Position statement part two: maintaining immune health

The physical training undertaken by athletes is one of a set of lifestyle or behavioural factors that can influence immune function, health and ultimately exercise performance. Others factors including potential exposure to pathogens, health status, lifestyle behaviours, sleep and recovery, nutrition and psychosocial issues, need to be considered alongside the physical demands of an athlete’s training programme. The general consensus on managing training to maintain immune health is to start with a programme of low to moderate volume and intensity; employ a gradual and periodised increase in training volumes and loads; add variety to limit training monotony and stress; avoid excessively heavy training loads that could lead to exhaustion, illness or injury; include non-specific cross-training to offset staleness; ensure sufficient rest and recovery; and instigate a testing programme for identifying signs of performance deterioration and manifestations of physical stress. Inter-individual variability in immunocompetence, recovery, exercise capacity, non-training stress factors, and stress tolerance likely explains the different vulnerability of athletes to illness. Most athletes should be able to train with high loads provided their programme includes strategies devised to control the overall strain and stress. Athletes, coaches and medical personnel should be alert to periods of increased risk of illness (e.g. intensive training weeks, the taper period prior to competition, and during competition) and pay particular attention to recovery and nutritional strategies. [...continues]

Cumulative Inflammatory Load Is Associated with Short Leukocyte Telomere Length in the Health, Aging and Body Composition Study

Background: Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction. Methodology/Principal Findings: To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70-79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-α had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-α had significantly higher odds for short LTL compared with those who had neither high (OR = 0.52, CI = 0.37-0.72), only IL-6 high (OR = 0.57, CI = 0.39-0.83) or only TNF-α high (OR = 0.67, CI = 0.46-0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL. Conclusions/Significance: Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population

Revealing the impact of lifestyle stressors on the risk of adverse pregnancy outcomes with multitask machine learning

Psychosocial and stress-related factors (PSFs), defined as internal or external stimuli that induce biological changes, are potentially modifiable factors and accessible targets for interventions that are associated with adverse pregnancy outcomes (APOs). Although individual APOs have been shown to be connected to PSFs, they are biologically interconnected, relatively infrequent, and therefore challenging to model. In this context, multi-task machine learning (MML) is an ideal tool for exploring the interconnectedness of APOs on the one hand and building on joint combinatorial outcomes to increase predictive power on the other hand. Additionally, by integrating single cell immunological profiling of underlying biological processes, the effects of stress-based therapeutics may be measurable, facilitating the development of precision medicine approaches.ObjectivesThe primary objectives were to jointly model multiple APOs and their connection to stress early in pregnancy, and to explore the underlying biology to guide development of accessible and measurable interventions.Materials and MethodsIn a prospective cohort study, PSFs were assessed during the first trimester with an extensive self-filled questionnaire for 200 women. We used MML to simultaneously model, and predict APOs (severe preeclampsia, superimposed preeclampsia, gestational diabetes and early gestational age) as well as several risk factors (BMI, diabetes, hypertension) for these patients based on PSFs. Strongly interrelated stressors were categorized to identify potential therapeutic targets. Furthermore, for a subset of 14 women, we modeled the connection of PSFs to the maternal immune system to APOs by building corresponding ML models based on an extensive single cell immune dataset generated by mass cytometry time of flight (CyTOF).ResultsJointly modeling APOs in a MML setting significantly increased modeling capabilities and yielded a highly predictive integrated model of APOs underscoring their interconnectedness. Most APOs were associated with mental health, life stress, and perceived health risks. Biologically, stressors were associated with specific immune characteristics revolving around CD4/CD8 T cells. Immune characteristics predicted based on stress were in turn found to be associated with APOs.ConclusionsElucidating connections among stress, multiple APOs simultaneously, and immune characteristics has the potential to facilitate the implementation of ML-based, individualized, integrative models of pregnancy in clinical decision making. The modifiable nature of stressors may enable the development of accessible interventions, with success tracked through immune characteristics

High-Anxious Individuals Show Increased Chronic Stress Burden, Decreased Protective Immunity, and Increased Cancer Progression in a Mouse Model of Squamous Cell Carcinoma

In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2–3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-γ gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship

Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings

Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of “accelerated aging” in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation.Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex.The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (≥9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of “accelerated cell aging.” Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05).These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure

Enhancing versus Suppressive Effects of Stress on Immune Function: Implications for Immunoprotection and Immunopathology

Stress is known to suppress immune function and increase susceptibility to infections and cancer. Paradoxically, stress is also known to exacerbate asthma, and allergic, autoimmune and inflammatory diseases, although such diseases should be ameliorated by immunosuppression. Moreover, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that enables the cardiovascular and musculoskeletal systems to promote survival, and it is unlikely that this response would suppress immune function at a time when it is most required for survival (e.g. in response to wounding and infection by a predator or aggressor). These observations suggest that stress may suppress immune function under some conditions while enhancing it under others. The effects of stress are likely to be beneficial or harmful depending on the type (immunoprotective, immunoregulatory/inhibitory, or immunopathological) of immune response that is affected. Studies have shown that several critical factors influence the direction (enhancing vs. suppressive) of the effects of stress or stress hormones on immune function: (1) Duration (acute vs. chronic) of stress: Acute or short-term stress experienced at the time of immune activation can enhance innate and adaptive immune responses. Chronic or long-term stress can suppress immunity by decreasing immune cell numbers and function and/or increasing active immunosuppressive mechanisms (e.g. regulatory T cells). Chronic stress can also dysregulate immune function by promoting proinflammatory and type-2 cytokine-driven responses. (2) Effects of stress on leukocyte distribution: Compartments that are enriched with immune cells during acute stress show immunoenhancement, while those that are depleted of leukocytes, show immunosuppression. (3) The differential effects of physiologic versus pharmacologic concentrations of glucocorticoids, and the differential effects of endogenous versus synthetic glucocorticoids: Endogenous hormones in physiological concentrations can have immunoenhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immunosuppressive. (4) The timing of stressor or stress hormone exposure relative to the time of activation and time course of the immune response: Immunoenhancement is observed when acute stress is experienced at early stages of immune activation, while immunosuppression may be observed at late stages of the immune response. We propose that it is important to study and, if possible, to clinically harness the immunoenhancing effects of the acute stress response, that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve. In view of the ubiquitous nature of stress and its significant effects on immunoprotection as well as immunopathology, it is important to further elucidate the mechanisms mediating stress-immune interactions and to meaningfully translate findings from bench to bedside

A hassle a day may keep the pathogens away: The fight-or-flight stress response and the augmentation of immune function

Stress is known to suppress or dysregulate immune function and increase susceptibility to disease. Paradoxically, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that galvanizes the neuroendocrine, cardiovascular, and musculoskeletal systems into action to enable survival. Therefore, it is unlikely that short-term stress would suppress immune function at a time when it may be critically required for survival (e.g., in response to wounding and infection by a predator or aggressor). In fact, studies have shown that stress can enhance immune function under certain conditions. Several factors influence the direction (enhancing versus suppressive) of the effects of stress on immune function: (1) DURATION: acute or short-term stress experienced at the time of activation of an immune response enhances innate and adaptive immune responses. Chronic or long-term stress can suppress or dysregulate immune function. (2) Leukocyte distribution: compartments (e.g., skin), that are enriched with immune cells during acute stress show immuno-enhancement, while those that are depleted of leukocytes (e.g., blood), show immuno-suppression. (3) The differential effects of physiologic versus pharmacologic stress hormones: Endogenous hormones in physiological concentrations can have immuno-enhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immuno-suppressive. (4) Timing: immuno-enhancement is observed when acute stress is experienced during the early stages of an immune response while immuno-suppression may be observed at late stages. The type of immune response (protective, regulatory/inhibitory, or pathological) that is affected determines whether the effects of stress are ultimately beneficial or harmful for the organism. Arguments based on conservation of energy have been invoked to explain potential adaptive benefits of stress-induced immuno-suppression, but generally do not hold true because most mechanisms for immuno-suppression expend, rather than conserve, energy. We propose that it is important to study, and if possible, to clinically harness, the immuno-enhancing effects of the acute stress response that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve

Stress-induced Changes in Immune Cell Distribution and Trafficking: Implications for Immunoprotection versus Immunopathology

Effective immunoprotection requires rapid recruitment of leukocytes into sites of surgery, wounding, infection, or vaccination. Immune cells circulate continuously on surveillance pathways that take them from the blood, through various organs, and back into the blood. This circulation is essential for the maintenance of an effective immune defense network (Sprent and Tough, 1994).The numbers and proportions of leukocytes in the blood provide an important representation of the state of distribution of leukocytes in the body and of the state of activation of the immune system. A stress-induced change in leukocyte distribution within different body compartments is perhaps one of the most underappreciated effects of stress and stress hormones on the immune system

Stress-induced augmentation of immune function—The role of stress hormones, leukocyte trafficking, and cytokines

Delayed-type hypersensitivity (DTH) reactions represent cell-mediated immune responses that exert important immunoprotective (resistance to viruses, bacteria, and fungi) or immunopathological (allergic or autoimmune hypersensitivity) effects. We initially utilized the skin DTH response as an experimental in vivo model to study neuro–endocrine-immune interactions in rodents. We hypothesized that just as an acute stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges which may be imposed by a stressor. The skin DTH model allowed us to examine the effects of stress at the time of primary and secondary exposure to antigen. Studies showed that acute (2 h) stress experienced before primary or secondary antigen exposure induces a significant enhancement of skin DTH. Importantly, this enhancement involved innate as well as adaptive immune mechanisms. Adrenalectomy eliminated the stress-induced enhancement of DTH. Acute administration of physiological (stress) concentrations of corticosterone and/or epinephrine to adrenalectomized animals enhanced skin DTH. Compared with controls, DTH sites from acutely stressed or hormone-injected animals showed significantly greater erythema and induration, numbers of infiltrating leukocytes, and levels of cytokine gene expression. In contrast to acute stress, chronic stress was immunosuppressive. Chronic exposure to corticosterone, or acute exposure to dexamethasone significantly suppressed skin DTH. These results suggest that during acute stress, endogenous stress hormones enhance skin immunity by increasing leukocyte trafficking and cytokine gene expression at the site of antigen entry. While these results are discussed from a mechanistic and clinical relevance perspective, it is acknowledged that much work remains to be done to elucidate the precise mechanisms mediating these bi-directional effects of stress and stress hormones and their clinical ramifications

A hassle a day may keep the doctor away: stress and the augmentation of immune function

Stress may be defined as a sequence of events, that begins with a stimulus (stressor), that is recognized by the brain (stress perception), and which results in the activation of physiologic fight/flight/fright systems within the body (stress response). Many evolutionary selection pressures are stressors, and one of the primary functions of the brain is to perceive stress, warn the body of danger, and enable an organism to respond. We hypothesized that under acute conditions, just as the stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges (e.g., wounding) which may be imposed by a stressor (e.g., an aggressor). Initial studies showed that acute (2h) stress induced a significant trafficking of immune cells to the skin. Since the skin is an organism's major protective barrier, we hypothesized that this leukocyte redistribution may serve to enhance skin immunity during acute stress. We tested this hypothesis using the delayed type hypersensitivity (DTH) reaction, which mediates resistance to various infectious agents, as a model for skin immune function. Acute stress administered immediately before antigen exposure significantly enhanced skin DTH. Adrenalectomy (ADX) eliminated the stress-induced enhancement of DTH while administration of physiological doses of corticosterone and/or epinephrine to ADX animals enhanced skin DTH in the absence of stress. These studies showed that changes in leukocyte distribution and circulating stress hormones are systemic mediators of the immunoenhancing effects of acute stress. We recently identified gamma interferon as a local cytokine mediator of a stress-induced immunoenhancement. Our results suggest that during acute stress the brain sends preparatory warning signals to the immune system just as it does to other fight/flight systems of the body