may have to rethink the relevance of experiments conducted in squeaky-clean facilities on mice that have never been exposed to a single germ in their lives. “It may even provide an evolutionary clue about why kids eat dirt,” said Davis. “The pre-existing immune memory of dangerous pathogens our immune systems have never seen before might stem from our constant exposure to ubiquitous, mostly harmless micro-organisms in soil and food and on our skin, our doorknobs, our telephones and our iPod earbuds.”
 * A sophisticated technique invented by Davis in 1996 and since refined in his and others’ laboratories permitted the Stanford team to identify a single CD4 cell targeting a particular epitope out of millions. Using this method, his team exposed immune-cell-rich blood drawn from 26 healthy adults, as well as from two newborns’ umbilical cords, to various epitopes from different viral strains. They were able to fish out, from among hundreds of millions of CD4 cells per sample, those responsive to each viral epitope. Nearly all of the 26 adult blood samples contained cells responsive to HIV; to HSV, the virus that causes herpes; and to cytomegalovirus, a common infectious agent that often produces no symptoms but can be dangerous to immune-compromised people. This wasn’t surprising, given humans’ exhaustive inventories of divergent CD4-cell affinities. What was surprising was that, on average, about half of the virus-responsive CD4 cells in each adult sample bore unmistakable signs of being in the “memory” state: a characteristic cell-surface marker, gene activation patterns typical of memory T cells, and rapid secretion of signature biochemical signals, called cytokines, that communicate with other immune cells — even though highly sensitive clinical tests showed that these individuals had never been exposed to any of these viruses in real life. The newborns’ blood contained similar frequencies of CD4 cells responsive to the same three viruses. However, all these cells were in the “naïve” rather than memory state. “This could explain, at least in part, why infants are so incredibly susceptible to disease,” said the study’s first author, Laura Su, MD, PhD, an instructor in immunology and rheumatology.
 * Another surprise: About one-fifth of the adult samples boasted “cross-reactive” memory CD4 cells responsive to other harmless environmental microbes. For example, CD4 cells selected specifically for their reactivity to HIV turned out to be able to recognize a large number of common environmental microbes, including three gut-colonizing bacteria, a soil-dwelling bacterial species and a species of ocean algae. Considering that the investigators tested only a negligible fraction of all the microbes a person might encounter, it’s a sure bet that this measure of CD4-cell cross-reactivity was an underestimate. Next, the researchers recruited two adults who hadn’t been vaccinated for flu in five years or longer, and then vaccinated them. In these volunteers, memory CD4s proliferated and otherwise became activated in response to exposure to certain components of the influenza virus, but also to epitopes of several different bacterial and protozoan microbes. This cross-reactivity could explain why exposure to common bugs in the dirt and in our homes renders us less susceptible to dangerous infectious agents. Which raises another point. “We grow and use experimental lab mice in totally artificial, ultra-clean environments,” Davis said. “That’s nothing like the environment that we live in. The CD4 cells from adult mice in the lab environment are almost entirely in the naïve state. They may be more representative of newborns than of adults.”

“Effect of exercise, heat stress, and hydration on immune cell number and function” (December 2002)
Joel B. Mitchell, Jonathan P Dugas, Brian K. McFarlin, and Matthew J. Nelson; “Effect of exercise, heat stress, and hydration on immune cell number and function”, Medicine & Science in Sports & Exercise, (December 2002), 34(12):
 * It is well documented that the immune system is affected by a variety of physiological and psychological stressors. Physical activity has been shown to cause disturbances in circulating white blood cell number and function that appear to be dependent on the intensity and duration of the exercise, and the associated release of stress hormones. Heat exposure is a form of physical stress in which elevations in body core temperature occur with concomitant alterations in hormonal responses and immune system function. Exercise in a thermally stressful environment represents a combination of physical stimuli that appears to have an additive effect on the hormonal and immune system disturbances. The difficulty that researchers have encountered in this area is separating the independent effects of heat exposure and exercise, as many of the immune system changes elicited by these stimuli are similar.
 * p.1941


 * To our knowledge, the interaction between exercise in a hot environment and hydration status on immune function has not been systematically studied. This question is of practical importance because the detrimental effects of severe exercise in a thermally stressful environment may be partially avoided with knowledge of the individual effects of heat and hydration on immune function. The purpose of this investigation was to determine the effects of exercise in a hot environment, in combination with exercise-induced dehydration, on circulating immune cell responses and immune cell function. Specifically, leukocyte and leukocyte subset numbers, lymphocyte proliferation, natural killer cell activity (NKCA), and O2 production by neutrophils were determined before and during recovery from 75 min of exercise in hot (38°C) and neutral (22°C) environments in both dehydrated and euhydrated conditions. It was hypothesized that the greatest disturbance in immune function would occur in the hot environment in combination with dehydration and that the other conditions would produce graded responses with the neutral environment in combination with euhydration eliciting the least disturbance.
 * p.1942


 * The primary findings of this investigation were that the fluid and environmental manipulations produced the expected differences between conditions in the body fluid balance, temperature, and cardiovascular responses; however, environment as an independent factor produced more pronounced differences in these variables than fluid manipulations. Further, there were metabolic and hormonal differences elicited by the experimental manipulations that were in proportion to the relative degree of stress imposed primarily by the differences in environment. The elevations in cell number after exercise were greatest in the hot environment for both levels of hydration; thus, hydration status did not influence the distribution of leukocytes, lymphocytes, or lymphocyte subsets. Elevations in cell function following exercise were also influenced primarily by the exposure to a hot environment with the only dehydration-induced effect being a postexercise elevation in superoxide production by neutrophils in the DH condition. The addition of a resting control condition in the hot environment would have helped in making more definitive conclusions regarding the separate effects of exercise and the hot environment.
 * p.1945


 * The current findings suggest that the combination of physical stressors stimulated the mobilization of all lymphocyte subsets to a greater extent than exercise alone. The additive effects of heat and exercise on circulating lymphocytes was also observed by Rhind et al., and others who found that exertional hyperthermia affects cell distribution via the combination of exercise and thermally induced activation of the sympathetic nervous system and the elevation of hormones associated with a generalized stress response. The significant elevation of cortisol in the EH and DH conditions would support this conclusion. Again, there was no fluid interaction; thus, the hot environment appears to be the primary mediator of the additive response with exercise. At 2 h postexercise, there was a significant depression in lymphocyte number that occurred in all conditions. This was driven primarily by the decreases in CD3 cells. Although this has been reported previously (12,22), it is somewhat unexpected in the EN and DN conditions because no exercise-induced elevation was observed and it could be assumed that an exercise and/or stress-induced elevation is a prerequisite to the subsequent depression. This finding suggests that exercise-induced depressions are not always tied to a preceding exercise-induced lymphocytosis.
 * p.1948

“Current Directions in Stress and Human Immune Function” (October, 2015)
Jennifer N. Morey, Ian A. Boggero, April B. Scott, and Suzanne C. Segerstrom, “Current Directions in Stress and Human Immune Function”, Curr Opin Psychol. 2015 October 1; 5
 * Stress is a broad concept that comprises challenging or difficult circumstances (stressors) or the physiological or psychological response to such circumstances (stress responses). In humans, among other species, one of the systems that responds to challenging circumstances is the immune system. Broadly, the immune system comprises cells, proteins, organs, and tissues that work together to provide protection against bodily disease and damage (see Box for explanations of relevant immunological parameters). Several facets of the human immune system have been empirically associated with stress. During acute stress lasting a matter of minutes, certain kinds of cells are mobilized into the bloodstream, potentially preparing the body for injury or infection during “fight or flight. Acute stress also increases blood levels of pro-inflammatory cytokines. Chronic stress lasting from days to years, like acute stress, is associated with higher levels of pro-inflammatory cytokines, but with potentially different health consequences. Inflammation is a necessary short-term response for eliminating pathogens and initiating healing, but chronic, systemic inflammation represents dysregulation of the immune system and increases risk for chronic diseases, including atherosclerosis and frailty. Another consequence of chronic stress is activation of latent viruses. Latent virus activation can reflect the loss of immunological control over the virus, and frequent activation can cause wear-and-tear on the immune system. Interestingly, these responses may not be the same for everyone. Those who have experienced early adversity, for example, may be more likely to exhibit exaggerated immune reactions to stress. Currently, the field is moving toward a greater understanding of who might be most at risk for chronic inflammation and other forms of immunological dysregulation, and why. This question is important not only for health, but also for longevity, as evidence suggests that the immunological effects of chronic stress can advance cellular aging and shorten telomere length. Meta-analyses provide a look backward at this research and summarize what has been learned about the relationship between stress and human immunity since it was first studied in the 1960s.
 * pp.13-14


 * As people age, they are less able to mount appropriate immune responses to stressors. These could be physical stressors, such as injury, or psychological stressors such as caregiving. In addition, psychological stress affects organisms in a manner similar to the effects of chronological age, and chronological aging coupled with chronic stress accelerates immunological aging. Research has suggested that older adults are unable to terminate cortisol production in response to stress. Cortisol is ordinarily anti-inflammatory and contains the immune response, but chronic elevations can lead to the immune system becoming “resistant,” an accumulation of stress hormones, and increased production of inflammatory cytokines that further compromise the immune response. Older adults often have to provide long term care for an ailing spouse or partner. Caregiving has been implicated in significantly lower antibody and cell-mediated immune responses after vaccination. Caregivers also experience longer wound healing times, lower lymphocyte proliferation, increased proinflammatory cytokine levels, and more reactivation of latent viruses.
 * pp.14-15


 * The linkages between stress and immunity may be mediated by specific health behaviors, psychosocial factors, or both. For instance, stress has been linked to being in troubled relationships, having negative or competitive social interactions, and feeling lonely, which have each in turn been linked to increases in pro-inflammatory responses to stress. Other potential mediators, like getting good sleep, are increasingly being recognized as important pieces of the stress-immunity puzzle. Even one night of total sleep deprivation was recently found to significantly increase neutrophil counts and decrease neutrophil function in healthy men.
 * pp.15-16


 * Research on the immunological effects of stress has burgeoned over the past decade following Segerstrom and Miller's meta-analysis [1]. This research has explored new avenues, including the areas reviewed here, that show particular promise for illuminating the conditions under which stress impacts the immune system. Research on stressors occurring early (i.e., childhood and adolescence) and late (i.e., aging) in the lifespan have suggested that individuals exposed to chronic stressors (e.g., abuse, caregiving) can exhibit immune dysregulation that may be persistent and severe. Stressor qualities (e.g., type, timing) as well as individual characteristics that make individuals more or less susceptible to these effects are targets for future work. Examinations of mediators and mechanisms of the stress-immune relation can also determine how and for whom exposure to stress impacts the immune response. Ecological immunology suggests that downregulating the immune response may sometimes be adaptive, and future work building from this perspective will help to further elucidate contexts in which immunosuppression may occur but progress toward superordinate goals is facilitated. Finally, research into the effects of stress on inflammation in clinical populations has demonstrated that stress exposure can increase the likelihood of developing disease, as well as exacerbating preexisting conditions. Further work in this area may help to treat or even prevent morbidity. Overall, this area of research is broad, rapidly developing, and holds promise for improving human health.
 * p.17

“Is Staying Home Harming Your Child’s Immune System?“ (Sept. 10, 2020)
Melinda Wenner Moyer, “Is Staying Home Harming Your Child’s Immune System?“, The New York Times, (Sept. 10, 2020)
 * First, some reassuring news: Some kids’ immune systems will benefit from having more time at home this year. Consider respiratory syncytial virus, or R.S.V., a common respiratory virus that kids typically catch before the age of 2 (often at day care). R.S.V. can be very serious, leading to some 57,000 hospitalizations in American babies and toddlers each year. R.S.V. is also believed, in rare cases, to trigger asthma, a disease sparked in part by an overactive immune response — and “the younger you are when you have R.S.V., the higher the risk,” said Tobias Kollmann, M.D., Ph.D., a pediatric infectious disease physician at the Telethon Kids Institute in Perth, Australia. So if babies who otherwise would have caught R.S.V. this year do not, that’s a win; when they eventually catch it later on (nearly all kids do), the potential risks will be lower. Yet the opposite can be said about other infections. Cytomegalovirus (C.M.V.) and Epstein-Barr virus (E.B.V.), two common infections caused by herpes viruses, incite few serious symptoms in toddlers and young kids. But when older kids catch them, they can cause infectious mononucleosis, a debilitating illness that can last for months. In rare cases, too, kids with mono have more serious complications; their spleens can rupture, which can be fatal.
 * Infections, though, aren’t the only things to consider. When kids are around other kids, they share microbes that don’t necessarily make anyone sick, but could be good for developing immunity because they seed a more hearty ecosystem of microbes in the body, or microbiome. In a 2015 study, researchers studied African baboons who had similar behaviors and diets and overlapping environments but who differed in one key way: One group engaged in social grooming — touching and picking things off each other — while the other did not. They found that the baboons that groomed each other had more similar microbiomes to one another, suggesting that social contact leads to meaningful microbial exchanges. Researchers theorized in another 2015 paper that when people isolate from one another and spend their time mostly inside, it may reduce “our exposure to richer microbiomes from other sources, thereby limiting the development of our immune system.”
 * “You need that microbial exposure to really develop your immune system fully,” said B. Brett Finlay, Ph.D., a microbiologist at the University of British Columbia and co-author of “Let Them Eat Dirt: Saving Your Child from an Oversanitized World.” “Our immune systems are built to be exposed to things early in life so we can then be ready for the rest of our life,” he added. Does this mean that if your kids stay home all year, their immune systems will be doomed? No. Because when it comes to how the immune system develops, “there’s so many things to consider,” said Ruchi Singla, M.D., a pediatric allergist and immunologist at the University of Chicago Medicine. “Just as the immune system is so complex, all of the things that affect it are so complex.” Immunity is largely shaped by genetics, for instance, which means that what your children do or don’t do this year will only shape certain aspects of their immunity.
 * [W]hen researchers try to tease out how specific behaviors and choices shape immune responses, they don’t always get clear-cut answers. Dozens of studies have tried to understand the health effects of attending day care by comparing kids who go to day care with those who stay home, hoping to identify differences in rates of allergies, asthma and other immune-related conditions. Yet the studies largely conflict — if one study comes to one conclusion, another one often contradicts it. Given that immunity is shaped by so many factors, Dr. Permar said, if isolating our kids for a year or two has any effect, “it will probably be subtle.”

“The compelling link between physical activity and the body's defense system” (May 2019)
David C. Nieman and Laurel M. Went; “The compelling link between physical activity and the body's defense system”, J Sport Health Sci. 2019 May; 8(3): 201–217.
 * This review summarizes research discoveries within 4 areas of exercise immunology that have received the most attention from investigators: (1) acute and chronic effects of exercise on the immune system, (2) clinical benefits of the exercise–immune relationship, (3) nutritional influences on the immune response to exercise, and (4) the effect of exercise on immunosenescence. These scientific discoveries can be organized into distinctive time periods: 1900–1979, which focused on exercise-induced changes in basic immune cell counts and function; 1980–1989, during which seminal papers were published with evidence that heavy exertion was associated with transient immune dysfunction, elevated inflammatory biomarkers, and increased risk of upper respiratory tract infections; 1990–2009, when additional focus areas were added to the field of exercise immunology including the interactive effect of nutrition, effects on the aging immune system, and inflammatory cytokines; and 2010 to the present, when technological advances in mass spectrometry allowed system biology approaches (i.e., metabolomics, proteomics, lipidomics, and microbiome characterization) to be applied to exercise immunology studies. The future of exercise immunology will take advantage of these technologies to provide new insights on the interactions between exercise, nutrition, and immune function, with application down to the personalized level. Additionally, these methodologies will improve mechanistic understanding of how exercise-induced immune perturbations reduce the risk of common chronic diseases.
 * Although exercise immunology is considered a relatively new area of scientific endeavor with 90% of papers published after 1990, some of the earliest studies were published well over a century ago. For example, in 1902, Larrabee provided evidence that changes in white blood cell differential counts in Boston marathon runners paralleled those seen in certain diseased conditions. He also observed that “the exertion had gone far beyond physiological limits and our results certainly show that where this is the case we may get a considerable leukocytosis of the inflammatory type.” The immune system is very responsive to exercise, with the extent and duration reflecting the degree of physiological stress imposed by the workload.
 * The earliest exercise immunology studies (1900–1979) focused on exercise-induced changes in basic immune cell counts and function. The human immunodeficiency virus was identified as the cause of the AIDS in 1984. One of the markers for AIDS diagnosis was the CD4 antigen on helper T cells that required a flow cytometer for detection. Many medical universities acquired flow cytometers in the 1980s, and these instruments became available to exercise investigators, initiating the modern era of exercise immunology research. Another impetus was the publication of a brief review in a special issue of the Journal of the American Medical Association for the 1984 Olympic Games in Los Angeles. This review concluded there was “no clear experimental or clinical evidence that exercise will alter the frequency or severity of human infections… Further studies will be needed before it can be concluded that exercise affects the host response to infection in any clinically meaningful way.” This conclusion was consistent with the existing evidence at that time and at the same time provided a framework for future investigations. During the same time period (1980–1989), seminal papers were published with evidence that heavy exertion was associated with transient immune dysfunction, elevated inflammatory biomarkers, and an increased risk of upper respiratory tract infections (URTIs). For example, acute bouts of intense and prolonged exercise were linked by several early exercise immunology pioneer investigators to suppressed salivary immunoglobulin A (IgA) output, decreased natural killer cell (NK) lytic activity, reduced T- and B-cell function, and a 2- to 6-fold increased URTI risk during the 1–2 week postrace time period. In 1989, the International Society of Exercise Immunology was founded, leading to biannual conferences and the highly successful Exercise Immunology Review journal.
 * In general, acute exercise is now viewed as an important immune system adjuvant to stimulate the ongoing exchange of leukocytes between the circulation and tissues. An ancillary benefit is that acute exercise may serve as a simple strategy to enrich the blood compartment of highly cytotoxic T-cell and NK cell subsets that can be harvested for clinical use. Metabolically, moderate exercise induces small, acute elevations in IL-6 that exert direct anti-inflammatory effects, improving glucose and lipid metabolism over time. Another benefit may include an enhanced antibody-specific response when vaccinations are preceded by an acute exercise bout, but more research is needed with better study designs to control for potential confounding influences. The measurement of immune responses to prolonged and intensive exercise by athletes continues to receive high attention. Taken together, the best evidence supports that high exercise training workloads, competition events, and the associated physiological, metabolic, and psychological stress are linked to immune dysfunction, inflammation, oxidative stress, and muscle damage. NK cell and neutrophil function, various measures of T- and B-cell function, salivary IgA output, skin delayed-type hypersensitivity response, major histocompatibility complex II expression in macrophages, and other biomarkers of immune function are altered for several hours to days during recovery from prolonged and intensive endurance exercise. The contrast in the magnitude of immune responses between a 30- to 45-min walking bout and 42.2-km marathon race is summarized in These immune changes occur in several compartments of the immune system and body including the skin, upper respiratory tract mucosal tissue, lung, blood, muscle, and peritoneal cavity. Although some investigators have challenged the clinical significance and linkage between heavy exertion and transient immune dysfunction, the majority of investigators in the field of exercise immunology have supported the viewpoint that the immune system reflects the magnitude of physiological stress experienced by the exerciser.
 * Although more research is needed, preliminary data support that immune cell metabolic capacity is decreased during recovery from physiologically demanding bouts of intensive exercise, resulting in transient immune dysfunction. Immunonutrition support, especially increased intake of carbohydrate and polyphenols, has been shown to counter these exercise-induced decrements in immune cell metabolic capacity.
 * The potential linkage between prolonged, intensive exercise and increased risk for illness has been an active area of research since the 1980s. Early epidemiologic studies indicated that athletes engaging in marathon and ultramarathon race events and/or very heavy training were at increased risk of URTI. For example, in a large group of 2311 endurance runners, nearly 13.0% reported illness during the week after the Los Angeles Marathon race compared with 2.2% of control runners (odds ratio (OR) = 5.9; 95% confidence interval (CI): 1.9–18.8). Forty percent of the runners reported at least 1 illness episode during the 2-month winter period before the marathon race, and those running more than 96 km/week vs. less than 32 km/week doubled their odds for illness. A 1-year retrospective study of 852 German athletes showed that URTI risk was highest in endurance athletes who also reported significant stress and sleep deprivation. These seminal studies indicated that illness risk may be increased when an athlete participates in competitive events, goes through repeated cycles of unusually heavy exertion, or experiences other stressors to the immune system including lack of sleep and mental stress. The direct connection between exercise-induced immune changes and infection risk has not yet been established, and will require long-term studies with large cohorts. More research is needed to more clearly demonstrate the linkage between heavy exertion, illness symptoms, and pathogen-based illnesses, and the relative importance of associated factors such as travel, pathogen exposure, exercise-induced immune perturbations, sleep disruption, mental stress, and nutrition support.
 * As illness data from additional studies mounted, several athletic organizations including the International Olympic Committee (IOC) and the International Association of Athletics Federation (IAAF) initiated acute illness surveillance systems to delineate the extent of the problem and underlying risk factors. The stated goal was to improve illness prevention and treatment procedures. The IOC has also focused on the inappropriate management of both internal (e.g., psychological responses) and external loads (e.g., training and competition workloads). Load management is a key strategy, according to the IOC, to decrease illness incidence and associated downturns in exercise performance, interruptions in training, missed competitive events, and risk of serious medical complications. The wealth of acute illness epidemiologic data collected during international competition events has revealed that 2%–18% of elite athletes experience illness episodes, with higher proportions for females and those engaging in endurance events. At least one-half of the acute illness bouts involve the respiratory tract, with other affected systems including the digestive tract, skin tissues, and the genitourinary tract. Significant illness risk factors include female gender, high levels of depression or anxiety, engaging in unusually intensive training periods with large fluctuations, international travel across several time zones, participation in competitive events especially during the winter, lack of sleep, and low diet energy intake. The decrease in exercise performance after an URTI can last 2–4 days, and runners who unwisely start an endurance race with systemic URTI symptoms are 2–3 times less likely to complete the race. Paralympic athletes have unique preexisting medical conditions that predispose them to an increased risk of illness, and the incidence rate of illness is high in the Summer (10.0–13.2 episodes per 1000 athlete-days) and Winter (18.7 episodes per 1000 athlete-days) Paralympic Games.
 * Athletes must train hard for competition and are interested in strategies to keep their immune systems robust and illness rates low despite the physiologic stress experienced. The ultimate objective is to achieve performance goals with little interruption from illness and fatigue from training-induced subclinical immune dysfunction. Several training, hygienic, nutritional, and psychological strategies are recommended, and these require the coordinated involvement of the medical staff, coaches, and athletes. The medical staff should develop and implement an illness prevention program, with a focus on full preventative precautions for high-risk individuals such as female endurance athletes. Adjustments to the guidelines can be applied based on how each individual athlete responds. Here is a summary of the most important guidelines provided from consensus statements:
 * Exercise training has immunomodulating effects that may alter the cross-talk between the immune system and tumorigenesis. For example, exercise may increase intra-tumoral cytotoxic T-cell infiltration and reduce regulatory T-cell infiltration, enhance the recirculation and function of tumor-specific NK cells, and decrease inflammatory influences that support cancer cell growth.
 * The immune system is very responsive to exercise, with the extent and duration reflecting the degree of physiological stress imposed by the workload. Key exercise immunology discoveries since 1980 include the following.
 * Acute exercise (moderate-to-vigorous intensity, less than 60 min) is now viewed as an important immune system adjuvant to stimulate the ongoing exchange of distinct and highly active immune cell subtypes between the circulation and tissues. In particular, each exercise bout improves the antipathogen activity of tissue macrophages in parallel with an enhanced recirculation of immunoglobulins, anti-inflammatory cytokines, neutrophils, NK cells, cytotoxic T cells, and immature B cells. With near daily exercise, these acute changes operate through a summation effect to enhance immune defense activity and metabolic health.
 * In contrast, high exercise training workloads, competition events, and the associated physiological, metabolic, and psychological stress are linked with transient immune perturbations, inflammation, oxidative stress, muscle damage, and increased illness risk. Metabolomics, proteomics, and lipidomics have revealed that metabolism and immunity are inextricably interwoven, providing new insights on how intense and prolonged exercise can cause transient immune dysfunction by decreasing immune cell metabolic capacity.
 * Illness risk may be increased when an athlete competes, goes through repeated cycles of unusually heavy exertion, and experiences other stressors to the immune system. The wealth of acute illness epidemiologic data collected during international competition events has revealed that 2%–18% of elite athletes experience illness episodes, with higher proportions for females and those engaging in endurance events. Other illness risk factors include high levels of depression or anxiety, participation in unusually intensive training periods with large fluctuations, international travel across several time zones, participation in competitive events especially during the winter, lack of sleep, and low diet energy intake.
 * The IOC has also focused on load management of both internal (e.g., psychological responses) and external factors (e.g., training and competition workloads), and lifestyle strategies (e.g., hygiene, nutritional support, vaccination, regular sleep) to reduce illness incidence and associated downturns in exercise performance, interruptions in training, missed competitive events, and risk of serious medical complications.
 * Randomized clinical trials and epidemiologic studies consistently support the inverse relationship between moderate exercise training and incidence of URTI. These data led to the development of the J-curve model that links URTI risk with the exercise workload continuum. Several epidemiologic studies also suggest that regular physical activity is associated with decreased mortality and incidence rates for influenza and pneumonia.
 * Regular exercise training has an overall anti-inflammatory influence mediated through multiple pathways. Epidemiologic studies consistently show decreased levels of inflammatory biomarkers in adults with higher levels of physical activity and fitness, even after adjustment for potential confounders such as BMI.
 * There is increasing evidence that the circulation surge in cells of the innate immune system with each exercise bout and the anti-inflammatory and antioxidant effect of exercise training have a summation effect over time in modulating tumorigenesis, atherosclerosis, and other disease processes.
 * Recent studies indicate that exercise and physical fitness diversifies the gut microbiota, but more human research is needed to determine potential linkages to immune function in physically fit individuals and athletes.
 * The most effective nutritional strategies for athletes, especially when evaluated from a multiomics perspective, include increased intake of carbohydrates and polyphenols. A consistent finding is that carbohydrate intake during prolonged and intense exercise, whether from 6%–8% beverages or sugar-dense fruits such as bananas is associated with reduced stress hormones, diminished blood levels of neutrophils and monocytes, and dampened inflammation. Gut-derived phenolics circulate throughout the body after increased polyphenol intake, exerting a variety of bioactive effects that are important to athletes including anti-inflammatory, antiviral, antioxidative, and immune cell signaling effects.
 * Immunosenescence is defined as immune dysregulation with aging. Emergent data support that habitual exercise is capable of improving regulation of the immune system and delaying the onset of immunosenescence.

“The Immune-Suppressive Effects of Pain”
Gayle G. Page, “The Immune-Suppressive Effects of Pain”
 * The immune-suppressive effects of painful experiences have been studied in both humans and animals for many years. Experimental pain has been induced by such means as electric shock and surgery in animals, and humans undergoing surgery have been studied extensively. In general, results have shown such perturbations to suppress the immune functions that are assessed. The exclusive contribution of the pain per se to these findings has only recently become a focus of study. If pain mechanisms were shown to mediate the observed immunosuppressive effects of experiences such as recovery from injury or undergoing surgery, then adequate pain management would become a vital adjunct to the overall care of such individuals. The importance of such an avenue of study relates to the crucial role played by the immune system in maintaining health and resisting infection and disease. In the latter case, animal studies provide direct evidence that natural killer (NK) cells play a key role in controlling metastatic processes as well as support for the hypothesis that the suppressed NK cell activity following surgery underlies surgery-induced metastatic promotion. Findings of human studies are corroborative; low NK activity during the perioperative period is associated with higher rates of cancer recurrence and mortality in patients with breast, head and neck, lung, and colorectal cancers.
 * Aversive stressors such as footshock and tail shock have been used as means by which to provoke pain without tissue damage in rats. Intermittent inescapable footshock delivered over some minutes has been shown to suppress several immune functions, including NK cell activity, peripheral blood mononuclear or spleen cell proliferative responses to mitogens including phytohemagglutinin and Concavalin A. Similarly, intermittent tail shock has been shown to suppress mixed lymphocyte reactions in lymph node cells and reduce in vivo responses to a novel antigen assessed as immunoglobulin (Ig) G antibody levels. An important consideration in these studies is the psychological stress that likely occurs in animals subjected to some period of repeated, uncontrollable, aversive stimuli; thus, the observed immune suppression may be attributed to mechanisms other than pain per se. Experimental surgery has been shown to suppress immune functions and to promote tumor development in rats and mice. Rats recovering from laparotomy exhibit decreases in both lymphocyte and splenocyte proliferative responses to mitogens and in NK cell activity; more invasive surgery is associated with greater decrements in immune function. Similarly, undergoing surgery promotes tumor development, and the magnitude of tumor promotion is associated with the invasiveness of surgery.
 * In humans, surgery is well known to result in immune suppression, including lymphocyte proliferative responses to mitogens and NK cell activity, decreased cell-mediated immunity, and alterations in the balance of Th1 versus Th2 cells, compromising cellular immunity. The invasiveness of the surgery has been associated with the magnitude of immune suppression, and immune function is comparatively more suppressed by surgery in individuals with cancer, although this finding is not a consistent one. If pain is a mediator of such surgery-induced immune suppression, then it would seem that anesthesia and analgesia techniques that reduce perioperative pain would also impact the observed postoperative immune suppression. Indeed, several studies comparing general inhalational anesthesia versus epidural or spinal anesthesia for surgical procedures that are below the waist have shown that immune outcomes were significantly better preserved in groups treated with epidural anesthesia, including NK cell activity following laparotomyand hysterectomy; however, this benefit was not observed in patients undergoing total hip replacement. Given the importance of immune function in resisting infection, that epidural anesthesia was also shown to result in fewer infectious complications compared to standard inhalational anesthesia supports the above-mentioned suggestion. Interleukin (IL)-6, a cytokine produced by a host of immune cells including monocytes, macrophages and lymphocytes, is involved in a broad array of actions including inflammation and the regulation of endocrine and metabolic functions, notably the hypothalamic-pituitary-adrenal axis and catecholamines. Undergoing surgery results in increased IL-6 levels in plasma as well as cerebrospinal fluid. Several direct comparisons have shown that more invasive surgeries are associated with greater levels of plasma IL-6, including laparoscope-assisted vaginal versus abdominal hysterectomy, and cholecystectomy using a laparoscope versus an open abdominal approach. Kristiansson et al. also showed the laparoscopic approach resulted in reduced pain scores. Given that prostaglandins promote inflammatory changes and hyperalgesia, and that prostaglandins have been associated with NK suppression, interventions that reduce inflammation would be expected to both reduce pain and its immunosuppressive effects. In animals, prostaglandin E2 antagonism via cyclooxygenase inhibition or a monoclonal antibody reduced paw swelling, and both paw and serum IL-6 levels resulting from adjuvant arthritis or carrageenan injection, and significantly reduced thermal hyperalgesia. In humans undergoing cholecystectomy, perioperative ibuprofen administration resulted in significantly lower levels of plasma IL-6 levels compared to placebo controls.
 * Fig. 1 offers selected possible interactions among nociceptive processes, local metabolic processes, neuroendocrine activation and immunity that are altered as a result of the cutting, tearing, and manipulation of tissues in the conduct of surgery. With particular relevance to the studies to be discussed are hypothalamic activation by ascending nociceptive (painful) impulses, and the resulting increases in sympathetic nervous system activity with epinephrine release and corticosteroid release from the adrenals, both of which have been shown to suppress NK cytotoxic activity. The release of local factors from the injury site further facilitate central pain processing by sensitizing peripheral fibers, thereby reducing the threshold for nociceptive impulse transmission and the self-perpetuating hyperresponsiveness to mechanical and thermal stimuli at the surgical site. Taken together, both central and peripheral changes contribute to the suppression of NK cytotoxicity that is observed postoperatively. To attribute some measure of biologic significance to NK suppression, we have used an NK-sensitive mammary adenocarcinoma cell line, MADB106, syngeneic to the inbred Fischer 344 rats. MADB106 tumor cells seed and colonize only in the lungs following intravenous injection, and the NK sensitivity of these processes has been shown to be limited to the first 24 hours after injection in a time-dependent and decremental manner. Thus, both the colonization of MADB106 cells in the lungs assessed at 3 weeks after tumor injection and the lung retention of radiolabeled MADB106 cells assessed at 18-24 hours after tumor injection provide an indication of host susceptibility to metastasis as well as in vivo levels of NK activity throughout the early hours following tumor injection. The overall goal of our work is to investigate possible mediation of specific pain mechanisms in surgery-induced decreases in NK activity and host resistance against metastasis. To explore the possibility that pain per se mediates these negative consequences of surgery, pharmacologic interventions have been employed with the rationale that if the drug significantly attenuates surgery-induced reductions in both host resistance against metastasis and exploratory behavior, then pain relief might be suggested as a biologically significant and beneficial treatment.
 * We found a significant interaction between the effects of surgery and morphine such that morphine attenuated the observed surgery-induced increase in both the colonization of MADB106 cells in the lungs assessed at 3 weeks after surgery and the retention of radiolabeled MADB106 cells in the lungs at 18 hours postoperative. Surgery resulted in a more than 5-fold increase in lung tumor cell retention, and morphine treatment reduced this effect by more than 50%. Morphine administration exerted no significant effects in the “anesthesia only animals” for both tumor outcomes.
 * Taken together, the findings of these studies support the suggestion that the provision of pain relief ameliorates surgery-induced decreases in host resistance against metastasis. In particular, these studies show that a variety of morphine regimens provide protection against the tumor-enhancing effects of surgery including both pre- and postoperative administration as well as only preoperative or only postoperative treatment. The pre- and postoperative systemic administration of fentanyl confers similar benefits as morphine in this paradigm and is also beneficial in the females. The benefits conferred by the preoperative intrathecal injection of bupivacaine plus morphine as well as the postoperative systemic administration of indomethacin on the metastatic-enhancing effects of surgery further support the suggestion that pain is a mediator of this negative consequence of undergoing and recovering from surgery. That either morphine or indomethacin administration completely restored surgery-induced activity suppression to normal levels, and that fentanyl significantly improved surgery-induced activity suppression suggests that these regimens provided pain relief.
 * In conclusion, these findings show that some analgesic techniques provide significant protection against the tumor-enhancing effects of undergoing and recovering from surgery. Although it remains unknown whether the alleviation of perioperative pain will provide similar benefits in humans, the current studies suggest that it will, specifically in patients with potentially metastasizing cancer. Therefore, it is suggested that the relief of perioperative pain becomes a high priority in the care of individuals with cancer.

“Recovery of the immune system after exercise” (01, May 2017)
Jonathan M. Peake, Oliver Neubauer, Neil P. Walsh, and Richard J. Simpson; “Recovery of the immune system after exercise”, Journal of Applied Physiology, Volume 122, Issue 5, (01, May 2017) pp. 1077-1087
 * The notion that prolonged, intense exercise causes an “open window” of immunodepression during recovery after exercise is well accepted. Repeated exercise bouts or intensified training without sufficient recovery may increase the risk of illness. However, except for salivary IgA, clear and consistent markers of this immunodepression remain elusive.
 * The immune system is integral to the body's defense against infection. It also influences other physiological systems and processes, including [[w:tissue repair, [[w:metabolism, [[w:thermoregulation, [[sleep/fatigue, and mental health. Over the past 40 years, exercise immunology has developed into its own discipline based on the recognition that the immune system mediates many exercise effects and that stress responses mediated through the nervous and endocrine systems play a key role in determining exercise-induced immune changes. A classic paradigm in exercise immunology is that an “open window” of immunodepression can occur during recovery from intense exercise. In particular, this paradigm proposes that after intense exercise, some immune variables (e.g., lymphocyte and natural killer cell numbers and antibody production) transiently decrease below preexercise levels. As a result of this immunodepression, microbial agents, especially viruses, may invade the host or reactivate from a latent state, leading to infection and illness. If exercise is repeated again while the immune system is still depressed, this could lead to a greater degree of immunodepression and potentially a longer window of opportunity for infection.
 * Sleep disturbances influence immunity via activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Chronic sleep disturbance and disruption to the normal circadian rhythm are associated with inflammation and desynchronization of rhythmic immune variables. These responses likely contribute to increased risk of infection, cardiovascular disease, and cancer in shift workers. Despite evidence that athletes experience poor sleep patterns compared with nonathletes, surprisingly little is known about how sleep disturbance influences the immune responses to exercise. Compared with normal sleep, a disrupted night's sleep appears to prime the immune system and enhance immunosurveillance by stimulating total lymphocytes, CD8+ T cells, NK cells, and γδ T cells to leave the blood and migrate to potential sites of infection during the early recovery period after exercise. By contrast, other studies indicate that a night without sleep does not influence leukocyte trafficking, neutrophil degranulation, or mucosal immunity at rest or after exercise. Subtle immune changes have been observed after a night without sleep, including a shift toward a T helper 2 cytokine profile.
 * The immunomodulatory effects of carbohydrate may depend on the timing of carbohydrate intake. The ingestion of a glucose solution 15 min, but not 75 min, before 1-h high-intensity cycling prevented immunoendocrine perturbations. The lack of an effect of carbohydrates ingested 75 min preexercise was potentially associated with an insulin-induced decrease in the plasma glucose concentration before exercise, which, in turn, might have enhanced immunoendocrine responses. Carbohydrate ingestion during either the first or the second of two 90-min bouts of cycling on the same day better maintained plasma glucose and attenuated plasma stress hormone responses to the second bout. By contrast, carbohydrate ingestion during the 2-h recovery period between these exercise bouts had no such effects. These findings suggest beneficial effects of a timely carbohydrate supplementation (i.e., shortly before and/or during exercise) on immune responses to exercise. This may be particularly relevant with more prolonged and/or intense exercise protocols and when the recovery duration between two consecutive exercise bouts is short.
 * Recognizing the importance of protein for immunocompetence, there are benefits of postexercise protein ingestion or a diet high in protein on immune responses to exercise. On the basis of previous results indicating that exercise-induced lymphocyte trafficking was impaired during high-intensity training, Witard et al. examined whether a high-protein diet can restore these impaired immune responses. Consuming a high-protein diet (3 g•kg−1•day−1) helped to minimize exercise-induced changes in lymphocyte distribution during a period of intense training. Interestingly, an energy- and carbohydrate-matched normal protein diet (1.5 g•kg−1•day−1) failed to provide the same benefit. The high-protein diet was also associated with fewer self-reported upper respiratory illnesses. Another study demonstrated that protein and leucine supplementation for 1–3 h postexercise during 6 days of high-intensity training enhanced neutrophil respiratory burst activity after the last exercise session. Consuming a carbohydrate-protein solution immediately, but not 1 h, after exercise prevents a decrease in neutrophil degranulation during the postexercise recovery period.
 * Cellular immune function in response to exercise is typically assessed in isolated cells ex vivo or at the cell population level in the blood compartment. This approach can make it difficult to interpret changes in immune cell function after exercise because of the massive alterations in the cellular composition of discrete leukocyte subtypes. On the one hand, it seems intuitive to interpret lower immune cell function measured in blood during the early stages of exercise recovery as indicative of immunodepression. On the other hand, it is equally possible that after exercise, the most functional immune cells (i.e., those with effector phenotypes and high tissue-migrating potential) are redeployed to other areas of the body where they are needed. If true, this suggests that systemic immunosurveillance may be enhanced during exercise recovery, despite an apparent depressed profile in the blood compartment.
 * The validity of the original paradigm of cumulative immunodepression with repeated bouts of exercise is somewhat difficult to assess. Months of intense training increase the incidence of illness in elite athletes. However, on the basis of these studies, we can only assume, but not assert, that increased incidence of illness results from an imbalance between training and recovery. Research that has systematically manipulated the balance between training and recovery has not identified any immune variables that are consistently depressed as a result of insufficient recovery after exercise. However, with one exception, these studies have not tracked the incidence of illness after repeated bouts of exercise.
 * Pedersen et al. suggested that there is a critical threshold for exercise intensity and duration that determines the risk of immunodepression after repeated bouts of exercise. However, no studies have systematically determined the effects of repeated exercise bouts of different intensity and duration. There are also no data on the effects of repeated bouts of anaerobic or resistance/strength exercise, or a combination of different types of exercise on the same day.
 * Among various nutritional interventions that have been studied to counteract immunodepression during exercise recovery, carbohydrate supplementation has proven the most effective. A balanced and well-diversified diet that meets the energy demands in athletes and exercising individuals is certainly a key component to maintain immune function in response to strenuous exercise and intense periods of training. Additional research is warranted to investigate how the timing and pattern in the ingestion of nutrients, particularly carbohydrates and protein/amino acids, influence recovery of the immune system after exercise. Sleep disturbances can depress immunity, increase inflammation, and promote adverse health outcomes in the general population. However, the limited data available on how sleep disturbances influence immune responses to exercise are inconsistent.

“Intrinsic Photosensitivity Enhances Motility of T Lymphocytes” (20 December 2016)
Thieu X. Phan, Barbara Jaruga, Sandeep C. Pingle, Bidhan C. Bandyopadhyay & Gerard P. Ahern; “Intrinsic Photosensitivity Enhances Motility of T Lymphocytes”, Scientific Reports volume 6, (20 December 2016)
 * Sunlight has important biological effects in human skin. Ultraviolet (UV) light striking the epidermis catalyzes the synthesis of Vitamin D and triggers melanin production. Although a causative element in skin cancers, sunlight is also associated with positive health outcomes including reduced incidences of autoimmune diseases and cancers. The mechanisms, however, by which light affects immune function remain unclear. Here we describe direct photon sensing in human and mouse T lymphocytes, a cell-type highly abundant in skin. Blue light irradiation at low doses (<300 mJ cm−2) triggers synthesis of hydrogen peroxide (H2O2) in T cells revealed by the genetically encoded reporter HyPerRed. In turn, H2O2 activates a Src kinase/phospholipase C-γ1 (PLC-γ1) signaling pathway and Ca2+ mobilization. Pharmacologic inhibition or genetic disruption of Lck kinase, PLC-γ1 or the T cell receptor complex inhibits light-evoked Ca2+ transients. Notably, both light and H2O2 enhance T-cell motility in a Lck-dependent manner. Thus, T lymphocytes possess intrinsic photosensitivity and this property may enhance their motility in skin.
 * Sunlight also has a prominent effect on immune cells and immune function leading to beneficial effects on human health, including reduced incidence of autoimmune diseases and cancers. The precise mechanisms by which sunlight affects immune function are unclear. Although, enhanced synthesis of Vitamin D is one possibility, there is emerging evidence for Vitamin D-independent effects of sunlight. Notably, normal skin contains a high density of T lymphocytes (~1 × 106 cells cm−2) performing immune surveillance, and the total number of T cells resident in skin is estimated to be double of that in circulation. The effects of light on T cells, however, remain unexplored. In this study we report that T cells possess intrinsic sensitivity to blue and UV light. The detection of light is coupled to generation of H2O2 and activation of Src kinase and PLC-γ1 leading to elevated intracellular [Ca2+]. Photosensitivity is greater in activated T cells and enhances T-cell motility. Thus, T cells are a new type of photoreceptive cell and their photosensitivity may contribute to the effects of sunlight on immune function.
 * Our data show that T cells possess the intrinsic capacity to sense and respond to light. We show that blue light triggers the production of H2O2 in T cells in vitro. In turn, light-evoked H2O2 leads to activation of Src, Zap-70, PLC-γ1 and intracellular [Ca2+] and these effects are accompanied by alterations in T cell motility. Importantly, these effects of light were reproduced by exogenous H2O2 and occurred in a Lck-dependent manner. Our experiments exclude photosensitization of dyes employed in some measurements. First, activation of Src and Zap-70 measured biochemically, as well as T cell migration occurred at similar light doses that produced Ca2+ responses. Second, the spectral sensitivity of T cells with peaks at both ~350 nm (UV) and ~470 nm (blue) does not match the absorption profile for Fluo4. Rather, this spectrum is consistent with involvement of flavin/flavoproteins. Flavins are abundant in mammalian cells with concentrations approaching 50 μM measured in cardiac myocytes, albeit much of this flavin is protein bound. Flavins are readily photoreduced leading to the generation of ROS including H2O2. Accordingly, we confirmed that blue light irradiation of flavin-containing solutions, at similar doses (600 mJ cm−2) used on T cells, produced H2O2 in vitro. There is also evidence in mammalian cells for high energy UV and blue light activating flavin oxidases and generating ROS. Further, high frequency UV light (<280 nm) activates a mammalian “UV response” involving Src kinase and the c-jun and c-fos genes, and this effect is blocked by the antioxidant N-acetyl cysteine. These light-evoked ROS signals are reported to emanate from peroxisomal or mitochondrial compartments. It should be pointed out that sensitivity of T cells to light that we report here using low light (4–30 mW cm−2, 50–600 mJ cm−2) is much greater than these earlier reports employing very high irradiances and doses (1–3 W cm−2, 20–40 J cm−2). Further, light signaling in T cells persisted in the presence of flavin oxidase or mitochondrial electron transport chain inhibitors ruling out enhanced flavin enzymatic activity or mitochondrial respiration as a source of H2O2.
 * The identification of T cell photosensitivity has implications for both immunological research and immunobiology. In the experimental setting, researchers exploiting light-based approaches, optogenetics for example, should consider the intrinsic actions of light on T cells. In the biological setting sunlight, particularly in the visible range, may impact the function of skin T cells. Although it needs to be confirmed in vivo, we propose that light may enhance the motility and migration of T cells through skin. Skin T cells comprise a population of memory cells performing immune surveillance (that can be activated in the skin by antigen-presenting cells) and others cell actively recruited by inflammation. These cells may be exposed to considerable solar radiation. Bright sunlight has a peak irradiance of 120 mW cm−2 and approximately 40% of the energy is contained in the visible spectrum with a peak flux in the blue-green region (450–500 nm). Blue light can penetrate several millimeters through skin. Indeed, blue-light irradiation of mouse skin has been used to drive subcutaneous optogenetic implants. Further, our observation that T cell photosensing involves an integration of the light signal (photon counting) indicates that photosignaling can proceed even with weak light levels given sufficient time. In summary, our data show that T cells possess intrinsic sensitivity to blue light and that light operating via a H2O2 signaling pathway enhances T-cell motility.

“Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry”, (July 2004)
Suzanne C. Segerstrom and Gregory E. Miller; “Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry”, Psychol Bull. 2004 Jul; 130(4): 601–630.
 * The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stressors were associated with suppression of both cellular and humoral measures. Effects of event sequences varied according to the kind of event (trauma vs. loss). Subjective reports of stress generally did not associate with immune change. In some cases, physical vulnerability as a function of age or disease also increased vulnerability to immune change during stressors.
 * Since the dawn of time, organisms have been subject to evolutionary pressure from the environment. The ability to respond to environmental threats or stressors such as predation or natural disaster enhanced survival and therefore reproductive capacity, and physiological responses that supported such responses could be selected for. In mammals, these responses include changes that increase the delivery of oxygen and glucose to the heart and the large skeletal muscles. The result is physiological support for adaptive behaviors such as “fight or flight.” Immune responses to stressful situations may be part of these adaptive responses because, in addition to the risk inherent in the situation (e.g., a predator), fighting and fleeing carries the risk of injury and subsequent entry of infectious agents into the bloodstream or skin. Any wound in the skin is likely to contain pathogens that could multiply and cause infection (Williams & Leaper, 1998). Stress-induced changes in the immune system that could accelerate wound repair and help prevent infections from taking hold would therefore be adaptive and selected along with other physiological changes that increased evolutionary fitness. Modern humans rarely encounter many of the stimuli that commonly evoked fight-or-flight responses for their ancestors, such as predation or inclement weather without protection. However, human physiological response continues to reflect the demands of earlier environments. Threats that do not require a physical response (e.g., academic exams) may therefore have physical consequences, including changes in the immune system. Indeed, over the past 30 years, more than 300 studies have been done on stress and immunity in humans, and together they have shown that psychological challenges are capable of modifying various features of the immune response. In this article we attempt to consolidate empirical knowledge about psychological stress and the human immune system through meta-analysis. Both the construct of stress and the human immune system are complex, and both could consume book-length reviews. Our review, therefore, focuses on those aspects that are most often represented in the stress and immunity literature and therefore directly relevant to the meta-analysis.
 * There are several useful ways of dividing elements of the immune response. For the purposes of understanding the relationship of psychosocial stressors to the immune system, it is useful to distinguish between natural and specific immunity. Natural immunity is an immune response that is characteristic not only of mammals but also lower order organisms such as sponges. Cells involved in natural immunity do not provide defense against any particular pathogen; rather, they are all-purpose cells that can attack a number of different pathogens1 and do so in a relatively short time frame (minutes to hours) when challenged. The largest group of cells involved in natural immunity is the granulocytes. These cells include the neutrophil and the macrophage, phagocytic cells that, as their name implies, eat their targets. The generalized response mounted by these cells is inflammation, in which neutrophils and macrophages congregate at the site of injury or infection, release toxic substances such as oxygen radicals that damage invaders, and phagocytose both invaders and damaged tissue. Macrophages in particular also release communication molecules, or cytokines, that have broad effects on the organism, including fever and inflammation, and also promote wound healing. These proinflammatory cytokines include interleukin(IL)-1, IL-6, and tumor necrosis factor alpha (TNFα). Other granulocytes include the mast cell and the eosinophil, which are involved in parasitic defense and allergy. Another cell involved in natural immunity is the natural killer cell. Natural killer cells recognize the lack of a self-tissue molecule on the surface of cells (characteristic of many kinds of virally infected and some cancerous cells) and lyse those cells by releasing toxic substances on them. Natural killer cells are thought to be important in limiting the early phases of viral infections, before specific immunity becomes effective, and in attacking self-cells that have become malignant. Finally, complement is a family of proteins involved in natural immunity. Complement protein bound to microorganisms can up-regulate phagocytosis and inflammation. Complement can also aid in antibody-mediated immunity (discussed below as part of the specific immune response).
 * How could stress “get inside the body” to affect the immune response? First, sympathetic fibers descend from the brain into both primary (bone marrow and thymus) and secondary (spleen and lymph nodes) lymphoid tissues (Felten & Felten, 1994). These fibers can release a wide variety of substances that influence immune responses by binding to receptors on white blood cells (Ader, Cohen, & Felten, 1995; Felten & Felten, 1994; Kemeny, Solomon, Morley, & Herbert, 1992; Rabin, 1999). Though all lymphocytes have adrenergic receptors, differential density and sensitivity of adrenergic receptors on lymphocytes may affect responsiveness to stress among cell subsets. For example, natural killer cells have both high-density and high-affinity β2-adrenergic receptors, B cells have high density but lower affinity, and T cells have the lowest density (Anstead, Hunt, Carlson, & Burki, 1998; Landmann, 1992; Maisel, Fowler, Rearden, Motulsky, & Michel, 1989). Second, the hypothalamic–pituitary–adrenal axis, the sympathetic–adrenal–medullary axis, and the hypothalamic–pituitary–ovarian axis secrete the adrenal hormones epinephrine, norepinephrine, and cortisol; the pituitary hormones prolactin and growth hormone; and the brain peptides melatonin, β-endorphin, and enkephalin. These substances bind to specific receptors on white blood cells and have diverse regulatory effects on their distribution and function (Ader, Felten, & Cohen, 2001). Third, people’s efforts to manage the demands of stressful experience sometimes lead them to engage in behaviors—such as alcohol use or changes in sleeping patterns—that also could modify immune system processes (Kiecolt-Glaser & Glaser, 1988). Thus, behavior represents a potentially important pathway linking stress with the immune system.
 * Conceptualizations of the nature of the relationship between stress and the immune system have changed over time. Selye’s (1975) finding of thymic involution led to an initial model in which stress is broadly immunosuppressive. Early human studies supported this model, reporting that chronic forms of stress were accompanied by reduced natural killer cell cytotoxicity, suppressed lymphocyte proliferative responses, and blunted humoral responses to immunization (see S. Cohen, Miller, & Rabin, 2001; Herbert & Cohen, 1993;Kiecolt-Glaser, Glaser, Gravenstein, Malarkey, & Sheridan, 1996, for reviews). Diminished immune responses of this nature were assumed to be responsible for the heightened incidence of infectious and neoplastic diseases found among chronically stressed individuals (Andersen, Kiecolt-Glaser, & Glaser, 1994; S. Cohen & Williamson, 1991). Although the global immunosuppression model enjoyed long popularity and continues to be influential, the broad decreases in immune function it predicts would not have been evolutionarily adaptive in life-threatening circumstances. Dhabhar and McEwen (1997, 2001) proposed that acute fight-or-flight stressors should instead cause redistribution of immune cells into the compartments in which they can act the most quickly and efficiently against invaders. In a series of experiments with mice, they found that during acute stress, T cells selectively redistributed into the skin, where they contributed to enhancement of the immune response. In contrast, during chronic stress, T cells were shunted away from the skin, and the immune response to skin test challenge was diminished (Dhabhar & McEwen, 1997). On the basis of these findings they proposed a biphasic model in which acute stress enhances, and chronic stress suppresses, the immune response.
 * If the stress response in the immune system evolved, a healthy organism should not be adversely affected by activation of this response because such an effect would likely have been selected against. Although there is direct evidence that stress-related immunosuppression can increase vulnerability to disease in animals (e.g., Ben Eliyahu, Shakhar, Page, Stefanski, & Shakhar, 2000; Quan et al., 2001; Shavit et al., 1985; Sheridan et al., 1998), there is little or no evidence linking stress-related immune change in healthy humans to disease vulnerability. Even large stress-induced immune changes can have small clinical consequences because of the redundancy of the immune system’s components or because they do not persist for a sufficient duration to enhance disease susceptibility. In short, the immune system is remarkably flexible and capable of substantial change without compromising an otherwise healthy host. However, the flexibility of the immune system can be compromised by age and disease. As humans age, the immune system becomes senescent (Boucher et al., 1998; Wikby, Johansson, Ferguson, & Olsson, 1994). As a consequence, older adults are less able to respond to vaccines and mount cellular immune responses, which in turn may contribute to early mortality (Ferguson, Wikby, Maxson, Olsson, & Johansson, 1995; Wayne, Rhyne, Garry, & Goodwin, 1990). The decreased ability of the immune system to respond to stimulation is one indicator of its loss of flexibility. Loss of self-regulation is also characteristic of disease states. In autoimmune disease, for example, the immune system treats self-tissue as an invader, attacking it and causing pathology such as multiple sclerosis, rheumatoid arthritis, Crohn’s disease, and lupus. Immune reactions can also be exaggerated and pathological, as in asthma, and suggest loss of self-regulation. Finally, infection with HIV progressively incapacitates T-helper cells, leading to loss of the regulation usually provided by these cells. Although each of these diseases has distinct clinical consequences, the change in the immune system from flexible and balanced to inflexible and unbalanced suggests increased vulnerability to stress-related immune dysregulation; furthermore, dysregulation in the presence of disease may have clinical consequences (e.g., Bower, Kemeny, Taylor, & Fahey, 1998).
 * In summary, stressful event sequences did not elicit a robust pattern of immune changes when considered as a whole. When these sequences are broken down into categories reflecting the stressor’s nature, the meta-analysis yields evidence of declines in natural immune response following the loss of a spouse, nonsignificant increases in natural and specific immune responses following exposure to natural disaster, and no immune alterations with breast biopsy. Unfortunately, we cannot determine whether these disparate patterns of immune response are attributable to features of the stressors, demographic or medical characteristics of the participants, or some interaction between these factors.
 * Chronic stressors included dementia caregiving, living with a handicap, and unemployment. Like other nonacute stressors, they did not have any systematic relationship with enumerative measures of the immune system. They did, however, have negative effects on almost all functional measures of the immune system (see Table 7). Both natural and specific immunity were negatively affected, as were Th1 (e.g., T cell proliferative responses) and Th2 (e.g., antibody to influenza vaccine) parameters. The only nonsignificant change was for antibody to latent virus; this effect size was substantial (r = .44), but there was also substantial heterogeneity. Further analyses showed that demographics did not moderate this effect: Immune responses to chronic stressors were equally strong across the age spectrum as well as across sex.
 * Most of the studies in this area examined whether immune responses varied as a function of the number of life events a person endorsed on a standard checklist, a person’s rating of the impact of those events, or both. As Table 9 illustrates, this methodology yielded little in the way of significant outcomes in healthy participants. To determine whether vulnerability to life events might vary across the life span, we divided studies into two categories on the basis of a natural break in the age distribution. These analyses provided evidence that older adults are especially vulnerable to life-event–induced immune change. In studies that used samples of adults who had a mean age above 55, life events were associated with reliable declines in lymphocyte-proliferative responses to PHA (r = −.40, p = .05; k = 2) and natural killer cell cytotoxicity (r = −.59, p = .001; k = 2). These effects were much weaker in studies with a mean age below 55: Life events were not associated with proliferative responses to PHA (r = −.22, p = .24; k = 2), and showed a reliable but modest relationship with natural killer cell cytotoxicity (r = −.10, p = .03; k = 8). The differences in effect size between older and younger adults were statistically significant for natural killer cell cytotoxicity ( p < .001) but not PHA-induced proliferation ( p <.15). None of the other moderators we examined—sex ratio, kind of life event assessed (daily hassle vs. major event), or the method used to do so (checklist vs. interview)—was related to immune outcomes.
 * The immune system, once thought to be autonomous, is now known to respond to signals from many other systems in the body, particularly the nervous system and the endocrine system. As a consequence, environmental events to which the nervous system and endocrine system respond can also elicit responses from the immune system. The results of meta-analysis of the hundreds of research reports generated by this hypothesis indicate that stressful events reliably associate with changes in the immune system and that characteristics of those events are important in determining the kind of change that occurs.
 * Selye’s (1975) seminal findings suggested that stress globally suppressed the immune system and provided the first model for how stress and immunity are related. This model has recently been challenged by views that relations between stress and the immune system should be adaptive, at least within the context of fight-or-flight stressors, and an even newer focus on the balance between cellular and humoral immunity. The present meta-analytic results support three of these models. Depending on the time frame, stressors triggered adaptive upregulation of natural immunity and suppression of specific immunity (acute time-limited), cytokine shift (brief naturalistic), or global immunosuppression (chronic). When stressors were acute and time-limited—that is, they generally followed the temporal parameters of fight-or-flight stressors—there was evidence for adaptive redistribution of cells and preparation of the natural immune system for possible infection, injury, or both. In evolution, stressor-related changes in the immune system that prepared the organisms for infections resulting from bites, puncture wounds, scrapes, or other challenges to the integrity of the skin and blood could be selected for. This process would be most adaptive when it was also efficient and did not divert excess energy from fight-or-flight behavior. Indeed, changes in the immune system following acute stress conformed to this pattern of efficiency and energy conservation. Acute stress upregu-lated parameters of natural immunity, the branch of the immune system in which most changes occurred, which requires only minimal time and energy investment to act against invaders and is also subject to the fewest inhibitory constraints on acting quickly (Dopp et al., 2000; Sapolsky, 1998). In contrast, energy may actually be directed away from the specific immune response, as indexed by the decrease in the proliferative response. The specific immune response in general and proliferation in particular demand time and energy; therefore, this decrease might indicate a redirection away from this function. Similar redirection occurs during fight-or-flight stressors with regard to other nonessential, future-oriented processes such as digestion and reproduction. As stressors became more chronic, the potential adaptiveness of the immune changes decreased. The effect of brief stressors such as examinations was to change the potency of different arms of specific immunity—specifically, to switch away from cellular (Th1) immunity and toward humoral (Th2) immunity. The stressful event sequences tended to fall into two substantive groups: bereavement and trauma. Bereavement was associated with decreased natural killer cell cytotoxicity. Trauma was associated with nonsignificantly increased cytotoxicity and increased proliferation but decreased numbers of T cells in peripheral blood. The different results for loss and trauma mirror neuroendocrine effects of these two types of adverse events. Loss—maternal separation in nonhuman animals and bereavement in humans—is commonly associated with increased cortisol production (Irwin, Daniels, Risch, Bloom, & Weiner, 1988; Laudenslager, 1988; McCleery, Bhagwagar, Smith, Goodwin, & Cowen, 2000). In contrast, trauma and posttraumatic stress disorder are commonly associated with decreased cortisol production (see Yehuda, 2001; Yehuda et al., 1998, for reviews). To the degree that cortisol suppresses immune function such as natural killer cell cytotoxicity, these results have the potential to explain the different effects of loss and trauma event sequences.
 * The most chronic stressors were associated with the most global immunosuppression, as they were associated with reliable decreases in almost all functional immune measures examined. Increasing stressor duration, therefore, resulted in a shift from potentially adaptive changes to potentially detrimental changes, initially in cellular immunity and then in immune function more broadly. It is important to recognize that although the effects of chronic stressors may be due to their duration, the most chronic stressors were associated with changes in identity or social roles (e.g., acquiring the role of caregiver or refugee or losing the role of employee). These chronic stressors may also be more persistent, that is, constantly rather than intermittently present. Finally, chronic stressors may be less controllable and afford less hope for control in the future. These qualities could contribute to the severity of the stressor in terms of both its psychological and physiological impact.
 * The results of this meta-analysis reflect the theoretical and empirical progress of this literature over the past 4 decades. Increased differentiation in the quality of stressors and the immunological parameters investigated have allowed complex models to be tested. In contrast, previous meta-analyses were bound by a small number of more homogenous studies. Herbert and Cohen (1993) reported on 36 studies published between 1977 and 1991, finding broadly immunosuppressive effects of stress. Zorrilla et al. (2001) reported on 82 studies published between 1980 and 1996, finding potentially adaptive effects of acute stressors in addition to evidence for immunosuppression with longer stressors. It is important to note that meta-analytic findings are bound by the models tested in the literature. As more complex models are tested, more complex relationships emerge in meta-analysis. We next consider some such areas of complexity that should be considered in future psychoneuroimmunology research.
 * The meta-analytic results indicate that organismic variables such as age and disease status moderate vulnerability to stress-related decreases in functional immune measures. Both aging and HIV are associated with immune senescence and loss of responsiveness (Effros et al., 1994; Effros & Pawelec, 1997), and both are also associated with disruption of neuroendocrine inputs to the immune system (Kumar et al., 2002; Madden, Thyagarajan, & Felten, 1998). The loss of self-regulation in disease and aging likely makes affected people more susceptible to negative immunological effects of stress. Finally, the meta-analysis did not reveal effects of sex on immune responses to stressors. However, these comparisons simply correlated the sex ratio of the studies with effect sizes. Grouping data by sex would afford a more powerful comparison, but few studies organized their data that way. Gender may moderate the effects of stress on immunity by virtue of the effects of sex hormones on immunity; generally, men are considered to be more biologically vulnerable (Maes, 1999), and they may be more psychosocially vulnerable (e.g.,Scanlan, Vitaliano, Ochs, Savage, & Borson, 1998). It seems likely to us that individual differences in subjective experience also make a substantive contribution to explaining this phenomenon. Studies have convincingly demonstrated that people’s cardiovascular and neuroendocrine responses to stressful experience are dependent on their appraisals of the situation and the presence of intrusive thoughts about it (Baum et al., 1993; Frankenhauser, 1975; Tomaka et al., 1997). Although the same logic should apply to people’s immune responses to stressful experience, few of the studies in this area have included measures of subjective experience, and those reports were limited by methodological issues such as aggregation across heterogeneous stressors. As a consequence, measures of subjective experience were not significantly associated with immune parameters in healthy research participants, with the exception of a modest (r = −.10) relationship between intrusive thoughts and natural killer cell cytotoxicity. Psychological variables such as personality and emotion can give rise to individual differences in psychological and concomitant immunological responses to stress. Optimism and coping, for example, moderated immunological responses to stressors in several studies (e.g., Barger et al., 2000; Bosch et al., 2001; Cruess et al., 2000; Segerstrom, 2001; Stowell, Kiecolt-Glaser, & Glaser, 2001).
 * Virtually nothing is known about the psychological pathways linking stressors with the immune system. Many theorists have argued that affect is a final common pathway for stressors (e.g., S. Cohen, Kessler, & Underwood, 1995; Miller & Cohen, 2001), yet studies have enjoyed limited success in attempting to explain people’s immune responses to life experiences on the basis of their emotional states alone (Bower et al., 1998; Cole, Kemeny, Taylor, Visscher, & Fahey, 1996; Miller, Dopp, Myers, Stevens, & Fahey, 1999; Segerstrom, Taylor, Kemeny, & Fahey, 1998). Furthermore, many studies have focused on the immune effects of emotional valence (e.g., unhappy vs. happy; Futterman, Kemeny, Shapiro, & Fahey, 1994), but the immune system may be even more closely linked to emotional arousal (e.g., stimulated vs. still), especially during acute stressors (S. Cohen et al., 2000). Finally, it is possible that emotion will prove to be relatively unimportant and that other mental processes such as motivational states or cognitive appraisals will prove to be the critical psychological mechanisms linking stress and the immune system (cf. Maier, Waldstein, & Synowski, 2003). In terms of biological mechanisms, the field is further along, but much remains to be learned. A series of studies in the mid-1990s was able to show via beta-adrenergic blockade that activation of the sympathetic nervous system was responsible for the immune system effects of acute stressors (Bachen et al., 1995; Benschop, Nieuwenhuis, et al., 1994). Apart from these findings, however, little is known about biological mechanisms, especially with regard to more enduring stressors that occur in the real world. Studies that have attempted to identify hormonal pathways linking stressors and the immune system have enjoyed limited success, perhaps because they have utilized snapshot assessments of hormones circulating in blood. Future studies can maximize their chances of identifying relevant mediators by utilizing more integrated measures of hormonal output, such as 24-hr urine collections or diurnal profiles generated through saliva collections spaced throughout the day (Baum & Grunberg, 1995; Stone et al., 2001). Future studies could also benefit from a greater emphasis on behavior as a potential mechanism. This strategy has proven useful in studies of clinically depressed patients, in which decreased physical activity and psychomotor retardation (Cover & Irwin, 1994; Miller, Cohen, & Herbert, 1999), increased body mass (Miller, Stetler, Carney, Freedland, & Banks, 2002), disturbed sleep (Cover & Irwin, 1994; Irwin, Smith, & Gillin, 1992), and cigarette smoking (Jung & Irwin, 1999) have been shown to explain some of the immune dysregulation evident in this population. There is already preliminary evidence, for instance, that sleep loss might be responsible for some of the immune system changes that accompany stressors (Hall et al., 1998; Ironson et al., 1997).
 * The most pressing question that future research needs to address is the extent to which stressor-induced changes in the immune system have meaningful implications for disease susceptibility in otherwise healthy humans. In the 30 years since work in the field of psychoneuroimmunology began, studies have convincingly established that stressful experiences alter features of the immune response as well as confer vulnerability to adverse medical outcomes that are either mediated by or resisted by the immune system. However, with the exception of recent work on upper respiratory infection (S. Cohen, Doyle, & Skoner, 1999), studies have not yet tied these disparate strands of work together nor determined whether immune system changes are the mechanism through which stressors increase susceptibility to disease onset. In contrast, studies of vulnerable populations such as people with HIV have shown changes in immunity to predict disease progression (Bower et al., 1998). To test an effect of this nature, researchers need to build clinical outcome assessments into study designs where appropriate. For example, chronic stressors reliably diminish the immune system’s capacity to produce antibodies following routine influenza vaccinations (see Table 7). Yet as far as we are aware, none of these studies has tracked illness to explore whether stress-related disparities in vaccine response might be sufficient to heighten susceptibility to clinical infection with influenza. Cytokine expression represents a relatively new and promising example of an avenue for research linking stress, immune change, and disease. For example, chronic stress may elicit prolonged secretion of cortisol, to which white blood cells mount a counterregulatory response by downregulating their cortisol receptors. This downregulation, in turn, reduces the cells’ capacity to respond to anti-inflammatory signals and allows cytokine-mediated inflammatory processes to flourish (Miller, Cohen, & Ritchey, 2002). Stress therefore might contribute to the course of diseases involving excessive nonspecific inflammation (e.g., multiple sclerosis, rheumatoid arthritis, coronary heart disease) and thereby increase risk for excess morbidity and mortality (Ershler & Keller, 2000; Papanicoloaou et al., 1998; Rozanski, Blumenthal, & Kaplan, 1999). Another example of the importance of cytokines to clinical pathology is in asthma and allergy, in which emerging evidence implicates excess Th2 cytokine secretion in the exacerbation of these diseases (Busse & Lemanske, 2001; Luster, 1998).
 * The results of this meta-analysis support this assertion in one sense: Stressors with the temporal parameters of the fight-or-flight situations faced by humans’ evolutionary ancestors elicited potentially beneficial changes in the immune system. The more a stres-sor deviated from those parameters by becoming more chronic, however, the more components of the immune system were affected in a potentially detrimental way. Further research is needed to support two other ideas elicited by this quote: the idea that subjective experience such as worry is more likely to result in stress-related immune change than objective experience and the idea that stress-related immune change results in stress-related disease. Though the results of the meta-analysis were not encouraging on the first point, many of these studies suffered from methodological limitations. We hope that these results will inform investigations that go beyond the relationship between a stressful event and an immune parameter to investigate the psychological phenomena that mediate that relationship. Finally, these results can also inform investigations into stress, immunity, and disease process. Whether the disease is characterized by natural or specific immunity, its cytokine profile, and its regulation by anti-inflammatory agents such as cortisol, may determine the disparate effects of different kinds of stressors.

Dialogue

 * Zhu: It seems that most studies and reviews say that the intensity of the exercises should be kept moderate. However, Campbell and Turner have recently challenged this belief and claimed that there is no harmful effect on immune function even when a vigorous bout of exercise intervention is employed. What is your view on the appropriate intensity of exercise for improving immune function?
 * Woods: The report from Campbell and Turner focuses on highly fit individuals who compete in, and are accustomed to, long endurance, high-intensity events. While I believe there is merit in the evidence they provide to refute the conclusions for that population, studies where sedentary people are forced to exercise at high intensities for prolonged periods might paint a different picture. There are few such studies due to the ethics and safety concerns and there are many other variables that contribute to natural infections that would need to be accounted and controlled for in such studies. The best studies would be ones that control exercise and infectious disease exposure in people. These are difficult to ethically perform in people and it would be very difficult or impossible to get approved by institutional review boards. Animal models, including ours as mentioned, may provide valuable insights into this argument and there are many studies demonstrating that prolonged, unaccustomed exercise can increase infectious disease morbidity and mortality. These studies were not reconciled in the Campbell and Turner article. However, as with all animal models, there are limitations, such as species differences, stress associated with forced exercise, the type of pathogen, and timing of exercise in relation to infection that would need to be taken into account before a firm conclusion could be drawn.
 * Weimo Zhu & Jeffrey A. Woods in “Should, and how can, exercise be done during a coronavirus outbreak? An interview with Dr. Jeffrey A. Woods”, J Sport Health Sci. (2020 Mar Published online 2020 Feb 4); 9(2): 105–107.