acute stress enhances while chronic stress suppresses skin immunity: the role of stress hormones and...

876

Acute Stress Enhances While Chronic Stress Suppresses Skin Immunity

The Role of Stress Hormones andLeukocyte Trafficking

FIRDAUS S. DHABHAR

a

College of Dentistry and College of Medicine, Ohio State University, 4179 Postle Hall, Columbus Ohio 43210-1241, USA

A

BSTRACT

: Delayed-type hypersensitivity (DTH) reactions are antigen-specific,cell-mediated immune responses that, depending on the antigen, mediate benefi-cial (resistance to viruses, bacteria, fungi) or harmful (allergic dermatitis,autoimmunity) aspects of immunity. Contrary to the widely held notion thatstress is immunosuppressive, we have shown that under certain conditions, stresscan enhance immune function. DTH reactions can be studied in rats or mice bychallenging the pinnae of previously sensitized animals with antigen. Studieshave shown that acute stress administered immediately before antigen exposuresignificantly enhances skin DTH. In contrast, chronic stress significantly sup-presses skin DTH. Stress-induced changes in leukocyte distribution may contrib-ute to these bidirectional effects of stress, since acute stress induces a significantmobilization of leukocytes from the blood to the skin, whereas chronic stress sup-presses leukocyte mobilization. In order to identify the hormonal mediators ofthe observed effects of stress, we first showed that adrenalectomy (ADX) elimi-nates the stress-induced enhancement of DTH. Acute administration (to ADXanimals) of low doses of corticosterone and/or epinephrine significantly enhanc-es skin DTH. In contrast, acute administration of high doses of corticosterone,low doses of dexamethasone, or chronic administration of moderate doses of cor-ticosterone suppress skin DTH. Thus, the timing and duration of stress may sig-nificantly affect the nature (enhancing versus suppressive) of the effects of stresson skin immune function. These results suggest that during acute stress, stresshormones may help enhance immune function by informing the immune systemabout impending challenges (e.g., wounding or infection) that may be imposed bya stressor (e.g., an aggressor). Thus, during acute stress, the brain may send awarning signal to the immune system, just as it does to other fight/flight systemsin the body.

INTRODUCTION

Stress

is a term that means different things to different people, but generally hasa negative connotation. Yet, stress is a familiar aspect of modern life, being a stimu-

a

Address for correspondence: College of Dentistry, Ohio State University, 4179 PostleHall, 305 W. 12th. Ave., #192, Columbus OH 43210-1241. Voice: 614-688-8562; fax:614-292-6087.

[email protected]

877DHABHAR: STRESS HORMONES AND LEUKOCYTE TRAFFICKING

lant for some individuals, but a problem for many others. We have defined

stress

asa constellation of events, which begins with a stimulus (

stressor

) that precipitates areaction in the brain (

stress perception

), which subsequently activates physiologicsystems in the body (

stress response

).

1,2

The physiologic stress response results inthe release of neurotransmitters and hormones that serve as the brain’s messengersto the rest of the body. The consequences of this physiologic response are generallyadaptive in the short run,

1,3

but can be damaging when stress is chronic and long last-ing.

1,4

Important distinguishing characteristics of stress include its duration and intensi-ty. We define

acute stress

as stress that lasts for a period of minutes to hours, and

chronic stress

as stress that persists for days to months. The magnitude of stress canbe gauged by the peak levels of stress hormones, neurotransmitters, and other phys-iological changes, such as increases in heart rate and blood pressure, and by theamount of time for which these changes persist during and following stressor expo-sure. Thus, the magnitude of stress can be regarded as a combination of its intensityand duration. An important marker for deleterious effects of chronic stress is a break-down in the regularity of the circadian corticosterone rhythm in rodents

1

and cortisolrhythm in humans.

5

Stress has long been suspected of playing a role in the etiology of many diseases.Numerous studies have shown that stress can be immunosuppressive, and hence thatit can be detrimental to health.

6–18

Moreover, glucocorticoid stress hormones areregarded widely as being immunosuppressive,

7

and are used clinically as anti-inflammatory agents.

19

In contrast to the generally accepted idea that stress andstress mediators are harmful, this chapter examines the beneficial effects of stressand stress hormones in preparing the immune system for dealing with potentialimmunologic challenges (e.g., wounding or infection) that may be imposed by theactions of a stressor (e.g., a predator).

AN EVOLUTIONARY PERSPECTIVE

An evolutionary perspective has guided our approach to the study of stress andimmune function. When viewed from this perspective, suppression of immune func-tion under all stress conditions does not appear to be evolutionarily adaptive becausestress is an intrinsic part of life for most organisms. Dealing successfully with stres-sors is what enables survival. Environmental challenges and most evolutionaryselection pressures are stressors that might be psychological (fear, anxiety), physical(wounding, infection), or physiological (food or water deprivation). One of the pri-mary functions of the brain is to perceive stress, warn of danger, and enable an organ-ism to deal with the consequences. This function is accomplished through the releaseof stress-responsive neurotransmitters and hormones. For example, when a gazellesees a charging lion, the gazelle’s brain detects a threat and orchestrates a physiolog-ic response to first prepare, and then enable, the gazelle to flee. We have suggestedthat under such conditions, just as the stress response prepares the nervous, cardio-vascular, musculoskeletal, and neuroendocrine systems for fight or flight, it may alsoprepare the immune system for challenges (e.g., wounding or infection) that may beimposed by the stressor.

1,3,20–22

A focus of our research has been to elucidate the

878 ANNALS NEW YORK ACADEMY OF SCIENCES

cellular and molecular mechanisms mediating the beneficial versus harmful effectsof stress on the overall health of an organism.

PARADOXICAL OBSERVATIONS ON THE EFFECTS OF STRESS ON IMMUNE FUNCTION

Three paradoxes present themselves when one reviews the extensive literatureexamining the relationship between stress, immune function, and health: First, as thepreceding discussion suggests, it is paradoxical that organisms should have evolvedto suppress immune function at a time when an active immune response may be crit-ical for survival—for example, under conditions of stress when an organism may beinjured or infected by the actions of the stress-inducing agent (e.g., an attackingpredator). Second, on the one hand stress is thought to suppress immunity andincrease susceptibility to infections and cancer,

13,15,23–25

but on the other hand it isthought to exacerbate inflammatory diseases

26–31

such as psoriasis, asthma, arthri-tis, and lupus erythematosus (which should be ameliorated by a suppression ofimmune function). Third, stress is known to exacerbate autoimmune and inflamma-tory diseases,

26–28

however, stress hormones (glucocorticoids) are used clinically totreat these diseases.

19

Keeping these paradoxical observations in mind, and based on our initial studieson the effects of stress on blood leukocyte distribution, we hypothesized that undercertain conditions, stress may enhance rather than suppress immune function. Thestudies described here were designed to test this hypothesis.

STRESS-INDUCED CHANGES IN LEUKOCYTE NUMBERS IN THE BLOOD

Immune cells or leukocytes circulate continuously from the blood, into variousorgans, and back into the blood. This circulation is essential for the maintenance ofan effective immune defense network,

32

The numbers and proportions of leukocytesin the blood provide an important representation of the state of distribution of leuko-cytes in the body and of the state of activation of the immune system. Numerous stud-ies have shown that stress and stress hormones induce significant changes in absolutenumbers and relative proportions of leukocytes in the blood. In fact, decreases inblood leukocyte numbers were used as an indirect measure for increases in plasmacorticosterone before methods were available to directly assay the hormone.

33

Stress-induced decreases in blood leukocyte numbers have been reported in fish,

34

mice,

35

rats,

20,21,36-38

rabbits,

39

horses,

40

non-human primates,

41

and humans.

12,42

Thissuggests that the phenomenon of stress-induced leukocyte distribution has been con-served through evolution, and that perhaps this redistribution has an important adap-tive and functional significance.

Studies have shown that stress-induced increases in plasma corticosterone areaccompanied by a significant decrease in numbers and percentages of lymphocytes,and by an increase in numbers and percentages of neutrophils. Dhabhar

et al.

haveshown that stress-induced changes in blood leukocyte distribution are apparent within


30 min of applying the stressor.

21

These authors reported a large decrease (45–60

%

lower than baseline) in total blood leukocyte numbers. FACS analyses revealed thatabsolute numbers of peripheral blood helper T cell (Th), cytolytic T cell (CTL), Bcells, natural killer (NK) cells, and monocytes all show a rapid and significantdecrease (40–70

%

lower than baseline) during stress.

21

Further experiments revealedthat stress-induced decreases in blood leukocyte numbers are rapidly reversed withleukocyte numbers returning to prestress baseline levels within three hours after thecessation of stress.

21

Dhabhar

et al.

have also shown that the stress-induced changes in leukocyte dis-tribution are mediated by hormones released by the adrenal gland.

22,43

Thus, themagnitude of the stress-induced changes in blood leukocyte numbers is significantlyreduced in adrenalectomized animals.

21,22

Cyanoketone treatment, which virtuallyeliminates the corticosterone stress response, also virtually eliminates the stress-induced decrease in blood lymphocyte numbers, and significantly enhances thestress-induced increase in blood neutrophil numbers.

22

Several studies have shownthat glucocorticoid treatment induces changes in leukocyte distribution in mice,

44–47

guinea pigs,

48

rats,

22,49,50

rabbits,

51

and humans.

52–54

It has been shown in rats thatboth adrenalectomy (which eliminates the corticosterone and epinephrine stressresponse)

21,22,35,55

or cyanoketone treatment (which eliminates only the corticoster-one stress response), virtually eliminate the stress-induced redistribution of bloodleukocytes.

22

Since adrenal steroids act at two distinct receptor subtypes, both of which showa heterogeneity of expression in immune cells and tissues,

56–59

Dhabhar

et al.

inves-tigated the role played by each receptor subtype in mediating changes in leukocytedistribution.

22

Acute administration of aldosterone (a specific Type I adrenal steroidreceptor agonist) to adrenalectomized animals did not have a significant effect onblood leukocyte numbers. In contrast, acute administration of corticosterone (theendogenous Type I and Type II receptor agonist) or RU28362 (a specific Type IIreceptor agonist) to adrenalectomized animals induced changes in leukocyte distri-bution that were similar to those observed in intact animals during stress. Theseresults suggest that corticosterone, acting at the Type II adrenal steroid receptor, is amajor mediator of the stress-induced decreases in blood lymphocyte and monocytedistribution. Taken together, these studies show that stress and glucocorticoid hor-mones induce a significant decrease in blood lymphocyte numbers when adminis-tered under acute or chronic conditions.

In apparent contrast to glucocorticoid hormones, catecholamine hormones havebeen shown to increase blood leukocyte numbers in rats

60

and humans.

61

On closerexamination it is observed that, following adrenaline or noradrenaline administra-tion, neutrophil and NK cell numbers increase rapidly and dramatically whereas Tand B cell numbers decrease.

62–65

Carslon

et al.

have shown that catecholamine pre-treatment results in increased accumulation of lymphocytes in the spleen and lymphnodes,

66

an observation that is in agreement with a catecholamine-induced decreasein lymphocytes in the blood. By acutely administering epinephrine, norepinephrine,selective

α

and

β

adrenergic receptor agonists, or corticosterone to adrenalectomizedanimals, Dhabhar and McEwen have shown that increases in blood granulocytenumbers may be mediated by the

α

1

and

β

adrenergic receptors, and are counteractedby corticosterone acting at the Type II adrenal steroid receptor.

43

Increases in


lymphocytes may be mediated by the

α

2

receptor while decreases in lymphocytesmay be mediated by

β

adrenergic and Type II adrenal steroid receptors.

43

Therefore, the absolute number of specific blood leukocyte subpopulations maybe significantly affected by the ambient concentrations of epinephrine, norepineph-rine, and corticosterone. Differences in concentrations and combinations of thesehormones may explain reported differences in blood leukocyte numbers during dif-ferent stress conditions (e.g., short- versus long-duration acute stress, acute versuschronic stress) and during exercise.

A STRESS-INDUCED DECREASE IN BLOOD LEUKOCYTE NUMBERS REPRESENTS A REDISTRIBUTION RATHER THAN A

DESTRUCTION OR NET LOSS OF BLOOD LEUKOCYTES

From the above discussion it is clear that stress and glucocorticoid hormonesinduce rapid and significant decreases in blood lymphocyte, monocyte, and NK cellnumbers. The decrease in blood leukocyte numbers may be interpreted in two pos-sible ways. The decrease in cell numbers could reflect a large-scale destruction ofcirculating leukocytes. Alternatively, it could reflect a redistribution of leukocytesfrom the blood to other organs in the body. Several studies have shown that gluco-corticoid-induced decrease in blood leukocytes reflects a redistribution rather than adestruction of immune cells.

44–47,67,68

Dhabhar

et al.

conducted experiments to test the hypothesis that acute stressinduces a redistribution of leukocytes from the blood to other compartments in thebody.

21,69

The first series of experiments examined the kinetics of recovery of thestress-induced reduction in blood leukocyte numbers. It was hypothesized that if theobserved effects of stress represented a redistribution rather than a destruction ofleukocytes, one would see a relatively rapid return of leukocyte numbers back tobaseline upon the cessation of stress. Results showed that all leukocyte subpopula-tions that showed a decrease in absolute numbers during stress, showed a completerecovery with numbers reaching prestress baseline levels within three hours after thecessation of stress.

21

Plasma levels of lactate dehydrogenase (LDH), a marker forcellular damage, were also monitored in the same experiment. If the stress-induceddecrease in leukocyte numbers were the result of a destruction of leukocytes, onewould expect to observe an increase in plasma levels of LDH during or followingstress. No significant changes in plasma LDH were observed, further suggesting thata redistribution rather than a destruction of leukocytes was primarily responsible forthe stress-induced decrease in blood leukocyte numbers.

21

It is important to recognize that glucocorticoids induce changes in variousimmune parameters,

7,70

and in immune cell distribution,

20,21,46–48,52,67,71

in theabsence of cell death even though these hormones are also known to induce leuko-cyte apoptosis.

72

It has been suggested that some species may be

steroid-resistant

and others may be

steroid-sensitive,

and that glucocorticoid-induced changes inblood leukocyte numbers represent changes in leukocyte redistribution in steroid-resistant species (humans and guinea pig), and leukocyte lysis in steroid-sensitivespecies (mouse and rat).

73

However, a large body of evidence now indicates that


even in species previously thought to be steroid-sensitive, adrenal steroids induceleukocyte redistribution rather than leukocyte destruction.

46,74–76

Based on the above discussion, the obvious question one might ask is: Where doblood leukocytes go during stress? Numerous studies using stress or stress hormonetreatments, have investigated this issue. Using gamma imaging to follow the distri-bution of adoptively transferred radio-labelled leukocytes in rabbits, Toft

et al.

haveshown that stress induces a redistribution of leukocytes from the blood to lymphatictissues.

39

It has been reported that anesthesia stress, as well as the infusion ofadrenocorticotropic hormone (ACTH) and prednisolone in rats results in decreasednumbers of labelled lymphocytes in the thoracic duct, while the cessation of druginfusion results in normal circulation of labelled lymphocytes.

71

This suggests thathormonal changes similar to those observed during stress induce the retention of cir-culating lymphocytes in different body compartments, thus resulting in a decrease inlymphocyte numbers in the thoracic duct and a concomitant decrease in numbers inthe peripheral blood.

71

Fleshner

et al.

have shown that acute stress results in anincrease in the percentage of CD4 and a decrease in the percentage of CD8 in themesenteric lymph nodes and have suggested that these changes in lymphocyte com-position may mediate changes in antibody production by the affected lymphnodes.

77

It has also been reported that a single injection of hydrocortisone, predniso-lone, or ACTH results in increased numbers of lymphocytes in the bone marrow ofmice,

46

guinea pigs,

48

and rats.

68

Fauci

et al.

have suggested that glucocorticoid-induced decreases in blood leukocyte numbers in humans may also reflect a redistri-bution of immune cells to other organs in the body.

52,78,79

Finally, corticosteroidshave been shown to induce the accumulation of lymphocytes in mucosal sites,

80

andthe skin has been identified as a target organ to which leukocytes traffic duringstress.

3

It is important to note that in these studies, a return to basal glucocorticoid levelsis almost always followed by a rapid return to baseline numbers of blood lympho-cytes, further supporting the hypothesis that the decrease in blood leukocyte numbersis the result of a glucocorticoid-induced redistribution rather than a glucocorticoid-induced destruction of blood leukocytes.

STRESS-INDUCED REDISTRIBUTION OF BLOOD LEUKOCYTES—FUNCTIONAL CONSEQUENCES

Dhabhar

et al.

were the first to propose that a stress-induced decrease in blood leu-kocyte numbers represents an adaptive response.

1–3,20–22

These authors have sug-gested that this decrease in blood leukocyte numbers represents a redistribution ofleukocytes from the blood to other organs, such as the skin, mucosal lining of gastro-intestinal and urinary-genital tracts, lung, liver, and lymph nodes that may serve as“battle stations” should the body defenses be breached. They have also suggested thatsuch a leukocyte redistribution may enhance immune function in compartments intowhich leukocytes traffic during stress.

1–3,20–22

Thus, an acute stress response may direct the body’s “soldiers” (leukocytes), toexit their “barracks” (spleen and bone marrow), travel the “boulevards” (blood ves-sels), and take position at potential “battle stations” (skin, lining of gastro-intestinal


and urinary-genital tracts, lung, liver, and lymph nodes) in preparation for immunechallenge.

1,3,20–22

In addition to “redeploying” leukocytes to potential “battle sta-tions” stress hormones may also better equip them for “battle” by enhancing pro-cesses like antigen presentation, phagocytosis, and antibody production. Thus, ahormonal alarm signal released by the brain upon detecting a stressor, may “prepare”the immune system for potential challenges (wounding or infection) that may arisedue to the actions of the stress-inducing agent (e.g., a predator or attacker).

An important, but under appreciated function of endocrine mediators releasedduring of acute stress may be to ensure that appropriate leukocytes are present in theright place and at the right time to respond to an immune challenge that might beinitiated by the stress-inducing agent (e.g., attack by a predator or invasion by apathogen). The modulation of immune cell distribution by acute stress, may be anadaptive response designed to enhance immune surveillance and increase the capac-ity of the immune system to respond to challenge in immune compartments (such asthe skin, epithelia of lung, and gastro-intestinal and urinary-genital tracts) that serveas major defense barriers for the body. Thus, endocrine mediators released duringstress may serve to enhance immune preparedness for potential (or ongoing)immune challenge.

STRESS-INDUCED ENHANCEMENT OF IMMUNE FUNCTION

Although a majority of studies in the field of psychoneuroimmunology havefocussed on the immunosuppressive effects of stress, several studies have alsorevealed that, under certain conditions, stress can be immunoenhancing. In general,acute stress is found to be immunoenhancing whereas chronic stress is found to beimmunosuppressive (in some cases the effects of stress on leukocyte numbers andproportions in the compartment being assayed need to be taken into considerationfor this statement to hold). Dhabhar

et al.

have suggested that a stress-inducedenhancement of immune function may be an adaptive response to prepare an organ-ism for potential immunologic challenges (e.g., a wound or infection inflicted by anattacker) for which stress perception by the brain, and subsequent stress hormoneand neurotransmitter release, may serve as an early warning.

1–3,21

As discussed above, acute stress induces a significant redistribution of leukocytesfrom the blood to other organs (e.g., skin and lymph nodes) in the body,

21,69

andadrenal stress hormones are major mediators of this leukocyte redistribution.

22

Sincethe skin is one of the targets to which leukocytes traffic during stress, Dhabhar andMcEwen hypothesized that a stress-induced leukocyte redistribution may increaseimmune surveillance in the skin and consequently enhance immune function shouldthe skin be exposed to antigen following acute stress.

3

To test this hypothesis, they examined the effects of acute stress on skin immunity,using a rodent model for a skin delayed type hypersensitivity (DTH) response.

3

Inorder to induce DTH, animals were initially sensitized to 2,4-dinitro-1-fluorobenzene(DNFB) by administering the chemical antigen to the skin of the dorsum. The

sensi-tization

phase of a DTH reaction is one in which the organism develops an immuno-logic memory (through the generation of memory T cells) for the antigen with whichit is immunized. Following sensitization, the ability of the animals to mount a DTH


response against DNFB was examined by administering DNFB to the dorsal aspectof the pinna. The DTH response was subsequently measured as an increase in pinnathickness proportional to the intensity of the ongoing immune reaction.

81,82 Thisphase, also known as the elicitation or challenge phase, involves recruitment of mem-ory T cells and effector cells (such as, neutrophils, macrophages, CTLs, and NK cells)that mount an immune response against the antigen to which the animal was previ-ously sensitized. Acute restraint stress administered immediately before the challengewith antigen resulted in a large and long-lasting enhancement of skin DTH.3 Histo-logical analysis revealed significantly larger numbers of leukocytes in the skin ofstressed animals both before and after exposure to antigen, and suggested that astress-induced redistribution of leukocytes was one of the factors mediating thestress-induced enhancement of skin immunity.3 Acute stress has similarly beenshown to enhance skin DTH in mice.83

Dhabhar and McEwen subsequently showed that acute stress administered at thetime of sensitization also significantly enhances a skin DTH response followingchallenge.84 In these studies animals were stressed acutely (2-h restraint) before theadministration of the sensitizing antigen. Compared to control animals, stressed ani-mals showed a significantly larger DTH response following challenge although nostress was applied at the time of challenge. These results showed that acute stressadministered either during sensitization or challenge, can significantly enhance askin DTH response.84

STRESS-INDUCED SUPPRESSION OF IMMUNE FUNCTION

Numerous studies have shown that stress can be immunosuppressive and hencemay be detrimental to health. Since these studies have been reviewed and discussedextensively,8–10,85–88 the reader is referred to these papers and to other papers in thisvolume for a more detailed account of the subject. It may be worth noting here thatmost stress conditions that are found to be immunoenhancing involve acute stress,and those that are found to be immunosuppressive involve chronic stress (with theeffects of stress on leukocyte distribution being an important factor to be taken intoaccount).

It has been shown that in contrast to acute stress, chronic stress suppresses the skinDTH response.1,89 A chronic stress-induced decrease in leukocyte mobilization fromthe blood to other body compartments is thought to be one of the mediators of thisstress-induced suppression of skin DTH.1 Similarly, in human and animal studies,chronic stress has also been shown to suppress different immune parameters exam-ples of which include: delayed type hypersensitivity,89,90 antibody production,91,92

NK activity,18,93–95 leukocyte proliferation,93,94,96 skin homograft rejection,97

virus-specific T cell and NK cell activity 98, and antimycobacterial activity of mac-rophages from susceptible mouse strains.99


ADRENAL HORMONES MEDIATE THE BIDIRECTIONAL EFFECTS OF STRESS ON SKIN IMMUNE FUNCTION

It was the immunosuppressive effects of glucocorticoid hormones that led PhilipHench and Edward Kendall to the Nobel Prize in 1950, awarded for their discoveryof the use of corticosteroids in the treatment of autoimmune disease.100,101 Henchobserved that patients suffering from autoimmune diseases showed recovery fromthese diseases during periods of other illnesses such as hepatitis. He postulated thatthe inflammatory response accompanying the other disease was stimulating the pro-duction of an endogenous immunosuppressive mediator that was responsible forinhibiting the autoimmune disease. Together with Kendall he determined that cortisolwas that endogenous mediator, and their finding revolutionized the treatment ofautoimmune disease and a host of other inflammatory disorders. Since that time, glu-cocorticoid hormones have been widely used as immunosuppressive agents in variousclinical and experimental situations (for reviews see References 19 and 102–104).

In contrast to the well-known immunosuppressive effects of glucocorticoids, sev-eral studies have revealed that glucocorticoid hormones also exert immunomodulat-ing (for reviews see References 105 and 106) and immunoenhancing effects (seeReferences 107 and 108). In general, pharmacological concentrations of glucocorti-coids exert immunosuppressive effects, whereas under different conditions, physio-logic concentrations may exert immunomodulatory, immunoenhancing, orimmunosuppressive effects. It is important to recognize that the source (natural ver-sus synthetic) and concentration (physiologic versus pharmacologic) of glucocorti-coid hormones, the effects of other physiologic factors (hormones, cytokines, andneurotransmitters), and the state of activation of an immune parameter (naïve versusactivated leukocyte, early versus late activation, etc.), are all important factors thatultimately determine the nature of the effects of glucocorticoids on a given immuneresponse.

Dhabhar and McEwen have demonstrated that the acute stress-induced enhance-ment of skin DTH is mediated by adrenal stress hormones.2 Adrenalectomy, whicheliminates the glucocorticoid and epinephrine stress response, eliminated the stress-induced enhancement of skin DTH.2 Low dose corticosterone or epinephrine admin-istration significantly enhanced skin DTH and caused a significant increase in T cellnumbers in lymph nodes draining the site of the DTH reaction.2 Moreover, simulta-neous administration of these two stress hormones, produced an additive increase inthe skin DTH response. These results showed that hormones released during an acutestress response may help prepare the immune system for potential challenges (e.g.,wounding or infection) for which stress perception by the brain may serve as an earlywarning signal.2 In contrast to the effects of physiologic doses of natural hormones,high dose corticosterone, chronic corticosterone, or low dose dexamethasone admin-istration, all significantly suppressed skin DTH.2

Thus, adrenal stress hormones mediate the bidirectional effects of stress on skinimmunity. Low doses of acutely administered corticosterone and epinephrinehave immunoenhancing effects, whereas high doses of corticosterone, chroniccorticosterone, or low doses of the synthetic steroid, dexamethasone, all exert immu-nosuppressive effects.2 Moreover, dexamethasone shows a significantly greaterimmunosuppressive potency than corticosterone.2 The cellular and molecular


mechanisms mediating these bidirectional effects of stress hormones on skinimmune function need to be investigated further.

STRESS-INDUCED ENHANCEMENT OF IMMUNE FUNCTION: IMPLICATIONS FOR DISEASE

In view of the above discussion, we hypothesize that a stress-induced enhance-ment of immune function may be beneficial in case of wound healing, infection orcancer, but could also be harmful in case of autoimmune or inflammatory disorders.The hypothesis that acute stress may increase in resistance to infections or cancerneeds to be rigorously investigated. However, numerous studies have reported stress-induced exacerbation of autoimmune and inflammatory diseases. Over thirty yearsago, Solomon and Moos described an association between stress and autoimmunedisorders.26 Rimon and Laakso have classified two categories of rheumatoid arthri-tis, a disease form more associated with genetic factors, and another more associatedwith psychodynamic factors such as stress.109 Thomason et al. found that minorstress events such as day to day irritants were associated with exacerbations of rheu-matoid arthritis.28 Similarly, stress has been shown be related with the onset andexacerbation of psoriasis.31 Stress has also been reported to precede the onset andexacerbation of multiple sclerosis,27 in some cases however, it was chronic but notacute stress that was reported to precipitate disease.110 It must be mentioned herethat many studies have also failed to discover consistent relationships between lifestress and autoimmune disease.111,112

We suggest that certain stress conditions, may enhance immune function andincrease resistance to infections and cancer, but may also exacerbate autoimmune orinflammatory disorders. In contrast, chronic stress may suppress immune functionand increase susceptibility to infections and cancer, but ameliorate autoimmune andinflammatory disorders.

STRESS-INDUCED SUPPRESSION OF IMMUNE FUNCTION:IMPLICATIONS FOR DISEASE

In addition to suppressing different immune parameters, human as well as animalstudies have shown that chronic stress increases susceptibility to the common cold,24

and to infection with viruses such as influenza,15 and bacteria such as Toxoplasma,113

and Salmonella.91 Stress has also been shown to increase susceptibility tocancer.23,114,115 Similarly, chronic stress has been shown to delay wound healing inmice16 and humans,14 and to impair the immune response to vaccination in humansubjects.13,116

If chronic stress suppresses immune function and increases susceptibility toinfectious disease and cancer, it may also be hypothesized that under these condi-tions, stress should ameliorate autoimmune or inflammatory diseases. Numerousstudies have investigated the effects of environmental or psychological stress onautoimmune reactions. Levine et al. in 1962, demonstrated that the administrationof prolonged restraint stress to rats before the induction of experimental allergic


encephalomyelitis (EAE) resulted in a suppression of the incidence and severity ofdisease.117 Rogers et al. in 1980, showed that exposure of rats to a variety of stres-sors results in a marked suppression of the clinical and histological manifestationsof type II collagen-induced arthritis. Similarly, Griffin et al. demonstrated suppres-sion of EAE by chronic stress.118

Thus, it is evident that under certain conditions, stress suppresses differentimmune parameters. Although this increases susceptibility to infectious disease andcancer, it may also confer protection against autoimmune and proinflammatory dis-eases. It is clear that further studies are needed to rigorously examine the mecha-nisms mediating both, stress-induced enhancement in resistance to infections andcancer, and stress-induced exacerbation of autoimmune and inflammatory disorders.

THE STRESS SPECTRUM HYPOTHESIS

Dhabhar and McEwen have proposed that a stress response and its consequenteffects on immune function may be viewed in the context of a stress spectrum (seeFIGURE 1).1 One region of the stress spectrum is characterized by eustress; that is,conditions of acute or short-duration stress that may result in immunopreparatory, orimmunoenhancing physiological conditions. An important characteristic of eustressis a rapid physiologic stress response mounted in the presence of the stressor, fol-lowed by a rapid shut-off of the response once the stress has subsided. The other end

FIGURE 1. Hypothetical model representing the stress spectrum and its relationshipto immune function.1 One region of the stress spectrum is characterized by eustress, thatis, conditions of acute or circumscribed amounts of stress, which may result in immuno-preparatory, or immunoenhancing conditions. The other end of the stress spectrum is char-acterized by distress, that is, chronic, repeated, or physiologically exhausting stress, thatmay result in immunosuppressive conditions. Between eustress and distress is an area thatrepresents resilience, that is, the ability of physiologic systems to enable survival forextended periods of time under increasingly demanding conditions. (From Dhabhar andMcEwen.1 Reproduced by permission.)


of the stress spectrum is characterized by distress; that is, chronic, repeated, or phys-iologically exhausting stress that may result in immunosuppression. An importantcharacteristic of distress is that the physiologic stress response either persists longafter the stress has subsided, or is activated repeatedly to result in an overall integrat-ed increase in exposure of the organism to stress hormones. Recently, the concept ofallostatic load has been proposed to define the constant wear and tear that takesplace while different physiologic systems respond to the exhausting demands placedby internal and external stressors under conditions of distress (see Reference 4 for areview). We suggest that conditions of high allostatic load results in deleteriousimmunosuppression. Importantly, a disruption of the circadian corticosteronerhythm may be an indicator and/or mediator of distress or high allostatic load.1,5 Thestress spectrum model also proposes that between eustress and distress is an area thatrepresents resilience, which we define as the ability of physiologic systems to enablesurvival for extended periods of time under increasingly demanding conditions.

CONCLUSIONS

Stress has long been suspected to play a role in the etiology of many diseases, andnumerous studies have shown that stress can be immunosuppressive and, hence, maybe detrimental to health. Moreover, glucocorticoid stress hormones are widely regard-ed as being immunosuppressive, and are used clinically as anti-inflammatory agents.However, this paper shows that under certain conditions, stress and glucocorticoidhormones exert immunoenhancing effects. Dhabhar et al. have suggested that thephysiologic stress response may play a critical evolutionarily adaptive role, withstress hormones and neurotransmitters serving as messengers to prepare the immunesystem for potential immunologic challenges (e.g., wounding or infection) that areperceived in advance by the brain (e.g., the detection of predator or attacker).1−3,20,21

However, it is important to recognize that, although a stress-induced enhancement ofimmune function may increase resistance to infections or cancer, it may also exacer-bate autoimmune and inflammatory disease. In contrast, a stress- or glucocorticoid-induced suppression of immune function may increase susceptibility to infections orcancer, but may ameliorate autoimmune and inflammatory disorders. Therefore, thereexists a Yin-Yang principle with respect to the effects of stress on immune function,and perhaps on most physiological parameters. Since these effects may potently influ-ence the overall health of an organism, one might hypothesize that a physiologic equi-librium among these different systems would be most favorable for the maintenanceof health.

It is also important to recognize that humans as well as animals experience stressas an intrinsic part of life, and in conjunction with many standard diagnostic, clini-cal, and experimental manipulations. Unintended stressors may significantly affectthese diagnostic and clinical measures and overall health outcomes. Thus, when con-ducting clinical, diagnostic, or experimental manipulations, it may be important toaccount for the effects of stress on the specific physiologic parameter or health out-come being measured.

A determination of the physiologic mechanisms through which stress and stresshormones enhance or suppress immune responses may help our understanding and


treatment of diseases thought to be affected by stress. The cellular and molecularmechanisms by which stress and stress hormones up- or downregulate an immuneresponse merit further investigation. A greater understanding of these mechanismswould help in the development of biomedical treatments which could harness anindividual’s physiology to selectively enhance (during vaccination, wounding, infec-tions, or cancer) or suppress (during autoimmune or inflammatory disorders) theimmune response depending on what would be most beneficial for the patient.

ACKNOWLEDGMENT

This work was supported by The John D. & Catherine T. MacArthur Foundation,and by a DeWitt Wallace Foundation Fellowship.

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