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Dermatologic Clinics
Volume 23 • Number 4 • October 2005
Copyright © 2005 W. B. Saunders Company





Stress and Psychoneuroimmunologic Factors in Dermatology


Mauro Urpe, PhD a, b
Gionata Buggiani, MD c
Torello Lotti, MD b, *



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a Centro Interuniversitario di Dermatologia Biologica e Psicosomatica, University of Florence, Florence, Italy
b University Unit of Physical Therapy and Dermatology, University of Florence, Florence, Italy
c Department of Dermatology, University of Florence, Florence, Italy
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* Corresponding author. Department of Dermatology, University of Florence, Via della Pergola, 58/60, 50121 Florence, Italy

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There is clinical and experimental evidence that the brain can start, influence, and stop biologic skin events. Studies suggest that the skin, as a relevant part of the “diffuse brain,” can modify the quality of perceptions and feelings. The immune and the endocrine systems seem to represent the protagonists of the modulation of those events and, in this context, psychosocial stressors and interventions can lead to global health changes of great interest for dermatologists.


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Psychologic and social factors are believed to influence disease processes via two main mechanisms: psychosocial processes and health-oriented behaviors. Psychosocial processes include factors that affect interpretation of and response to life events and stressors, such as mental health and mood factors, personality characteristics, and resources, such as social relationships. Health-oriented behaviors (exercise, nutrition, and smoking) serve as indirect pathways by which psychosocial processes can influence health, as they may be influenced strongly by factors such as mood [1]. Within the domains of psychosocial processes and behavioral health, there are factors believed to serve as resources to enhance health (eg, social support and exercise) and vulnerability (eg, depression and cigarette smoking). These factors can be acute (eg, temporary lack of sleep before writing a grant) or chronic (eg, caregiving for a chronically-ill spouse). According to the biopsychosocial model, these psychosocial factors interact with a person's biologic characteristics (eg, genetic or constitutional) creating a vulnerability to disease processes [2]. Moreover, according to this model, a genetic predisposition to disease development (also known as “diathesis”) may remain latent until stress events, which can be represented bypsychosocial factors interacting with a person's biologic characteristics, make the disease unfold.

Psychoneuroimmunology (PNI) was comprehensively described for the first time about 30 years ago. The influence of mental status on the course and outcome of a large number of diseases, however, was suspected long before then. The links between mental and affective disorders and immune status repeatedly were also suggested. PNI is commonly associated with the work of Ader and colleagues [3]. There also is clinical and experimental evidence that the body and mind communicate closely in health and illness. The association between illness and behavioral and psychologic states has been closely investigated recently showing that anxiety, sleep loss, bereavement, and certain external stress factors (eg, family illness, academic stress, unemployment) seem to affect immune function in some way. Not all the measured immune parameters were significantly altered in all these observations, however [4], [5], [6], [7], [8], [9]. More available data also seem to link mental affective disorders, such as major depression and mania, with impaired immune function [10], [11], [12].

The link between personal relationships and immune function is one of the most significant findings in PNI [13]. When close relationships are discordant, they can be associated with immune disregulation. For example, pervasive differences in endocrine and immune function are associated reliably with hostile behaviors during marital conflict among diverse samples, including newlyweds selected on the basis of stringent mental and physical health criteria and couples married for an average of 42 years [14], [15], [16], [17], [18]. On the basis of findings for negative affect and social support, aspects of personality and coping styles associated with negative moods or social relationships might well demonstrate, under certain circumstances, immunologic disorders. For example, personality and coping styles (repression, rejection sensitivity, attributional style, sociability) are associated with altered levels of leukocytes in peripheral blood counts and with a dysregulation in cellular immune function [19]. Indeed, optimism has been associated with more positive moods, coping, and differences in response to stress among law students in their first year of study, and these differences seemed to mediate optimists' better immune function [20]. In another study, highly hostile individuals exhibited an increase in natural killer (NK)–cell cytotoxity after self-disclosure, greater than that observed in individuals who had lower levels of hostility [21]. This supports the authors' hypothesis that persons high in cynical hostility find disclosure more threatening; no differences between highly hostile and less hostile participants were observed in the nondisclosure condition. The study of individual differences in PNI is in its infancy, but the data are promising. As the data on personality and coping suggest, differences in perceptions and reactions to the same events can provoke different endocrine and immune responses. In fact, neuroendocrine mechanisms may mediate the associations between personality and coping styles and immune function [19].



INTERVENTIONS
PNI intervention studies involve different strategies, including hypnosis, relaxation, exercise, classical conditioning, self-disclosure, exposure to a phobic stressor to enhance perceived coping self-efficacy, and cognitive-behavioral therapies with a range of populations [22]. One excellent series of studies demonstrates that 10-week cognitive-behavioral stress management and aerobic-exercise training programs buffer distress responses and immune alterations [23], [24], [25].



HOW DO PSYCHOLOGIC FACTORS INFLUENCE IMMUNE FUNCTION?
The endocrine system serves as a central gateway for psychologic influences on health. Stress and depression can cause the release of pituitary and adrenal hormones that have multiple effects on immune function [26]. For example, negative emotions may also indirectly contribute to immune dysregulation evidenced by proinflammatory cytokine overproduction and repeated chronic or slow-resolving infections or wounds that enhance the secretion of proinflammatory cytokines—a process leading to further inhibition of certain branches of immune responses (eg, decreased levels of interleukin [IL]-2, an important defense against infection)—thus perhaps contributing to the immunodepression of aging [27]. Negative emotions, such as those evoked by depression or anxiety, can affect the immune system effectors directly and either up- or down-regulate proinflammatory cytokine secretion. In addition, negative emotions may also contribute to the self-maintenance mechanisms of chronic infections and pathologic delay in wound healing; two processes that indirectly boost proinflammatory cytokine production.

The relationship between psychiatric syndromes or symptoms and the immune system has been a consistent theme for decades. Early studies of psychotic subjects report various immune alterations, including abnormal levels of lymphocytes [28], [29] and weaker-than-normal antibody response to whooping cough (Bordetella pertussis) vaccination [30] compared with nonpsychiatric controls. Subsequently, immunologic alterations are reported across a range of psychiatric disorders [31], [32]. The majority of psychopathologically focused studies, however, have dealt with immunologic alterations associated with affective and anxiety symptoms and disorders [33], [34], [35], [36]. There is consistent evidence that depression and anxiety can enhance the production of proinflammatory cytokines, including IL-6 [33], [34], [35], [36], [37], [38]—an significant finding related to the broad literature on the morbidity and mortality associated with depressive and anxiety disorders (discussed later) [33], [34], [35], [36], [37], [38], [39]. In addition to syndromal depressive disorders, depressive symptoms can also provoke immune system alterations leading to dysregulation with serious health consequences. Elevated depressive symptoms, for example, are associated with lower CD8+ T-lymphocyte counts and a higher rate of genital herpes simplex virus 2 recurrence over 6 months [34]. Depressive symptoms in HIV-positive homosexual men parallel decreased CD4+ T-cell count, increased B-cell count, and increased immune activation marker HLA-DR, even when standardized for disease stage and health behaviors [36].

The evidence supporting a relationship between psychopathologic symptoms and disorders and immunologic alterations seems convincing. Furthermore, negative affect, a characteristic of most psychopathologic diseases, is conceptualized as a key pathway for other psychologic modifiers of immune function (described later), in particular interpersonal relationships and personality.



PERSONALITY AND COPING
Personality and coping styles reflect individual differences in appraisal and response to stressors that may influence immune function. Reflecting the broader field of psychosomatic medicine at the time, much of the work before 1970 attempted to link personality traits to various diseases. For example, some researchers attempted to identify personality variables that predisposed individuals to allergic disorders [40], [41], [42]; skin reactivity to injected allergens (ie, wheal and flare size) was weaker in individuals who had personality styles described as passive, negative, withdrawn, unhappy, anxious, dissatisfied, and impulsive [4], [41], [42], [43]. In another arena, relatives of patients who had rheumatoid arthritis and who lacked rheumatoid factor in their serum were more anxious and dysphoric than those who had the factor [44]. Specific personality characteristics, such as academic achievement, motivation, and aggression, are associated with immunologic alterations.

Among cadets at a military academy, high motivation to perform well interacted with poor actual academic performance and predicted greater susceptibility to Epstein-Barr virus (EBV) infection [45]. Aggression, operationalized using Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition antisocial personality disorder symptoms [46], was positively associated with T- and B-cell levels in male military personnel; this effect was independent from testosterone level, age, health status, or behavior [47]. Coping styles associated with altered immunity include repression, denial, escape-avoidance, and concealment. Greater reliance on repressive coping is associated with lower monocyte counts, higher eosinophil counts, higher serum glucose, more self-reported medication-reactions in a retrospective chart review of medical outpatients [48], and higher EBV antibody titres in students (the latter finding suggesting a decrease in memory T-cell response to the latent virus [49]). Among family members of bone marrow transplant patients, escape-avoidance coping coupled with anxiety traits was associated with fewer total T cells and fewer CD4+ T cells; escape-avoidance coping by itself was associated with increased B-cell counts during the period preceding the transplant [50]. Denial coping seemed to have protective effects in homosexual men anticipating HIV-status notification. Among HIV-negative men, denial coping was associated with reduced intrusive thoughts, lower cortisol, and greater lymphocyte proliferation to phytohemagglutinin [51]. Although the majority of these studies were cross-sectional and involved students or young-to-middle–aged adults, one prospective study provided provocative evidence of notable health consequences. Concealment of homosexual identity predicted an accelerated course of HIV over 9 years of disease (assessed by CD4+ T-cell counts), AIDS diagnosis, and AIDS mortality, even when controlling for demographic, health, and psychopathology factors [52]. Personality or coping style associated with emotional or affection regulation is likely to have immunologic correlates and styles that influence interpersonal relationships. In this context, it is not surprising that self-disclosure interventions may have immunologic consequences. For example, high-hostility subjects exhibited greater increases in NK-cell cytotoxicity after self-disclosure than low-hostility subjects (discussed previously). Greater emotional disclosure by students on a written task was associated with lower EBV virus capsid antigen IgG antibody titers than students who expressed less emotion when describing a personal stressful event [49]. Thus, self-disclosure is believed to be a factor associated with the health benefits of psychotherapy. These data are consistent with recent evidence of improvements in disease activity after self-disclosure in patients who had asthma and arthritis [53].

The support provided by social relationships can serve as a buffer during acute and chronic stressors, protecting against immune dysregulation. For example, early studies suggest that lonelier medical students and psychiatric inpatients had poorer cell immune function than their counterparts who reported less loneliness [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57]. Subsequent investigators report that lower levels of social support in the context of naturalistic stressors, such as job strain [58], dementia caregiving [59], [60], and surgery [61], are associated with poorer immune function. Social support also may be important for immunity during the exposure to short-term stressors, such as examination tasks. Moreover, greater social support is linked with better immune responses to the hepatitis B vaccine in medical students [55]. The link between personal relationships and immune function is one of the strongest findings in PNI spanning diverse populations and stressors [13]. In a sample of men who were HIV-positive, low-perceived emotional support was associated with a more rapid decline in CD4+ T cells, an important marker of HIV-infection progression [62]. Higher NK-cell activity in female patients who had breast cancer was related to high-quality emotional support from husbands or mates, perceived social support from the patients' physicians, and the patients' actively seeking social support as a coping strategy [63]. Disruption of close relationships has well-documented consequences for immune function, whether or not the disruption is the result of bereavement [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [47], [48], [49], [50], [51], [52], [53], [54], [55] or divorce [58], [64], [65]. In addition, the maintenance of abrasive close relationships also exerts a toll; among newlywed couples engaged in a 30-minute conflict-resolution task, individuals who exhibited more hostile or negative behaviors during conflict showed greater decrements in functional immune measures 24 hours later [66] and concurrent alterations in stress hormones [63]. Similar patterns emerged in older couples married an average of 42 years [64]. These results were striking, particularly given that the majority of young and old couples had happy marriages; thus, these findings actually may underestimate the physiologic impact of troubled relationships [67].

Furthermore, a well-recognized model of chronic stress (eg, stress of caring for a spouse who has Alzheimer's disease) is linked to a host of immune impairments, including decreased NK response to interferon (IFN)-γ and IL-2, poorer lymphoproliferative response to mitogens, impaired antibody response to influenza vaccine, poorer responses to delayed hypersensitivity skin testing, higher levels of the sympathetic neurotransmitter neuropeptide Y, slower wound healing [68], and higher levels of IL-6 F [69]. Moreover, compared with noncaregivers, dementia caregivers exhibited higher percentages and increased numbers of CD4+ and CD8+ cells expressing T-helper cell–2 (Th-2) cytokine and IL-10; but no changes in expression of Th-1 cytokines, IFN-γ, or IL-2 in these cells were noted, suggesting a stress-related Th-1 to -2 shift. Dementia caregivers also reported more days of infectious illness than noncaregivers [1]. These findings indicate the importance of considering interactions between stress and aging in the context of the additional vulnerability that may be conferred by individual medical history. Repetitive patterns of short-term negative emotions also are believed to constitute chronic stressors [1].

PNI research has thus contributed to the larger literature on social relationships and health by delineating another pathway through which relationships can be beneficial or detrimental to health outcomes.

There now are sufficient data to conclude that immune modulation by psychosocial stressors or interventions can lead to actual health changes. Although changes related to infectious disease and wound healing provide the strongest evidence to date, the clinical importance of immunologic dysregulation is highlighted by increased risks across diverse conditions and diseases related to proinflammatory cytokines [62], [63], [67], [68], [69], [70], [71], [72], [73], [74], [75]. The PNI field has grown tremendously over the past two decades, and the future looks even more promising.



PSYCHONEUROIMMUNOLOGY IN DERMATOLOGY
Mental and psychic issues are also important in the genesis or development of many diseases. The psychologic or psychiatric genesis of a skin disease, however, still remains one of the most debated and controversial arguments present in contemporary medicine and academia. This controversy is in part due to the ease with which a poorly understand and hard to treat disease can be labeled as having “psychosomatic pathogenesis”. Labeling occurs often in dermatology because it is a field in which “elementary psychosomatic signs” are common (ie, pallor, sweat, horripilation, itch, and redness). Psychologic influence should be considered in dermatologic affections [76] and many common dermatologic diseases have some form of psychomediated pathogenesis that partly accounts for the development of lesions. Clinical observations show a well-defined link between acute or chronic emotional stressors, psychiatric diseases, conflict, hostility, personality, mood, and dermatoses (whether increased, developing, or in remission) and also report positive effects of psychopharmacology and psychotherapy on the same diseases. “Mental” events, such as hypnosis and psychologic stress, can influence delayed-type hypersensitivity responses, ultraviolet B ray–induced erythema, and the genesis of wheals after hystamine prick test [77]. Hyperhydrosis, telogen effluvium, idiopathic itch, lichen simplex, rosacea, alopecia areata, vitiligo, seborrhoic dermatitis, psoriasis, acnes, atopic dermatitis, viral warts, herpes simplex, and urticaria all can be associated with some psychomediated mechanism.

The psycho-immune-endocrine-cutaneous system functions as a primary route of communication between mind and body. The skin can be seen as the juncture of the simultaneous and connected activity of brain, immune system, and the skin itself. Neuropeptides, interleukines, and immune-system messengers are the means through which communication among the three entities takes place. α–Melanocyte-stimulating hormone (α-MSH) is one of the most investigated mediators in this system. α-MSH is a neuropeptide whose immune-modulating activity seems to inhibit inflammation generated in the skin [78], [79]. It is a 13-amino-acid–polipeptide derived from pro-opiomelanocortin and primarily synthesized by the hypophisis. α-MSH can also be released by the skin when a series of structures not belonging to the nervous system synthesize and release pro-opiomelanocortin, its derivatives, and a series of other substances after the “diffuse-brain” demonstration (substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, neuropeptide Y, etc), which are capable of influencing human sensations, feelings, and behavior [80].

Neuropeptides are released by skin cells and Aδ and C nerve fibers that link the nervous system and the skin itself. α-MSH, in particular, seems to decrease tumor necrosis factor α (TNF-α) and IL-1 release from macrophages and neutrophils and stimulates anti-inflammatory cytokine production (eg, IL-10). Furthermore, α-MSH may regulate the expression of cell mediators on the surface of immune cells. In animal models, the injection of α-MSH into the central nervous system of mice can inhibit cutaneous inflammation caused by topical irritatives and intradermic inoculation proinflammatory cytokines, such as IL-1β, IL-8, leukotriene B4, and platelet activating factor [81]. This may possibly occur through the local release of other neuropeptides, such as vasoactive intestinal peptide and calcitonin gene-related peptide. The mechanism of action, however, still remains partially unknown, but it would seem that these neuropeptides may also act directly by inhibiting proinflammatory cytokine production (TNF- α, IL-6, IL-1, and IL-2) and nuclear factor κB (NF-κB) expression (a proinflammatory transcription factor) by monocytes, macrophages, and neutrophils. Furthermore, α-MSH reportedly decreases IFN-γ release from activated lymphocytes and increase IL-10 production in peripheral blood monocytes [82], [83], [84].

α-MSH also seems to interfere with leukocyte migration from blood to sites of inflammation, modifying the expression of leukocyte and endothelial adhesion molecules and endothelial leukocyte and vascular cell adhesion molecules–1. These data suggest that α-MSH and other neuropeptides may function as novel powerful therapeutic antinflammatory agents in dermatology [84].

Only a few clinical and experimental studies, however, have investigated the association of these data and well-defined clinical entities (psoriasis, itch, etc.). A majority of the observations are limited to parallel clinical entities and macroscopic psychologic states. In other words, it is common knowledge that psoriasis is worsened by stress, but no clinical study convincingly reports which defined molecular mechanisms are involved in this phenomenon.

For other dermatoses, more investigation is required. Various speculative etiology and epidemiologic studies of atopic dermatitis are discussed repeatedly [85]. The basic consensus is that this disease consists of complex immunologic reactions that partially are inherited, although a few reports suggest that “allergy” is not always central to the development of atopic dermatitis [86]. Because atopic dermatitis is also a chronic skin disease, psychologic aspects of the disease must also be taken into account. Kasamatsu and colleagues stated that IL-4 serum levels in patients who have atopic dermatitis were significantly higher than those of normal controls [87]. Other investigators report that IFN-γ production by Th-1 and -0 cells predominates IL-4 production by Th-2 and -0 cells in the late and chronic phases of atopic patch tests in patients who have atopic dermatitis. Hashiro and Okumura [88] investigated the relationship between the psychologic and immunologic states in patients who had atopic dermatitis by measuring IL-4 and IFN-γ levels in serum. Although no significant correlation was detected between any pair of psychologic and immunologic results in patients or normal controls, psychologic variables seemed to affect serum IFN-γ significantly and, to a lesser degree, IL-4, in patients who had atopic dermatitis. Trait and state anxiety seem to affect NK-cell activity, although psychosomatic symptoms do not affect NK activity in patients who have atopic dermatitis. In sum, patients who have moderate or severe atopic dermatitis score significantly higher in depressive or anxiety states and, alternatively, show significantly lower NK-cell activity and IL-4 levels in serum than normal controls. Thus, in patients who have atopic dermatitis, psychologic factors seem to affect serum IFN-γ and IL-4, whereas NK activity is affected not by psychosomatic complaints but mainly by anxiety. Patients who have atopic dermatitis may differ from nonaffected ones by low NK-cell activity and slightly higher serum IFN-γ.

Regarding urticaria, in a high percentage of cases of chronic recalcitrant disease, the authors were not able to isolate the antigen or substances provoking the symptoms. This may be because an incomplete number of antigens were tested. Alternatively, it seems that “emotional allergy” [89] is more common than currently acknowledged. Psychologic factors also may contribute to urticaria in which the antigen is well known. Psychosocial and psychiatric factors may act in the pathogenesis of urticaria, increasing the release of neuro- and immunemediators, mainly from mast cells (eg, IL-4, IL-5, IFN-γ, and TNF-α) and release of vasoactive peptides (including histamine) paralleling the pathogenetic pathways of other systemic diseases discussed previously (viral and chronic infections, delayed wound healing, poorer antibody-mediated responses, etc.). There is no evidence, however, of these pathways in urticaria.

There is conclusive evidence of psychoneuroimmune mechanisms in the pathogenesis of vitiligo—a hypomelanotic skin disorder usually aesthetically compromising, so that a somatopsychic rebound seems logical. Vitiligo changes one's personal body image so that maintaining or forming relationships becomes more difficult [90]. Many patients who have vitiligo feel depressed, experience a reduced self-esteem, and perceive a reduction in quality of life [91], [92]. Some investigators have examined the role of life stress events as factors provoking the development of vitiligo [93]. Newly diagnosed patients and matched controls were asked to complete the 12-month version of the Schedule of Recent Experience, a questionnaire measuring the frequency and number of stressful life events occurring over a specified period. The results suggest that these patients endure a significantly higher number of stressful life events than do controls, suggesting that psychologic distress may have contributed to the onset of their condition.

The same investigators tested the effect of cognitive-behavioral support therapy on coping with vitiligo and adaptation to the negative effects on body image, self-esteem, and quality of life in adult patients who had vitiligo and in control patients receiving a classic treatment. The study also examined if any psychologic gains acquired from psychologic therapy influenced the progression of the condition itself. Results suggested that patients could benefit from cognitive behavioral therapy in terms of coping with vitiligo. Preliminary evidence also suggests that psychologic therapy may have a positive effect on the progression of the condition itself [94].

The above observations are partly consistent with two of the numerous pathogenetic pathways of vitiligo: the neural and autoimmune hypotheses. Patients who have vitiligo show abnormal secretion of neuromediators (eg, β-endorphin and metenkephalin) and a higher immunoreactivity to neuropeptide Y and vasoactive intestinal peptide [95]. Not all effects of neuropeptides on melanocytes are known, though the nervous system seems to play a role in activating melanocytes; psychologic and psychiatric issues and chronic stress are demonstrated to be linked to and increase expression of neuropeptide Y and other mediators.

Alternatively, much clinical and experimental evidence suggests a role of humoral and cellular autoimmunity in vitiligo pathogenesis. Alteration in the levels and ratio of CD4+ and CD8+ T-lymphocytes reported in vitiligo are somewhat consistent with the same alterations seen in particular mental states, such as depression, anxiety, chronic stressors, and mood disturbances. These alterations may be strictly linked and altered mental and psychologic states may produce, at least in this context, a portion of the alterations reported in vitiligo pathogenesis [96].



SUMMARY
Clinical and experimental data supports the brain's ability to start, influence, and stop biologic events in the skin. The skin, as a relevant part of the diffuse brain, can modify the quality of perceptions and feelings, as suggested by relevant studies. The immune and the endocrine systems may act as protagonists of the modulation of these events and, in this context, psychosocial stressors and interventions can lead to global health changes of great interest to dermatologists.


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