Chronic Stress,Immune Dysregulation,and Health

Abstract

In the past 40 years, a growing body of literature has shown that chronic psychological stress can lead to immune dysregulation. Notably, these stress-induced immune changes are large enough to be clinically relevant. Chronic stress has been associated with a state of chronic low-grade inflammation, delayed wound healing, poor responses to vaccine, and increased susceptibility to infectious illnesses. Activation of neuroendocrine and sympathetic systems provides physiological pathways linking stress and these immune outcomes. Behavioral changes under conditions of chronic stress also contribute to immune dysregulation. Behavioral and pharmacological interventions may attenuate stress-induced immune dysregulation.

In contemporary studies, technological advances have allowed the measurement of immune parameters that can be more closely related to health outcomes and therefore provide stronger evidence for the clinical significance of chronic stress-induced immune dysregulation.

Stress occurs when environmental demands solicit or exceed the individual’s capacity to cope. ¹ Acute and chronic stress have different physiological consequences. Acute or intermittent stress (eg, bouts of exercise) can transiently enhance immune responses leading to more efficient responses to certain challenges (eg, vaccines).^2,3 In contrast, persistent stress has been related to detrimental health outcomes. Chronic stressors are conceptualized as events that persist for an extended period of time or events that have an undetermined duration (eg, caregiving, disability, unemployment). Some time-limited events may also have lingering consequences for several months and even years (eg, sexual abuse). Other major life events such as the loss of a spouse or exposure to a major disaster lead to sequences of multiple stressful events. ⁴ Contemporary models in psychoneuroimmunology suggest that chronic psychological stress can directly affect immune functioning via activation of neuroendocrine and sympathetic systems. Furthermore, stress can indirectly influence immune function by modulating the adoption of health-related behaviors.

Stress-induced activation of the neuroendocrine and sympathetic systems is essential for the organism’s adaptation and survival. In most circumstances, the transient immune changes associated with a given acute stressor are unlikely to have an immediate clinically relevant health impact. However, repeated or persistent activation of these systems may cause, over the long run, a wear and tear of the body’s organs, called allostatic load. ⁵ Chronic stress may then lead to immune dysregulation, an underexpression or overexpression of certain immune molecules, which is characterized by either impaired immune responses or loss of the natural regulatory mechanisms that ordinarily preserve allostasis and protect the body against damage from its own immune system. A growing body of literature shows that chronic stress-induced immune dysregulation has a large enough impact to be clinically relevant. The goal of this article is to present an overview of key human studies exemplifying contemporary research on chronic stress and immune dysregulation.

Early Human Studies on Chronic Stress and Immunity

Early psychoneuroimmunology studies evaluated the impact of chronic stress on a series of nonspecific measures of immunity. Studies often assessed the impact of stress on enumerative immunity, such as counts of T-helper lymphocytes, T-cytotoxic lymphocytes, natural killer cells, and total lymphocytes, and on measures of functional immunity such as natural killer cell cytotoxicity and mitogen-induced lymphocytes proliferation. A meta-analytic study revealed that chronic stressors such as caregiving, spousal bereavement, disability, or unemployment were not associated with enumerative measures of immunity but led to impairment in cellular immunity as evidenced by a reduced natural killer cell cytotoxicity and mitogen-induced lymphocytes proliferation.^6-8 However, because of the natural redundancy of the immune system and the choice of these nonspecific immune measures, the clinical relevance of these findings was often unknown. In contemporary studies, technological advances have allowed the measurement of immune parameters that can be more closely related to health outcomes and therefore provide stronger evidence for the clinical significance of chronic stress-induced immune dysregulation.

Inflammation

Inflammation is an essential immune response triggered by infection and injury. It is the initial, automatic, and nonspecific reaction of the innate immune system on exposure to an antigen. Inflammation promotes the destruction and clearance of pathogens and initiates wound healing. This process is enacted by a series of proinflammatory (eg, interleukin [IL]-1, IL-6, tumor necrosis factor-α [TNF-α]) and anti-inflammatory (eg, IL-4, IL-10) markers. Acute-phase reactants, such as C-reactive protein (CRP), are also produced in response to inflammatory stimulation.

Although inflammation is a critical response to acute infection or injury, chronic or excessive inflammation may be detrimental to health. In fact, chronic low-grade inflammation has been implicated in a number of age-related medical conditions.^9,10 In epidemiological studies, high levels of circulating inflammatory markers have been associated with higher incidence of cardiovascular disorders, diabetes, certain cancers, autoimmune diseases, frailty, and even death. ⁹ In experimental studies, pharmacological increases in inflammation led to worse outcomes in animal models of cardiovascular diseases and cancer,^11,12 suggesting that enhanced inflammation does not only reflect increased disease activity, but may be directly implicated in pathophysiological processes.

Acute psychological stress (eg, public speaking and mental arithmetic laboratory tasks) reliably induce elevations in systemic levels of IL-6 and CRP. ¹³ Acute stress leads to transient increases in circulating inflammatory biomarkers that are observable 30 minutes after exposure to the stressor. ¹³ Stress-induced activation of the transcription factor NF-κB initiates the gene production of a host of inflammatory proteins. ¹⁴ The magnitude of the stress-induced anxiety has been related to greater IL-1β mRNA expression in peripheral blood monocytes (PBMCs), ¹⁵ providing a molecular mechanism by which psychological stress is translated into inflammatory mediators production. Some authors have conceptualized the production of inflammatory proteins as an integral part of the physiological stress response. ¹⁶

Chronic stress has also been associated with a state of chronic low-grade inflammation. A common model to study chronic stress in humans is family dementia caregiving. Individuals providing care for a spouse or parent with a neurodegenerative dementia are confronted daily with the changes in cognitive functioning, behavioral disturbances, and impairment in activities of daily living of their loved ones. Caregiving is intensive and often lasts several years, ¹⁷ and this subsequent stress places the caregiver at increased risk for depressive and anxiety disorders. ¹⁸ Furthermore, dementia caregiving can have a detrimental impact on health. ¹⁹ For example, stressed caregivers were more likely to be diagnosed with cardiovascular disorders than controls. ²⁰ Moreover, in a longitudinal study, distressed caregivers had a 2-fold higher risk of mortality than matched noncaregiving controls. ²¹ Family dementia caregiving therefore represents an excellent model to study the impact of chronic stress on immune dysregulation.

Women caring for a spouse with dementia had greater plasma IL-6 levels than older women undergoing housing relocation, and older and younger control women who did not report major life stress at the time of the study. ²² This effect of caregiving stress on IL-6 has been replicated in a larger study of dementia caregivers. ²³ Moreover, younger individuals providing care for a loved one with brain tumors also displayed an elevation in circulating markers of inflammation. Over the course of the first year following the cancer diagnosis of their loved one, caregivers exhibited an increase in plasma CRP levels. ²⁴

There is a natural age-related increase in IL-6 starting around the age of 55 years. ⁹ Chronic stress can exacerbate this natural IL-6 increase. In a 6-year longitudinal study, the rate of increase in IL-6 over time was 4 times higher among caregivers than among demographically similar noncaregiving controls. ²⁵ The health impact of these results is substantial. Epidemiological studies suggest that individuals with IL-6 levels greater than 3.19 pg/mL are at higher risk of death than individuals with lower levels of the proinflammatory cytokine. ²⁶ Extrapolating from that data of Kiecolt-Glaser et al, ²⁷ caregivers would reach this threshold at the age of 75 years, whereas controls would join the high-risk group at the age of 90 years. Furthermore, there was also some evidence that chronic stress had a long-term impact on the inflammatory system. Some dementia patients died in the course of the longitudinal study. Even after their loved one died, bereaved caregivers maintained IL-6 levels that were similar to those of current caregivers and significantly higher than those of noncaregiving controls for the remainder of the observation period. This indicates that the stress-induced chronic low-grade inflammation persisted even after the death of the loved one with dementia.

Other interpersonal stressors also promote chronic low-grade inflammation. Couples who engaged in frequent hostile and negative interactions during the discussion of a marital disagreement exhibited greater plasma IL-6 production than less hostile couples. ²⁸ In daily diary studies, a high frequency of daily interpersonal conflict was associated with greater lipopolysaccharide (LPS)-stimulated IL-6 production by PBMCs and higher plasma CRP levels.^29,30 In a longitudinal study, greater chronic interpersonal stress was related to larger increases in NF-κB and LPS-stimulated IL-6 production over the course of a 6-month period. ³¹ Furthermore, childhood sexual abuse, a traumatic stressor with lingering interpersonal consequences, has been associated with greater adulthood CRP levels. ³²

Converging evidence suggests that depression, a condition frequently associated with chronic stress, has been linked to a state of chronic low-grade inflammation. In epidemiological studies, higher levels of depressive symptoms have been associated with greater plasma IL-6 and CRP levels.^33,34 There is some evidence that the depressive symptoms fuel the chronic low-grade inflammation. In a 6-year prospective study, initial levels of depression predicted increases in circulating IL-6 levels, whereas initial IL-6 levels did not predict changes in depression over time. ³⁵ Furthermore, among clinically depressed patients, successful antidepressant treatment leads to a reduction in circulating inflammatory markers. ³⁶ In animal studies, administration of proinflammatory cytokine causes a series of depressive-like behaviors such as psychomotor retardation, anhedonia, and anorexia. ³⁷ These sickness behaviors disappear with the cessation of the cytokine administration or with the administration of cytokine antagonists or anti-inflammatory compounds. ³⁸ Similarly, administration of interferon-α for the treatment of hepatitis C infection or certain cancers is associated with the onset of neurovegetative and cognitive symptoms of depression in up to 40% of the patients. ³⁹ Collectively, these results suggest that there is a bidirectional relationship between depression and inflammation. By inducing depressive symptoms, chronic stress may fuel the depression–inflammation cycle.

Depression and chronic stress can sensitize the inflammatory response. Depressed patients displayed an amplified inflammatory response to a laboratory stressor, as compared with nondepressed controls. ⁴⁰ Older adults reporting depressive symptoms also had an exacerbated and persistent IL-6 response following a vaccination challenge in comparison with their nondepressed counterparts. ⁴¹ Furthermore, individuals who received a typhoid vaccine and engaged in a laboratory stressor exhibited greater IL-6 responses than participants who received the vaccine but were not exposed to the stressor, participants who underwent the laboratory stressor but did not receive the vaccine, and participants who neither received the vaccine nor participated in the stressful task. ⁴² These amplified inflammatory responses to acute stressors may promote chronic low-grade inflammation among depressed and chronically stressed individuals.

Several physiological mechanisms regulate proinflammatory cytokine production; however, chronic stress appears to alter some of these mechanisms. Usually, glucocorticoids downregulate proinflammatory cytokine production. However, persistent exposure to high levels of cortisol during chronic stress can elicit a downregulation of the glucocorticoid receptors on immune cells. This leads to the development of a state of glucocorticoid resistance, a condition in which immune cells become nonresponsive to the cortisol’s anti-inflammatory role. An in vitro model was developed to assess this phenomenon. PBMCs stimulated in vitro with LPS produce IL-6. Usually, in vitro administration of dexamethasone, a synthetic glucocorticoid, downregulates IL-6 production to LPS stimulation. Among individuals caring for a child with cancer, the ability of dexamethasone to suppress IL-6 production from stimulated PBMCs was diminished, compared with control parents of healthy children. ⁴³ Furthermore, in a genome-wide DNA microarray study, genes underexpressed by family cancer caregivers included glucocorticoid response elements, whereas genes overexpressed included NF-κB response elements, as compared with noncaregiving controls. ⁴⁴ Chronic stress-induced glucocorticoid insensivity may then promote chronic low-grade inflammation.

The anti-inflammatory cytokine, IL-10, can curb exaggerated IL-6 production. Family dementia caregivers have higher plasma IL-10 levels than noncaregiving controls. The increased anti-inflammatory cytokine production is likely in response to the enhanced circulating IL-6 levels. ⁴⁵ What is interesting is that depression was associated with a loss of the regulatory function of IL-10 on IL-6 production. Unmedicated depressed patients had lower plasma IL-10 levels and a higher IL-6/IL-10 ratio than nondepressed healthy controls. ⁴⁶ Furthermore, there was a strong positive association (r = 0.81) between IL-10 and IL-6 among controls, whereas there was no significant association (r = 0.01) between the 2 cytokines among depressed patients. Stress and depression may then be associated with a loss of the regulatory function of IL-10 on IL-6 production, suggesting another physiological pathway by which chronic stress promotes chronic low-grade inflammation. ⁴⁶

Wound Healing

Wound healing is a critical response to naturally occurring injury as well as surgical interventions. Wound repair is a process broadly comprising 3 overlapping phases. During the first inflammatory phase, hemostatis and inflammatory cell migration to the wound site occurs. The proliferative phase consists of migration and proliferation of keranocytes, fibroblast, and endothelial cells leading to reepithelialization, neovascularization, and granulation tissue formation. The remodeling phase involves extracellular tissue maturation. ⁴⁷ The wound healing process occurs in a sequential and predictable manner. Success of the later stages of wound healing depends on the integrity of the early response. ⁴⁸ Chronic stress-induced physiological changes can perturb the wound repair process primarily by altering the initial inflammatory phases.

The impact of psychological stress on wound healing has been observed in both clinical and experimental studies. In prospective studies of patients undergoing coronary artery bypass surgery, individuals who reported the highest level of depressive symptoms had longer postoperative stays, and more surgery-related complications and were more likely to be rehospitalized, compared with less distressed patients.^49,50 Similarly, among older adults with chronic leg ulcer wounds, those who reported the highest levels of anxiety and depression were 4 times more likely to be categorized as slow healers than individuals experiencing less negative affect. ⁵¹

Chronic stress also delayed wound healing in laboratory studies. Older women caring for a spouse with dementia and matched noncaregiving controls had a punch biopsy performed on their nondominant forearm. Pictures of the wound were taken daily to assess wound closure. It took on average 9 more days or 24% longer for the full-thickness dermal wound to heal in caregivers when compared with noncaregiving women, indicating that caregiving stress can impair wound healing. ⁵² Among healthy young men who underwent a similar punch biopsy procedure, for those who reported greater stress on the Perceived Stress Scale, it took longer to heal the experimental wound than for their less stressed counterparts. ⁵³ Furthermore, men who perceived more stress also had a greater cortisol awakening response; this increased glucocorticoid production was in turn related to slower healing, providing 1 physiological mechanism by which stress can affect wound repair. ⁵³

More transient stress, such as the stress associated with academic examinations, can also disrupt the healing process. In a within-subject design study, dental students had a punch biopsy placed on the hard palate 3 days prior to a major examination as well as during their vacation period. It took longer for all participants to heal the mucosal wound during their examination period than during their vacation. ⁵⁴ In a larger study of mucosal wound healing, individuals reporting high levels of depressive symptoms were 3.6 times more likely to be classified as slow healers than participants reporting less dysphoria. ⁵⁵

Interpersonal stress can also delay wound healing. Married couples completed two 24-hour admissions at a hospital research unit. During the first visit, couples participated in a structured social support task, whereas they discussed marital disagreements during the second visit. The quality of the interaction was assessed by coding positive and negative behaviors using a standardized system. During each admission, eight 8-mm blisters were gently raised on the participants’ nondominant forearms using a vaccum pump. Wound healing was assessed by measuring changes in the rate of transepidermal water loss during the 12 days following discharge. ²⁸ Results showed that the blister wounds healed faster after the social support interaction than following the conflict discussion, indicating that the stress associated with the discussion of marital disagreements slowed the healing process. Furthermore, some couples exhibited more negative and hostile interactions across both the social support and the conflict visits. For these more hostile couples, the blister wounds healed on average 75% more slowly than for less hostile couples, suggesting that chronic marital stress further delayed wound healing. ²⁸

Tape stripping, another model used to study the impact of stress on wound healing, consists of the repeated application of cellophane tape to remove a layer of epidermis cells and to cause a disruption of the stratum corneum barrier function of the skin. In a within-subject design study with healthy young women, skin barrier recovery after tape stripping took longer following exposure to a laboratory stressor when compared with a stress-free period. ⁵⁶ Similar findings were observed in a between-subject design study. Individuals exposed to a stressor had longer skin barrier recovery times than individuals who engaged in a reading control task. ⁵⁷ Furthermore, academic examination stress also delayed skin barrier recovery following tape stripping as compared with vacation periods. ⁵⁸

Stress can delay wound repair by altering proinflammatory cytokine production at the wound site. The blistering wound model described above allowed the examination of early inflammatory events. To collect information on cytokine production at the wound site, the blister’s roofs were removed and wells filled with a salt solution, and autologous serum was placed on top of the blisters. Fluid was extracted from the wells at 4, 7, and 22 hours after the blistering procedure. Women who reported more perceived stress had lower levels of IL-1α and IL-8 at the wound site. ⁵⁹ Among married couples, the production of IL-6, IL-1β, and TNF-α at the wound site was less following discussion of a marital disagreement than after a structured social support interaction. ²⁸ This indicates that stress-induced disruption of the early inflammatory phases may delay wound healing.

Immune Responses to Infectious Illnesses

Converging data from different research paradigms suggest that chronic stress can increase susceptibility to infectious diseases. In observational studies, greater stress enhanced the likelihood of developing infectious illnesses. In a 15-week prospective study of 117 adults, a larger number of stressful life events during the past year was associated with a greater likelihood of developing a clinically verified upper-respiratory illness. ⁶⁰ Furthermore, over the course of a 13-month period, family dementia caregivers reported more upper-respiratory infections than noncaregiving controls. ⁶¹

Live Virus Inoculation Studies

Studies using experimental inoculation of live influenza virus strains provide the most convincing evidence of the impact of stress on infectious illness susceptibility. In these studies, an in-depth assessment of acute and chronic stressors was followed by the administration of nasal drops containing 1 strain of rhinovirus, respiratory syncytial virus, or corona virus. Participants were quarantined for 5 days after exposure to the viral challenge. Nasal secretion samples were collected, and nasal respiratory symptoms were assessed during each day of the quarantine period.^62,63 About one third of the participants developed a clinically verified upper-respiratory illness. Higher perceived stress was associated with a greater likelihood of developing a clinical illness in a dose-dependent manner. ⁶² Furthermore, individuals who experienced a chronic stressor (ie, lasting more than 1 month) in the past year had a higher risk of developing clinical symptoms following inoculation with the live influenza virus, compared with individuals who did not report chronic stressors in the past year. ⁶³ In fact, the risk of developing a clinically verified illness was proportional to the duration of the stressor. Participants experiencing stressors lasting between 1 and 6 months had a 2 times higher risk of developing clinical influenza symptoms than individuals reporting no chronic stressors, whereas individuals reporting stressors lasting more than 2 years had a 3.5 times greater risk. ⁶³ In subsequent studies, individuals who reported greater stress and less positive affect had more illness symptoms, greater mucus weight, and higher IL-6 levels in nasal secretions.^64,65 The enhanced nasal IL-6 production associated with stress is thought to be related to the exacerbated illness symptoms. ⁶⁴

Vaccination Studies

Inoculation with live attenuated or inactivated viruses also provides a window to study the impact of chronic stress on in vivo immune responses. The immunization challenge represents a proxy for the immune response to an actual viral challenge. Indeed, poorer responses to vaccination are associated with a greater risk for developing infectious illnesses. ⁶⁶ Vaccination allows the individual to enhance the immune response to a given antigen. The memory lymphocytes formed during the primary response ensure a faster and stronger immune response on reexposure to the live virus. For most vaccines, optimal responses involve both humoral and cellular immunity. The individuals must be able to mount and maintain an antigen-specific antibody response to the vaccine. Furthermore, cellular immune responses such as production of IL-2 and IFN-γ following antigen exposure are necessary for an effective clearance of the pathogen.

Dementia caregiving stress impairs vaccination responses. An influenza vaccine was administered to family dementia caregivers and demographically similar noncaregiving controls. A month later, IgG antibody levels and PBMCs’ IL-2 response to an influenza challenge were assessed. Caregivers were less likely to exhibit a 4-fold increase in IgG antibodies, that is, a protective response to the vaccine compared with controls. Following an in vitro influenza challenge, caregivers’ PBMCs exhibited a smaller IL-2 response than the cells from noncaregiving controls, indicating an impairment in both humoral and cellular immunity to the vaccine. ⁶⁷ Similarly, parents caring for a child with developmental disability had fewer antigen-specific antibody titers following influenza and pneumococcal immunization compared with parents of developmentally normal children.^68,69 Caregiving stress was also associated with greater cortisol production, which was in turn related to smaller IgG antibody titers 2 weeks postimmunization. ⁷⁰ In addition to the impact of stress on the initial response to the immunization, chronic stress also impaired the maintenance of the vaccine response over time. Although family dementia caregivers and noncaregiving controls had a similar IgG response to pneumococcal pneumonia vaccination 1 month postimmunization, current caregivers exhibited a greater decrease in IgG antibody titers than controls at the 3- and 6-month follow-up. ⁷¹ This rapid decrease in IgG antibody titers may leave these older adults more vulnerable to develop potentially life-threatening respiratory illnesses.

A series of studies examined how self-reported distress influenced vaccination responses among college students. Medical students received the 3 doses of the hepatitis B inoculation during 3 academic examination periods. Individuals who seroconverted after the first dose had less stress and anxiety across the 3 examination periods. ⁷² Greater perceived stress and a larger number of stressful life events in the past year has also been associated with poorer antibody response to influenza, hepatitis B, and meningitis C vaccination among healthy young adults.^73-77 However, these results have not been replicated in all studies.^78-80 One possible explanation for these nonreplications is the notion that more intense stress or stress occurring among vulnerable populations is more likely to induce immune dysregulation.

Latent Viruses

Most viruses are cleared after the primary infection. However, viruses from the herpes virus family remain in the host’s body by transitioning into a latent state in which they are not detected by the host’s immune system. Reactivation of these opportunistic viruses occurs when cellular immunity wanes. During reactivation, a large quantity of viral proteins is produced. Therefore, higher circulating levels of the latent-virus–specific antibodies paradoxically represent a proxy for impairment in cell-mediated immunity.

The clinical impact of latent virus reactivation depends on the type of virus and on the population infected. Latent virus reactivation predicted increased morbidity and mortality among immunosuppressed individuals such as organ transplant recipients and treated HIV-positive individuals.^81,82 Among healthy individuals, reactivation of herpes simplex virus (HSV) I and II can lead to cold sores, whereas reactivation of varicella zoster virus (VZV) can promote shingles. Reactivation of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) typically does not cause clinical symptoms among healthy individuals. ⁸³ However, recent data suggest that these latent viruses may contribute to immunosenescence. ⁸³

Although there is heterogeneity of results between studies, a meta-analysis suggests that greater self-reported stress and distress are associated with a higher risk for symptomatic HSV I recurrence. ⁸⁴ However, as stated above, latent viruses often reactivate without leading to clinical symptoms. Nevertheless, latent virus reactivation can be conceptualized as a marker of stress-induced immune dysregulation.

More than 95% of the adult population is infected with the ubiquitous EBV. ⁸⁵ Because of the high prevalence of this herpes virus, changes in EBV antibody titers may represent a sensitive marker to study stress-induced immune dysregulation at the population level. ⁸⁶ Family dementia caregivers had greater EBV and HSV-1 antibody levels compared with demographically similar noncaregiving controls.^61,87 Furthermore, individuals who experienced the traumatic stress of living close to the Three Mile Island damaged nuclear plant exhibited higher HSV-1 antibody levels in comparison with matched community controls who lived more than 80 miles from the damaged facility. ⁸⁸

Interpersonal stress can also impair immune control over latent viruses. Women who experienced divorce or separation in the previous year had greater EBV antibody titers than women who were currently married. ⁸⁹ Men reporting dissatisfaction in their marital relationship exhibited greater EBV reactivation than those who reported better marital quality. ⁹⁰ Furthermore, the presence of childhood abuse was associated with higher HSV-I antibody titer levels among adolescents. ⁹¹

More time-limited stressors such as academic examinations can also promote latent virus reaction. Medical students showed greater EBV, HSV-1, and CMV antibody titers on the day of an examination than during a non–examination period.^92-95 Greater levels of depression and anxiety have also been related to greater EBV, HSV-1, and VZV antibody titers.^96,97 Among community-dwelling adolescent girls, a greater number of stressful life events was associated with higher EBV antibody titers. ⁸⁶ Taken together, results from live virus inoculation, vaccination, and latent virus studies suggest that chronic stress may increase susceptibility to infectious illnesses.

Chronic Stress and Behavioral Change

As detailed above, chronic stress–induced immune dysregulation can occur via some direct physiological routes. In addition, an indirect behavioral pathway can also promote immune dysregulation. Individuals undergoing chronic stress tend to adopt behaviors that can be damaging to their health and discontinue behaviors that could have protective health effects.^98,99 These behavioral changes are thought to underlie some of the immune changes observed among individuals experiencing chronic stress. ¹⁰⁰

Regular physical exercise and greater cardiovascular fitness have been associated with lower circulating levels of proinflammatory cytokines and CRP. ¹⁰¹ Regular physical activity also speeds up the wound healing process. ¹⁰² Furthermore, individuals who exercised more than 3 times per week had a lower risk of developing an upper-respiratory infection after an experimental exposure to influenza viruses compared with participants who engaged in physical activity less often. ¹⁰³

Smoking and large alcohol intake have been associated with increased circulating inflammatory mediators.^104-106 Tobacco can impair wound healing, and heavy alcohol use delays cell migration and collagen deposition at the wound site.^107,108 Moreover, tobacco use also has been associated with a greater likelihood of developing a common cold after an experimental exposure to rhinovirus. ¹⁰³

Sleep deprivation in laboratory studies led to increases in inflammatory mediators the following day. ¹⁰⁹ In epidemiological studies, self-reported sleep quality has also been related to circulating markers of inflammation. ¹¹⁰ Furthermore, low sleep efficiency (the percentage of time spent sleeping over the percentage of time spent in bed) was associated with an increased risk of developing clinical symptoms following exposure to influenza viruses. ¹⁰³

Diet can influence immune function, and stress promotes poor diet choices. A high-fat meal, but not a high-carbohydrate meal, was associated with subsequent increases in plasma IL-6. ¹¹¹ In epidemiological studies, high levels of omega-3 (n-3) polyunsaturated fatty acids have been associated with lower circulating markers of inflammation. ¹¹² Furthermore, inadequate intake of glucose, polyunsaturated fatty acids, proteins, and certain vitamins can delay the wound healing process.^113,114

Behavioral Interventions and Immune Outcomes

Some behavioral stress management interventions can attenuate stress-induced immune dysregulation. In a pilot study, a cognitive-behavioral therapy reduced plasma levels of IL-6 and CRP among women who underwent a coronary artery bypass surgery. ¹¹⁵ Frequent yoga practitioners also have lower CRP levels compared with non–yoga practitioners. ¹¹⁶ Moreover, cognitive-behavioral stress management improved antibody response to influenza among family dementia caregivers. ¹¹⁷ A mindfulness meditation intervention also enhanced immune responses to influenza vaccination among healthy adults. ¹¹⁸ Cardiovascular exercises training improved the primary antibody response to vaccines and antigens and lowered inflammation in animal and human studies.^119-121 Furthermore, progressive muscle relaxation training, but not an increased social contact intervention, led to a reduction in EBV antibody titers among healthy older adults. ¹²² A 16-week Tai Chi intervention increased VZV-specific immunity compared with a health education intervention. The magnitude of the change associated with the Tai Chi intervention was similar to that of a VZV vaccine. Furthermore, the Tai Chi intervention augmented the impact of a VZV vaccine, inducing additive increases in cell-mediated immune response to VZV among participants who received both the Tai Chi intervention and the VZV vaccine. ¹²³ A written emotional disclosure intervention, in which the participants are invited to write about a traumatic event that occurred in their life, can decrease emotional distress. In healthy young men who were randomized to the written emotional disclosure intervention, a standard punch biopsy wound healed faster compared with the healing time for participants who wrote about neutral topics. ¹²⁴ This section presented studies reporting positive impact of stress reduction interventions on immune function. However, it is important to note that not all studies have found such an effect or that the effect found is sometimes so small that it is unlikely to be clinically significant. ¹²⁵ Replication of the positive effect presented above is therefore an important endeavor.

Conclusions and Future Directions

A growing body of literature shows that chronic stress can lead to immune dysregulation. Specifically, replicated evidence suggests that chronic stress induces a state of chronic low-grade inflammation, delays wounds healing, increases susceptibility to upper-respiratory infections, weakens vaccine responses, and disrupts immune control of latent viruses. Notably, the chronic stress–induced physiological changes are large enough to affect disease processes and responses to medical interventions.

Given the broad impact of chronic stress on psychological well-being, health behaviors, and immune function, routine assessment of chronic stress is warranted among vulnerable or at-risk populations. Adoption of health-related behaviors, stress management interventions, and pharmacotherapy can prevent or attenuate stress-induced immune dysregulation.

Stress-induced immune changes can be site- or cell-specific. ¹²⁶ Future research should examine the impact of chronic stress on disease-specific immune processes rather than relying on nonspecific or circulating immune markers. The elucidation of the precise physiological mechanisms of stress-induced immune dysregulation will promote the development of targeted pharmacological interventions. Furthermore, because behavioral changes account for some of the stress-induced immune dysregulation, the development and refinement of effective behavioral interventions in the context of chronic stress is also much needed.