Health care education, delivery, and quality Update review Stress and atopic disorders

Rosalind J. Wright, MD, MPH Boston, Mass

Evidence linking psychological stress to the expression of asthma and atopy continues to grow. Examining the underlying molecular mechanisms linking stress to asthma and other allergic phenomena is an active area of research. Evidence is reviewed for the inuence of stress on neuroimmunoregulation and oxidative stress pathways, which, in turn, may affect biological hypersensitivity to environmental stimuli characteristic of atopic disorders. Critical periods of development, including in utero environment, are underscored. The role of genetics and gene-by-environment interactions is also discussed. (J Allergy Clin Immunol 2005;116:1301-6.) Key words: Asthma, atopy, psychological stress, oxidative stress, psychoneuroimmunology, genetics

Abbreviations used CNS: Central nervous system CRH: Corticotrophin-releasing hormone HPA: Hypothalamic-pituitary-adrenocortical ROS: Reactive oxygen species SAM: Sympathetic and adrenomedullary

Asthma and other allergic diseases have long been considered psychosomatic disorders. Indeed, before we better understood the underlying inammatory basis of asthma, it was among the disorders believed to be purely psychogenic in origin, commonly referred to as asthma nervosa in early medical texts.1 Atopy may be dened as a genetically and environmentally determined predisposition to clinically expressed disorders, including allergic rhinitis, atopic dermatitis or eczema, and allergic asthma, regulated through immune phenomena in which many cells (ie, mast cells, eosinophils, and T lymphocytes) and associated cytokines, chemokines, and neuropeptides play a role. Overlapping mechanisms of inammation central to the pathophysiology of these atopic disorders involve a cascade of events that include the release of immunologic mediators triggered by both IgE-dependent and IgE-independent mechanisms. Biological hypersensitivity to environmental stimuli is a central feature of atopic disorders. Increasingly, atopy has been conceptualized as an epidemic of dysregulated immunity. The exploration of host and environmental factors that may alter neuroimmune
From the Channing Laboratory, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School; and the Department of Society, Human Development, and Health, Harvard School of Public Health. Supported by the National Heart, Lung, and Blood Institute: R01 ES10932, R01 HL64108, and U01 HL072494. Received for publication June 2, 2005; revised September 27, 2005; accepted for publication September 29, 2005. Reprint requests: Rosalind J. Wright, MD, MPH, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115. E-mail: rosalind.wright@ channing.harvard.edu. 0091-6749/$30.00 2005 American Academy of Allergy, Asthma and Immunology doi:10.1016/j.jaci.2005.09.050

expression and potentiate the expression of atopic disorders is an active area of research. Both genetic and environmental factors affecting maturation of the immune system during childhood set the stage for the inammatory processes and altered reactivity to stimuli that are characteristic of atopic disorders. Psychological stress may thus play an important role in both the onset of these disorders and the exacerbation of existing atopic disease. It is helpful to begin the discussion by summarizing key aspects of how psychological stress has been conceptualized in human research.2 Three broad traditions of assessing the role of psychological stress in disease risk have been distinguished (ie, environmental, psychological, and biological). The environmental tradition focuses on assessment of events associated with adaptive demands, whereas the psychological tradition focuses on the subjective evaluation of ones ability to cope with these demands. If environmental demands are found to be taxing or threatening, and coping resources are viewed to be inadequate, individuals perceive themselves as being under stress.3 This perception is presumed to result in negative emotional states (eg, fear, anxiety, posttraumatic stress symptoms, depression). Finally, the biological tradition focuses on activation of specic physiological systems. Behavioral and emotional changes that follow the effort to adapt to stressors are accompanied by complex patterns of neuroendocrine and immunologic alterations.4 Typical stressors considered in health research include factors such as major life events, trauma, and abuse, as well as less intense chronic psychological pressure induced during work and personal relationships.2 Exposure to acute stress generates an adaptive individual response, such as ght or ight. Chronic stress is generally thought of as the chronic load of day-to-day stressors. Researchers have long recognized that stress may protect the body, but when more chronic, can also damage it.5 Furthermore, there appear to be individual or host differences in the bodys response to similar levels and duration of stress.6,7 An individuals response to acute challenges is
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FIG 1. Model of the stress process designed to illustrate the integration of psychological responses to environmental stressors, which, in turn, may inuence the expression of atopic disorders.

altered when superimposed on chronic stress.8,9 The reasons behind such individual differences in susceptibility may be key in understanding the functional consequences of chronic psychological stress. These central themes in stress research need to be considered when interpreting studies linking psychological stress and emotion to health outcomes. Mechanisms linking psychological stress, personality, and emotion to neuroimmunoregulation10-12 as well as increased risk of atopy13 have been increasingly elucidated. Advances in our understanding of psychoneuroimmunology and the bidirectional links among the central nervous system (CNS), autonomic nervous system in the periphery, endocrine system, and immune system have been critical. Hormones and neuropeptides released into the circulation when individuals experience stress may also regulate both immune-mediated and neurogenic inammation. Our current understanding of the role of psychological stress in atopy is discussed. Note that this review focuses specically on proposed physiological mechanisms linking stress to asthma as summarized in Fig 1. The expression of asthma may also be inuenced by behavioral stress responses that have been reviewed previously.14

balance, and the absence of this optimal balance in levels of glucocorticoids and catecholamines (for example) allows other immune mediators to overreact and increases the risk of autoimmune and inammatory disorders. The direction of the HPA response to chronic stress may depend on the nature of the stressor (ie, with respect to duration, severity, controllability, and predictability). Moreover, a well-known characteristic of stress axis functioning is the marked interindividual variability of responses to challenge,6 and the understanding of the relevance of this neuroendocrine system in asthma and allergy pathophysiology requires the identication of the determinants of this variability. Genetic factors, in utero and postnatal environmental factors, and the timing of exposures likely affect differentiation of this response. Although hormones of the sympathetic and adrenal medullary and HPA systems (eg, cortisol, epinephrine) are those most often discussed as the biological substances involved in stress responses, alterations in a range of other hormones, neurotransmitters, and neuropeptides demonstrated in response to stress may also play a part. Regulatory pituitary (ie, corticotrophin) and hypothalamic hormones (ie, corticotrophin-releasing hormone [CRH] and arginine vasopressin) of the HPA axis have systemic immunopotentiating and proinammatory effects. Mast cell mediators are responsible for many of the immediate symptoms of nasal allergy and manifestations of atopic dermatitis. Acute psychological stress (immobilization in rats) has been shown to result in skin mast cell degranulation, an effect inhibited by anti-CRH serum administered before stress. Mechanisms linking stress and mast cell function have been extensively reviewed recently.15 For example, stressor-associated increases in substance P, growth hormone, and prolactin secreted by the pituitary gland and in the natural opiate b-endorphins and enkephalins released in the brain are also thought to play a role in immune regulation. Although these factors have been less well studied to date, increasing attention has been given to the role of substance P in mediating inammatory responses in the lung.

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PSYCHOLOGICAL STRESS AND THE ENDOCRINE SYSTEM

Psychological stress has been associated with the activation of the sympathetic and adrenomedullary (SAM) system and the hypothalamic-pituitary-adrenocortical (HPA) axis (see detailed review14). It is the disturbed balance of these systems that is relevant to disease. Immune, metabolic, and neural defensive biological mechanisms important for the short-term response to acute stress may produce long-term damage if not checked and eventually terminated in the face of more chronic stress.5 Negative emotional responses to environmental stressors disturb the regulation of the HPA axis and the SAM systems; that is, in the face of stress, physiological systems may operate at higher or lower levels than during normal homeostasis. The central notion is that some optimal level of these mediators is necessary to maintain a functional

STRESS AND AUTONOMIC CONTROL OF AIRWAYS

The balance between functional parasympathetic and functional sympathetic activity in relation to stress, emotional stimuli, and immune function may also be important for the expression of asthma and allergic rhinitis. Local interactions between the immune system and the autonomic nervous system are only partially understood.16,17 Increased activity of the parasympathetic nervous system was once thought to be the dominant mechanism responsible for the exaggerated reex bronchoconstriction (airway narrowing) that occurs in subjects with asthma, although more recent work challenges this idea. Evidence suggesting several cholinergic anti-inammatory pathways triggered through vagus nerve activation18 complicate our understanding and need to be explored in the context of atopy.

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Evidence demonstrating nervemast cell communication in response to stress and the potential import of these interactions in the respiratory system suggests this may be a fruitful area of research relative to stress and allergic asthma.17 Tachykinins derived from nonadrenergic noncholinergic (NANC) nerves inuence airway smooth muscle contraction, mucus secretion, vascular leakage, and neutrophil attachment. In experimental studies, tachykinins, especially substance P, have been linked to neurogenic inammation and regulation of stress hormonal pathways and have been implicated in asthma and neurogenic skin disorders.17 When immune cells (ie, T cells, mast cells, dendritic cells, and macrophages) are activated locally (eg, in the airways) and release proinammatory molecular mediators, these signals not only inuence cells of the innate and adaptive immunological system in the periphery but also activate sensory pathways that relay information to the CNS.16 The precise mechanisms by which the peripheral immune system signals the CNS is only partially understood. Stimulation of sensory nerves in the airways specically ascending vagus nerve bers as well as pain sensory pathways (vagal nonmyelinated lung C bers and Ad rapidly adapting receptors)results in CNS reex responses consistent with asthma symptoms (eg, bronchoconstriction, cough, mucous secretion). These neural inammation-sensing pathways can function at low thresholds of detection and activate responses even when inammatory mediators are present in the airway tissues in quantities too low to reach the brain through the bloodstream. Both animal studies and human imaging data have identied neurobiological correlates that shed further light on neuroimmunological mechanisms underlying the lungbrain link. Airways function in response to stimuli, including irritants, allergens, and inammatory mediators. Chen et al19,20 have demonstrated the ability of the nucleus tractus solitarius, a CNS region containing neurons that process lung sensory signals, to undergo marked changes in excitability in the face of extended exposure to irritants (ie, allergen exposure, ozone exposure, and tobacco smoke). These toxicants share commonalities in the responses they may illicit in the airways (eg, local release of inammatory mediators, oxidative stress, and activation of sensory neurons) that may contribute to the respiratory inammatory and motor response. These processes may be mediated, in part, through substance P.21 A logical extension of this work in the context of this discussion is whether extended episodic exposures to psychological stressors would change the neural behavior of neurons in the CNS and also inuence the CNS neural contribution to asthma and the allergic airway response. Further research into the neurobiological correlates of atopy may lead to a more complete understanding of the lung-brain link.

STRESS AND IMMUNE FUNCTION

Atopic inammation is thought to be orchestrated by activated T lymphocytes and the cytokines they produce.

The TH2 cytokine phenotype promotes IgE production, with subsequent recruitment of inammatory cells that may initiate and/or potentiate allergic inammation. For most children who develop allergies or asthma, the polarization of their immune system into an atopic phenotype probably occurs during early childhood. These ndings have sparked vigorous investigation into the potential inuence of early life environmental risk factors for asthma and allergy on the maturation of the immune system, in the hopes of understanding which factors will potentiate (or protect from) this polarization. There is evidence that parental reports of life stress are associated with subsequent onset of wheezing in children in early childhood22 (also see references within article22). This relationship led to speculation that stress may trigger hormones in the early months of life, which may in turn inuence TH2 cell predominance, perhaps through a direct inuence of stress hormones on the production of cytokines that are thought to modulate the direction of differentiation. Further examination of the relationships between caregiver stress on markers of early childhood immune response including IgE expression, mitogen-specic, and allergen-specic lymphocyte proliferative response, and subsequent cytokine expression (IFN-g, TNF-a, IL-10, and IL-13) was performed in the same prospective birth cohort mentioned23 when the children were 2 to 3 years of age. In adjusted analyses, higher caregiver stress in the rst 6 months after birth was associated with increases in the childrens allergen-specic proliferative response (a marker of the allergic immune response), higher total IgE levels, and increased production of TNF-a and reduced IFN-g. Recent animal data suggest that increased maternal stress prenatally is associated with an elevated cortisol response to stress in the newborn, affecting TH1/TH2 cell differentiation.24 Although the ability to activate an increase in cortisol in response to some stimuli in early life may be adaptive, prolonged exposure to stress may change the cortisol response if examined at a later developmental stage. Chronic stress may induce a state of hyporesponsiveness of the HPA axis whereby cortisol secretion is attenuated, leading to a shift in the balance of proinammatory/anti-inammatory cytokines secreted (ie, increased production of proinammatory cytokines typically counterregulated by cortisol). Several altered neuroendocrine and immune changes in response to stress have been demonstrated in subjects with atopic dermatitis: altered responsiveness of the HPA axis and the SAM system, increased eosinophil counts, and elevated IgE expression.25 Whether the altered HPA responsiveness will lead to increased risk of developing atopy in later life remains to be seen. A state of stress-induced HPA hyporesponsiveness has been demonstrated in some research subjects with chronic atopic disorders.26 An attenuated cortisol response has been found among adolescents with positive skin test reactivity and a clinical history of allergic rhinitis, atopic dermatitis, or asthma compared with those with skin test positivity alone or nonatopic individuals. Further studies are needed to examine relationships between individual patterns of cortisol response to

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stress across different developmental periods and the subsequent expression of atopy.

STRESS AND GLUCOCORTICOID RESISTANCE

An alternative hypothesis linking stress, neuroendocrine and immune function, and inammatory disease expression considers a glucocorticoid resistance model.27 As we have come to understand the central role of airway inammation and immune activation in asthma pathogenesis, asthma treatment guidelines have focused on the use of anti-inammatory therapy, particularly oral and inhaled glucocorticoids or steroids. Patients with asthma, however, have a variable response to glucocorticoid therapy. Although the majority of patients readily respond, a subset of patients has difcult-to-control asthma even when treated with high doses. Notably, the majority of subjects with glucocorticoid-resistant or glucocorticoid-insensitive asthma have an acquired form of steroid resistance thought to be induced by chronic inammation or immune activation. Thus, it is important to investigate those factors that may potentiate the development of functional steroid resistance so that we might intervene to prevent or reverse it. It has been proposed that chronic psychological stress, resulting in prolonged activation of the HPA and SAM axes, may result in a counterregulatory response in stimulated lymphocytes and consequent downregulation of the expression and/or function of glucocorticoid receptors leading to functional steroid resistance.27,28 This in part may be mediated through downregulation of the gene coding for the expression of the glucocorticoid receptor (Miller G, personal communication, September 2005).

RELEVANCE OF PERINATAL PHYSIOLOGICAL PROGRAMMING AND EARLY LIFE STRESS

Studies suggest that characteristics of the in utero environment, independent of genetic susceptibility, inuence fetal development, including immune development.29,30 The concept that nongenetic factors act early in life to organize or imprint physiological systems permanently is known as perinatal programming. Adverse environmental inuences at critical periods of development (ie, stress) may be important in this regard. The HPA axis seems particularly susceptible to early life programming.31 Maternal and fetal stress stimulates placental secretion of CRH, which in turn may stimulate the fetal HPA axis to secrete glucocorticoids, amplifying fetal glucocorticoid excess. These in utero responses may be adaptive in the short term (ie, increasing the availability of glucose and other fuels), geared toward coping with predicted increased environmental challenges, but they exact a toll in that there is an increased risk of disease in later life. Moreover, gestational exposure to maternal stress has been shown to alter the development of humoral immunocompetence in offspring as well as their hormonal and immunologic responses to postnatal stress.32

Early childhood environment can also affect these processes. Studies in both rodents and primates have shown that environmental manipulations that increase maternal stress result in elevated cortisol levels and dysfunctional behaviors in offspring that are evident later in life, which may be mediated, in part, through effects on gene expression.33 Numerous retrospective studies in human HPA functioning suggest that increased reactivity of the HPA system is associated with early life trauma and severe deprivation. Studies of infants and toddlers have linked maternal depression to dysregulation of the childs HPA axis in both cross-sectional and longitudinal studies. Other studies of preschoolers and older children suggest that childrens cortisol levels are positively correlated with numerous social stresses and to broader family characteristics known to be associated with higher stress levels (eg, low socioeconomic status). For example, Essex et al34 examined the relationships of maternal stress beginning in infancy and concurrent stress on preschoolers (age 4.5 years) HPA activity and later mental health outcomes. A cross-sectional analysis revealed that preschoolers exposed to high levels of concurrent maternal stress had elevated cortisol levels. Longitudinal analyses showed that concurrently stressed children with elevated cortisol also had a history of high maternal stress exposure in infancy. Importantly, children exposed only to high levels of concurrent or early stress had cortisol levels that did not signicantly differ from those never exposed to stress. Also of note, further analysis of the components of stress indicated that maternal depression beginning in infancy was the most potent predictor of childrens cortisol. Preschoolers with high cortisol levels also were more likely to have greater mental health difculties in rst grade. Future studies should be designed to examine whether the link between early stress (specically maternal stress even starting in pregnancy) and later expression of asthma/wheeze clinical and immune phenotypes is in part mediated through dysregulation of the HPA axis.

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PSYCHOLOGICAL STRESS AND OXIDATIVE STRESS

Oxidative stress pathways also play an important role in the regulation of inammatory mediators that may be involved in atopy. Inammation is frequently mediated by reactive oxygen species (ROS), either acquired exogenously or as byproducts of normal metabolism. Individuals differ in their ability to deal with oxidant burdens because of either genetic factors or other environmental factors that induce or augment oxidative stress. It has been proposed that differences in host detoxication provide the basis for either resolution or progression of inammation in atopic individuals and that the inability to detoxify ROS species among atopic subjects leads to the release of chemotactic factors, the activation and recruitment of immune effector cells, prolonged inammation, and the stimulation of bronchoconstricting mechanisms.35 Suggested factors that

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GENETICS
Variation in genes involved in immune regulation is associated with biologic and clinical phenotypes in the rst year of life that may increase risk for the subsequent development of childhood asthma.39 Moreover, geneenvironment interactions inuencing the early patterning of the immune system and the subsequent development of asthma have been described in the rst year of life. By considering genetic factors that may be relevant to both the stress response and atopy, we may better elucidate the mechanisms underlying the links among stress, the HPA axis, and HPA-related clinical states (eg, asthma/atopy). Transient changes in the expression of stress responsive genes and more prolonged aberrant gene regulation may lead to maladaptive physiologic and behavioral changes to inuence disease.40 Most advances in our knowledge of the genetic and molecular events underlying the neurobiology of the stress response have occurred in animal models. Studies to determine the role of genetics in modifying the risk of the social/physical environment experienced through psychological stress may further inform pathways through which stress may affect asthma expression. Genetic factors of potential import include those that

CONCLUSION
Psychological stress should be conceptualized as a social pollutant that can be breathed into the body and disrupt several physiological pathways, similar to how air pollutants and other physical toxicants may lead to increased risk for atopy. Stress may have independent effects but also may play a role through the enhancement of neuroimmune and hypersensitivity responses to other environmental factors operating through overlapping pathways.

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predispose susceptible subjects to allergic inammation and asthma include chronic exposure to oxidative toxins (tobacco smoke, air pollution).36,37 Psychological stress may be an additional environmental factor that augments oxidative toxicity and increases airway inammation. There is evidence that psychological stress has pro-oxidant properties that augment oxidative processes. Psychological stress has been noted to decrease DNA repair and will inhibit radiation-induced apoptosis in human blood cells, ndings suggesting that psychological stress may increase the likelihood of oxidative stress induced pathology. Rats treated with ferric nitrilotriacetate, an oxidant, and conditioned to associate treatment with taste aversion therapy produced increased levels of 8-deoxy-hydroxy-guanosine, a commonly used biomarker of oxidative stress, with further taste therapy than unconditioned animals. Perhaps most interestingly with respect to mechanism, psychological stress has been demonstrated to increase activity of hepatic enzymes, which activate polycyclic aromatic hydrocarbons in rats. Similarly, chronic stress has been shown to increase the levels of lipoperoxides in rat livers and plasma and decrease levels of reduced glutathione in erythrocytes and liver. Evidence also supports the notion that psychological stress modies the host response to other inammatory oxidative toxins. Recent animal data support a role for an oxidative/antioxidative imbalance inuencing a shift toward a TH2 phenotype in a model of autoimmunity in the rat.38 These studies have been reviewed elsewhere.13 Given that both tobacco smoke and air pollution contain toxins that generate ROS when metabolized, stress may interact with these physical environmental factors to augment oxidative toxicity, leading to increased expression of asthma and allergic rhinitis.

inuence immune development and airway inammation in early life, corticosteroid regulatory genes, adrenergic system regulatory genes, biotransformation genes, and cytokine pathway genes. A recent review summarized studies that address the question to what extent genetic factors contribute to interindividual differences in HPA axis activity.40 Studies demonstrate the inuence of genetic factors on variation in the cortisol awakening response and baseline cortisol levels in both adults and children.40,41 Variants of the glucocorticoid receptor gene may contribute to interindividual variability in HPA axis activity and glucocorticoid sensitivity in response to stress. Additional presumably good candidates include polymorphisms in the genes coding for factors involved in the feedback mechanisms in the glucocorticoid response to stress such as corticotrophin-releasing hormone (CRHR1 and CRHR2 genes), TNF-a, and other cytokine loci. Proinammatory cytokines (including TNF-a) are considered the principal messengers between the CNS and immune system in the biological stress response. Elevated TNF-a can activate the HPA axis and has been associated with increased cortisol.42 In chronic stress, more persistently elevated TNF-a may result in dysregulation of the HPA axis. Moreover, many effects of TNF-a are mediated by the induction of a cellular state consistent with oxidative stress.43 The inuence of stress on physiologic programming may also vary based on an individuals genetic background. This is supported by strain differences in hormonal and behavioral responses to stress in rats and mice. For example, data suggest that feto-placental 11-b-hydroxysteroid dehydrogenase type 2 may play an important role in modulating the programming effects of prenatal endogenous glucocorticoid exposure.44 Interperson and interstrain (mouse) variability in the expression and efciency of feto-placental 11-b-hydroxysteroid dehydrogenase type 2 has been documented.45,46 Genes expressed in the lung involved in determining the effects of oxidative stress, specically the glutathione S transferases, have been found to be functionally and clinically signicant in recent studies related to atopic risk. Specic glutathione-S-transferase P1 variants have been associated with increased histamine and IgE responses to air pollution oxidants and allergen in vivo. Maternal genetics related to oxidative stress genes may inuence the childs atopic risk beginning in utero.47

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