REVIEW ARTICLES The Influence of the Psyche and the ......REVIEW ARTICLES The Influence of the Psyche and the Brain on Immunity and Disease Susceptibility: A Critical Review MALCOLM

REVIEW ARTICLES

The Influence of the Psyche and the Brain onImmunity and Disease Susceptibility:A Critical Review

MALCOLM P. ROGERS, MD, DEVENDRA DUBEY, PHD, AND PETERREICH, MD

In critically reviewing the sources of evidence connecting psyche and brain with the immunesystem, the authors include a brief review of current knowledge of the immune system, itsinteractions with the neuroendocrine system, and other factors influencing its regulation. Theseinclude developmental stages, aging, rhythmicity, and a variety of exogenous influences. Theneed for developing further information about normal base lines is emphasized. Against thatbackground, many sources of data demonstrating connections between the central nervoussystem and the immune system are presented: indirect evidence from clinical and experimentalillnesses involving the immune system, and direct changes in either humoral or cellular immu-nity after natural or experimental stress, conditioning, hypnosis, and direct brain stimulation.Possible mechanisms are discussed, as well as some important methodological issues for furtherresearch.

INTRODUCTION

Historically, psychosomatic medicinehas often followed advances on the soma-tic side of the mind-body axis. For exam-ple, developments in endocrinology, car-diovascular and renal physiology, andneurophysiology have each been as-sociated with surges of research on the re-lationship between mental states and dis-orders and normal functions of thesespecific areas. As new biological tech-niques and approaches emerge, they be-come the instruments of investigators

From the Division of Psychiatry, Department ofMedicine, Peter Bent Brigham Hospital, the Depart-ment of Psychiatry, Harvard Medical School, and theSidney Farber Cancer Institute, Boston, Mas-sachusetts.

Address reprint requests to: Malcolm P. Rogers,M.D., 721 Huntington Avenue, Boston, MA 02115.

Received for publication November 7, 1978; revi-sion received December 8, 1978.

who are trying to narrow the gap in thepsychosomatic process referred to byWeiner as "the transduction of experi-ence" (1).

In recent years one of the most rapidlyadvancing areas in medicine has beenimmunology and, not surprisingly, its in-teractions with various psychologicalstates, especially those associated withstress, have been the focus of intenseinterest. Two reviews, one by Amkrautand Solomon (2) and the other by Steinand colleagues (3), have summarizedmuch of the recent research in this area. Acentral premise underlying much of thework that has been done is that stress mayincrease an organism's vulnerability tocertain diseases by means of exerting animmunosuppressive effect, especiallythose diseases intimately associated withimmunologic mechanisms, such as infec-tion, malignancy, and autoimmune dis-ease. The purpose of this article is to re-

Psychosomatic Medicine Vol. 41, No. 2 (March 1979)

Copyright * 1979 by the American Psychosomatic Society, Inc.Published by Elsevier North Holland, Inc.

1470033-3124/79/02014718/$01.75

M. P. ROGERS, D. DUBEY, AND P. REICH

view in a critical fashion the evidence forthis premise, including several areas notcovered in recent reviews and somewhich have developed since their publi-cation. In doing so, we will also brieflyreview recent advances in our knowledgeof the immune system, and the many fac-tors which either endogenously orexogenously influence its regulation. Theinvestigation of psychosomatic relation-ships involving the immune system offersus a unique opportunity. The immunesystem has a fundamental role in themaintenance of body horrieostasis andhealth (4). Even minor fluctuations in thissystem have direct implications for thedevelopment of disease. In recent yearsthere have been many advances in ourunderstanding of the effect of mentalstates on the endocrine and autonomicnervous systems, although the implica-tions of those changes for disease suscep-tibility have often been less obvious. Theimmune system provides us with a furthercritical link in the psychosomatic processand disease susceptibility.

IMMUNOLOGY: BRIEF REVIEWINCLUDING RECENTADVANCES

The field of immunology is expandingat an extraordinarily rapid pace. Accord-ingly, our knowledge of the normal regu-lation of immunity and the choices ofmeasurable immune functions whichmight provide the most sensitive index ofimmunocompetence are also changing.Before focusing on more recent advances,a brief overview of the entire systemmight be helpful. For additional reading,we refer the reader either to Austen's "In-troduction to Clinical Immunology," inHarrison's Principles of Internal Medicine

(5), or to Roitt's Essential Immunology (6).The immunologic apparatus is broadly

divided into two large components. Thefirst is that of humoral, or antibody-mediated reactions. In these, antigen-specific reactions are carried out by vari-ous classes of immunoglobulin mole-cules, such as IgA, IgG, IgM, or IgE. Whenstimulated by specific antigens, B lym-phocytes are transformed into plasmacells, actively producing a specific anti-body. These antigen-antibody interactionsare closely associated with amplificationsystems involved in the inflammatoryprocess, such as the classical or alternatecomplement pathways. Such reactions in-clude defenses against toxic and bacterialantigens, transfusion reactions, and vari-ous forms of autoimmune reactions(hemolytic anemia).

The second major component is that ofcell-mediated immunity, the primary pro-cess involved in delayed hypersensitivity(such as the tuberculin skin test) and therejection of transplanted tissue. In thissystem, f lymphocytes are activated byspecific antigens interacting with surfacereceptors and release nonantibody sub-stances called lymphokines. These in turnact upon other cells which result in aninflammatory process. Neither circulatingantibodies nor the complement system areinvolved in cell-mediated immunity.

An individual's immune system has thecapacity to differentiate between self (towhich there is tolerance) or foreign mac-romolecules (to which an immune re-sponse is directed). When an antigen isfirst introduced, it triggers a primaryhumoral or antibody response. After aperiod of time, the level of antibody de-clines but after reexposure to the antigen(for example as with a booster shot) anenhanced secondary response is elicited.In general, an antigen is taken up by a

148 Psychosomatic Medicine Vol. 41, No. 2 (March 1979)

REVIEW ARTICLE

macrophage in the spleen if administeredintravenously, or in the lymph node ifadministered subcutaneously. The mac-rophage in turn presents the antigen to thelymphocyte for recognition. Lymphocytesare thought to be genetically precon-ditioned to interact with a particular anti-gen. It is the B lymphocyte, derived frombone marrow stem cells in mammals,which produces immunoglobulins whenso stimulated. The B lymphocytes repre-sent about 20% of the peripheral bloodlymphocytes and about 50% of the spleenlymphocytes.

IgG composes 70-80% of the serum an-tibodies in the human being and is almostexclusively responsible for the antibodiesto viruses, toxins, and gram-positivepyogenic bacteria. IgM makes up between5 and 10% of the total serum antibody,typically elicited by antigens of gram-negative bacteria. IgA comprises about10-20% of the total serum antibody andfunctions predominantly in body se-cretions, for example, in parotid saliva,nasal, and gastrointestinal secretions. Byactivating mast cells in the presence ofspecific antigens, IgE plays an importantrole in immediate hypersensitivity (aller-gic) reactions, such as in anaphylaxis. Thelevel of humoral immunity can be as-sessed by measurements of serum im-munoglobulin levels, by specific antibodytiters raised to specific antigens, or, infact, by measuring the activity of plasmacells in the spleen after antigenic stimula-tion (the so-called plaque-forming assay).It is also possible in vitro to stimulate Blymphocytes differentially and to measurevarious functional capacities of these cellsalone.

One of the most important advances inrecent years has been the differentiation ofB lymphocytes from T lymphocytes. Thethymus gland has a critical role in the dif-

ferentiation of T lymphocytes from pre-cursor cells and has other important reg-ulatory functions, especially in cellularimmunity. T lymphocytes, those derivedfrom the thymus, make up about 80% ofperipheral blood lymphocytes. As men-tioned above, they are involved in cell-mediated immunity, such as delayedhypersensitivity reactions and transplantrejection reactions. The differentiation ofT and B lymphocytes has led to a prolifer-ation of different tests which provide in-dices of cellular immunocompetence. Inaddition to the older in vivo methods, i.e.,skin testing (delayed hypersensitivity toantigens such as mumps, streptokinase, orstreptodornase—antigens to which virtu-ally everyone has been exposed) and thepattern of rejection of tissue transplants(which provide only crudely quantifiablemeasures of T-cell function), a variety ofnew in vitro techniques have been de-veloped. These include lymphocyte re-sponse to mitogens, substances likephytohemagglutinin or concanavalin A,which stimulate mitosis in these cells,T-lymphocyte cytotoxicity (the capacityof T cells to kill cultured cells to whichthey have been sensitized), or the evenmore recent natural killer-cell activity(first identified in 1974). The latter has re-cently emerged as an important index ofgeneral immunocompetence because itmeasures a natural function of the cellswithout requirement of prior sensitiza-tion, and it is thought to provide an im-portant host defense against the develop-ment of malignancy and viral infection(7). For some time the immune system hasbeen thought to perform a surveillancefunction in recognizing cells undergoingmalignant transformation and eliminatingthem before tumor growth occurs.

To make matters more complicated, itturns out that another function of T cells

Psychosomatic Medicine Vol. 41, No. 2 (March 1979) 149


is in regulating the humoral responses ofB lymphocytes, either in augmenting(helper T cells) or in suppressing (sup-pressor T cells) such reactions. Naturalkiller cells have been described as anothersubset of lymphocytes and undoubtedlyothers will be defined in the future. All ofthese cells function in a complex, inter-regulatory network maintaining phy-siological homeostasis. The explosion ofresearch in immunology, particularly incellular immunology, is at the forefront ofresearch in cancer, arthritis, transplanta-tion, and many other medical areas, and ithas opened up new vistas for thepsychosomaticist. It should be obvious,however, that the immune system is avery complex network, and that there isno single measure of immunity, but manydifferent measures. That makes a conceptlike immunosuppression, for example,more complicated, in that the suppressionof suppressor T cells may, in fact, aug-ment other components of the immunesystem, and the suppressor T cells arethought to be particularly sensitive toregulatory substances.

NORMAL REGULATION OF THEIMMUNE SYSTEM

As a Function of Time

Although we will present some intrigu-ing data suggesting alterations in immu-nity after psychological stress and othercentral nervous system effects, our rela-tively limited knowledge of the normalregulation and base line of the immunesystem over time requires caution inevaluating the significance of many ofthese findings. A great variety of eithercongenital or acquired immunodeficiency

syndromes, like the DiGeorge syndromeor an isolated deficiency of IgA, have beendescribed and more are being describedall the time. But, beyond these gross de-ficiencies which have obvious clinicalmanifestations, the question arises as tohow much variability exists within indi-viduals over time, or between racialgroups, sexes, and perhaps along otherdimensions. How much fluctuation isthere in both cellular and humoral im-mune mechanisms? And, if there are dif-ferences, are they significant either statis-tically or biologically? For any given in-dividual, how much variation occurswithin the course of a day? A week? Amonth? A lifetime?

Age is certainly an important variable.It has been known for some time that inhuman beings humoral immunity is notfully developed at birth and does not be-come so until approximately 1-2 years ofage. At least that is when IgM reachesadult levels. By that time IgG will also beat adult levels, but levels of IgA con-tinue to increase throughout life (8). Thereis relatively little information about cellu-lar immunity in newborns, except that itis grossly intact, as judged by the presenceof delayed hypersensitivity reactions. It isunclear whether any alteration in im-munologic competence occurs at the timeof puberty (when the thymus gland un-dergoes involution), but pregnancy is as-sociated with an impairment in cell-mediated immunity both in women (9)and in animals (10], presumably in protec-tion of the fetus. Whether other major en-docrinologic milestones, such as meno-pause, are associated with alterations inimmune functions is not as yet known.

However, later stages of aging in rela-tion to immunity is one area where con-siderably more data are available. Numer-ous changes in the immune system are as-


REVIEW ARTICLE

sociated with aging and are well sum-marized in a recent book (11). In brief,these include a diminution in both cellu-lar and humoral immunity, and an in-crease in substances like amyloid (nowidentified as a fragment of immunoglobu-lin molecules] and autoantibodies, both ofwhich reflect a failure in the regulation ofimmunity.

Do these changes associated with aginghave any significance? There is evidenceto suggest that they do. Increasing num-bers of autoantibodies coincide with therising risk of developing autoimmunedisorders in an older population. Fur-thermore, the prevalence of malignancyincreases in an older population andmany people feel that disordered immu-nity contributes to the development ofmalignancies. There has also been moredirect evidence. A prospective study of 52persons over age 80 showed significantcorrelations between diminished delayedtype hypersensitivity and greater mortal-ity (12). These data lend support to thenotion that immunosuppression of themagnitude that stress can induce may addto an organism's susceptibility to diseaseand death.

However, between the extremes of earlydevelopment and old age and major lifechanges associated with endocrinologicshifts, we have considerably less informa-tion about the variabilities in the normalbase line. The studies that do exist reportthat human immunoglobulin levels varyrelatively widely between individuals butprobably by no more than about 20%within individuals during the course of ayear (13). Differences in sex (females have20% more IgM) and race (blacks havemore IgG than whites) are also reported(14).

Little data about the constancy of cellu-lar immunity exist, although there do ap-

pear to be sex differences and probablyracial differences there as well. Basically,however, no normal quantitative baselines have been established.

How much variation is there during thecourse of a day? We now know that thereare significant circadian rhythms in im-mune functioning, both in humoral andcellular functions in man and in labora-tory animals, much of the work havingbeen summarized in a recent volume enti-tled Chronobiology in Allergy and Im-munology (15). Included are papers de-scribing circadian variations in secretoryIgA, plasma cell, and immunoglobulinlevel response to antigen stimulation, andquantitative levels of circulating lympho-cytes as well as their response tomitogenic stimulation. Recently we havefound a marked diurnal variation innatural killer activity.1

These data should make us cognizant ofthe sketchy nature of the base-line pat-terns of immunologic variations againstwhich attempts have been made to mea-sure the effects of psychological stress. Itis obvious that methodologic approachesin the future need to be very precise aboutnot only the gender of the subject, but theexact stage of the life cycle and the time ofday during which measurements are ta-ken. It may also turn out that changes inimmunologic rhythms may be as or moresignificant than demonstrated changes inisolated levels.

The Neuroendocrine Apparatusand the Immune System

A further look at the factors which regu-late the immune system leads us to con-sider the role of the neuroendocrine sys-

'Rogers, MP, Dubey D, Halberg F, Yunis E: work inprogress.

Psychosomatic Medicine Vol. 41 , No. 2 (March 1979) 151


tern. There are by now many well-documented interactions between im-mune processes and neuroendocrinefunctions, described in recent reviews byBesedovsky and Sorkin (16), Ahlqvist(17), and Wolstenholme and Knight (18).In all likelihood, the diurnal variations inrhythmicities in the immune system de-scribed above are intimately related towell-established rhythmicities in theneuroendocrine system, but the exact in-terrelationships remain to be worked out.

In any case, the neuroendocrine systemappears to be essential for the normal on-togenetic development of the immunesystem and vice versa. Neonatal thymec-tomy in mice, in addition to impaired cel-lular immunity, leads to altered sexualmaturation, adrenal hypertrophy, andother endocrine disturbances. In fact, for along time the thymus has been assumed tobe an endocrine organ, and more recently,a thymus hormone-like substance knownas thymopoietin has been isolated, al-though its biological properties are not asyet well understood (19). The thymus inturn is dependent on a normal neuroen-docrine environment, especially ad-renocorticoids. Many years ago Selye de-scribed accelerated thymic involution asone of the cardinal manifestations of thestress response syndrome in conjunctionwith elevated corticosteroid levels andadrenal hypertrophy (20), a finding whichlapsed into obscurity because the impor-tance of the thymus in immunity was notthen known. High doses of exogenoussteroids are known to be immunosuppres-sive both in humoral and cellular immu-nity, and are used for this purpose in awide range of clinical situations. It is lesswell known that physiological levels ofcorticosteroids have been found to be re-quired for several normal functions ofimmunity (21). Thus, the direction of theeffect of corticosteroids is dose-related. In

addition to the corticosteroids, thyroidhormone, growth hormone, insulin, andsex hormones at physiological levels haveall been shown to be required for the nor-mal development and functioning of theimmune system (22).

The existence of insulin receptors onthe surface of lymphocytes at certainstages of activity is noteworthy in consid-ering the interrelatedness of the immuneand endocrine systems (23). In addition tothis receptor, histamine, E prostaglandins,acetylcholine, and /3-adrenergic ca-techolamines all seem to have specificreceptor sites through which they affectthe functional activity of lymphocytes.They all exert their effect through the sec-ond messenger system, intracellular cyc-lic AMP and cyclic GMP (24). The factthat cholinergic and /3-adrenergic recep-tor sites exist on certain lymphocytes isespecially relevant to our consideration oflinks between the central nervous system(CNS) and the immune system.

Other studies have emphasized the im-portance of the neuroendocrine systemduring the induction of an immune re-sponse. In one study, Besedovsky and hiscolleagues immunized rats with two dif-ferent antigens, and then discovered astriking increase in serum hydrocortisoneand a moderate decrease in thyroxine,which coincided with the time of elabora-tion of antibody-forming cells. That find-ing, associated with a simultaneous in-crease in electrical activity in individualneurons in the ventral medial hy-pothalamus of the rat, led them to post-ulate an afferent pathway between theperipheral initiation of an immune re-sponse and the hypothalamus (25). A re-cent report by Pierpaoli and Maestroni hassuggested that pharmacologic interrup-tion of that neuroendocrine response afterimmunization suppresses transplantationimmune reactions. The authors made the

152 Psychosomatic Medicine Vol. 41 , No. 2 (March 1979)

REVIEW ARTICLE

empiric discovery that a combination ofdrugs, including L-5-hydroxytryptophan(a serotonin precursor), dopamine,haloperidol, and phentolamine (an alphaadrenergic blocking agent), when ad-ministered a few days before and afterimmunization, led to specific and long-lasting unresponsiveness to the specificantigens administered (26).

CNS CHANGE ALTERINGIMMUNITY

Having briefly reviewed the normalfunction and regulation of the immunesystem and some of the factors known toaffect its homeostasis, we will now pulltogether evidence from various sourcesindicating that the CNS and psychologicalexperience, including stress, produce alt-erations in the functioning of the immunesystem. Since much of the psychologicalchange has been defined as stress, a briefdiscussion about the use of the term"stress" is warranted before proceeding.

The Meaning of Stress

The term "stress" has been used in somany different ways that it immediatelypresents a semantic nightmare. In this re-view, our main focus will be on psycho-logical stress rather than physical stresses,such as starvation or exposure to extremecold, etc. In real life, however, these twodifferent kinds of stress are often interre-lated. For example, the physical stress ofstarvation is accompanied by the psycho-logical stress of hunger and fear of dying.Conversely, the experience of extremeanxiety and /or fear in an animal usuallyleads to changes in behavior, such aswithdrawal or the fight or flight response.In human beings, the range of behaviordesigned to alleviate anxiety may be far

more complicated, including such behav-iors as drug-taking, including the use ofalcohol and cigarettes, as well as potentialchanges in dietary and sleep and wakingbehavior. So, in talking about stress pro-ducing somatic change, it is useful toclarify whether stress has produced thatchange by the CNS causing internalphysiological alterations or whether theCNS has created an external, behavioralchange which has in turn altered theinternal milieu.

Furthermore, the stress itself may notbe purely psychological in nature. Obvi-ously, if one used starvation as a psycho-logical stressor, there would be a pro-found concurrent physical trauma whichmight compound any psychosomatic ef-fect that such a stress would have. But thisquestion also arises with more subtlestressors. The use of electrical shocks inavoidance conditioning and the use ofhandling or overcrowding may all pro-duce subtle but important somaticchanges. On the other hand, certain stres-sors which have been used in experimen-tal animals, such as visual, auditory, orolfactory exposure to a predator who can-not physically touch the animals, providea "purer" psychological stress. Finally,there is often confusion about whetherstress is the stimulus or the response. Ingeneral, it makes more sense to us to de-fine stress in terms of the stimulus ratherthan the response which, as others havesuggested, might best be called strain. Ul-timately, of course, we are more interestedin the amount of psychological strain thatoccurs. The difficulty comes in measuringthis, however. For experimental animals,we have no direct way of knowing theanimal's inner psychological experience.And in human beings, the same "stress-ful" stimulus may produce two widelyvarying responses. Human beings areexquisitely sensitive to the symbolic



meaning of various stimuli which are notphysically traumatic, for example, wordsconveying the death of a child. What isstressful to one person may be a source ofpleasure to another. It is beyond the scopeof this review to deal with all of the con-troversy and confusion about the use ofthe term "stress." However, we will beexplicit about the particular definitions ofstress used in the individual studies re-ferred to and return to this issue in thesection on Methodologic Issues.

Stress and Illness: Clinical Data

The clinical literature and indeed clini-cal experience has repeatedly emphasizedthe importance of psychological factors inboth the onset and the course of a varietyof illnesses known to be influenced atleast in part by disturbances in immunity,including cancer (27), infectious disease(28, 29), autoimmune disease (30, 31), andallergy (32). In at least two studies done,one of patients with breast cancer (33) andanother of patients with rheumatoid ar-thritis (34), there have been specific corre-lations between immunoglobulin levelsand emotional states. Both individual casestudies and detailed, although retrospec-tive, clinical studies have argued persua-sively for the importance of psychologicalstress in the onset and course of many ofthese illnesses.

On the epidemiologic side, the mea-surement of the magnitude of recent lifechange, developed initially by Holmesand Rahe as a quantifiable measure ofstress, has provided further suggestiveevidence for the contribution of stress tothe development of a variety of illnessesin a variety of different populations (35).In addition, other studies have found anincreased incidence of disease in popula-tions experiencing the same major lifechange, such as bereavement (36) or loss

of work (37). These epidemiologic studieswould lead us to conceptualize stress asdefined by recent life change as a risk fac-tor, increasing the likelihood of disease ata level that is statistically significant butby no means uniformly associated withdisease. In this regard, it is important toavoid simplistic notions of stress and psy-chological experience as the "cause" ofdisease but rather to view stress as havinga complex interaction with the personal-ity and biology of the host and hence withthe expression of disease. Further, Cobband others have shown that if social sup-port is included in the equation, the rela-tionship between stress and disease be-comes more sharply defined (38). Whensocial support is high, it tends to protectagainst the effects of stress; when it is low,it tends to magnify it. With some successother researchers have included differentmeasures designed to evaluate subjects'capacity to cope with stress as a furthermodifier of this relationship.

Stress and Experimental Illness

Animal experiments have also demon-strated definite but, in many cases, com-plex effects of stress on disease suscepti-bility. In this discussion we are againfocusing on diseases which are closelylinked with failures in immune regula-tion.

With regard to infection, experimentalstress, typically created either by physicalrestraint or avoidance conditioning usingelectrical shocks, has been associatedwith increased susceptibility to numerousviral illnesses, including herpes simplex(39), poliomyelitus virus (40), Coxsackie Bvirus (41), and polyoma virus (42). Otherstressful manipulations, such as exposureto high intensity sound (43), overcrowd-ing (44,45), or exposure to a predator (46),


REVIEW ARTICLE

have also increased susceptibility to cer-tain infections. In the latter study, Hamil-ton showed that exposure to a predator(cat) dramatically increased the rate ofreinfection of mice to tapeworm, and wasalso correlated with adrenal hypertrophyand splenic atrophy, including an atrophyof splenic corpuscular germinal centerscontaining high concentrations of lym-phocytes.

To add to the complexity, however, ithas also been observed in at least twostudies that stress may have a protectiveeffect against infection (47, 48). The exactnature of the stress and the timing of itsapplication in relation to a particular or-ganism, as well as the genetics of the host,are all important factors in determiningthe effect which stress has on susceptibil-ity to infection. Furthermore, the time ofexposure to an infectious agent needs tobe considered both in terms of the stage ofthe life cycle and of the diurnal rhythmic-ity of the host. As pointed out above, avariety of functions of the immune systemhave a circadian rhythm.

The incidence and rate of growth of ex-perimental animal tumors have been al-tered by stress. A strain of mice carryingthe Bittner oncogenic virus usually de-velops mammary tumors within 8-18months after birth. Riley demonstratedthat stress, as defined by overcrowding,was associated with a 92% incidence oftumor, whereas only 7% developedtumors in the nonstressful environment(49). Elevated cortisol levels and involu-tion of the thymus gland were also foundin the stressed animals. In another study,brief daily handling and mild electricshock, if administered early in life, dif-ferentially retarded the rate of tumor de-velopment and decreased the survival ofrats infected with Walker 256 sarcoma(50). Both the nature of the stress and the

exact time of the stress accounted for asignificant variability in the response. Inyet another study, stimulation by han-dling during the first 3 weeks of life hasbeen shown to shorten the survival time ofmice after transplantation of lymphoidleukemia as compared to unstimulatedmice (51).

Adjuvant-induced arthritis in rats hasbeen used as an animal model forrheumatoid arthritis. Amkraut et al. havereported that group housing stress signifi-cantly increases the intensity of this dis-ease in male rats and that it also acceler-ates the time of maximal disease and rateof recovery (52).

Stress and the Immune System

In addition to the more indirect evi-dence just presented, there is also directevidence for the effect of CNS change onthe immune level.

Cellular Immunity

In both human and animal studies,stress has been associated with alterationsin cellular immune mechanisms. In a re-cent human study, bereavement wasfound to be associated with depressedlymphocyte function, specifically inT-cell response to mitogens at 5 weeks butnot at 2 weeks after a bereavement (53).There was a 10-fold difference in thisT-cell function at 5 weeks between the 26bereaved spouses and the controls. No dif-ference was found in the number of T andB cells, antibody titers, presence of au-toantibodies, or in the hormonal studiesincluded. Unfortunately, the report lacksany description of the degree of severity ofthe grief reactions as well as sufficient de-tail about the presence of medications ormedical illnesses which might have al-



tered their lymphocyte function. Similardepression in T-cell response to mitogenshas been noted in astronauts in the sky labprogram for the first 3 days in the post-flight period (54). It is unclear, however,whether the apparent impact ofsplashdown had its effect on the lympho-cytes by virtue of psychological stress orby the physical stress of splashdown.Palmblad and his colleagues showed thatthe stress of a 77-hour sleepless vigil inman, in which exposure to loud noise alsooccurred, was associated with an increasein interferon production, a function of Tcells, as well as a biphasic change inphagocytic activity (55].

Recently attention has shifted to lym-phocytotoxicity as an important index ofimmunocompetence. Two recent papersgiven at the 1978 Annual Meeting of theAmerican Psychosomatic Society citeddata in human beings linking stress andimmunosuppression as measured by lym-phocyte cytotoxicity. In one study, Greeneand his colleagues from Rochester, N.Y.,demonstrated a statistically significantcorrelation between increased stress asdefined by life change units combinedwith a high vigor score on the profile ofmood states (POMS) and a decrease inlymphocyte cytotoxicity (56). Theyhypothesized that the high vigor score re-flected denial used as an unsuccessfulcoping mechanism in the face of in-creased stress. In a similar study reportedat the same meeting, also involving col-lege students, Locke and colleagues founda statistically significant correlation be-tween high stress combined with poorcoping and a decline in natural killer ac-tivity (57). In Locke's study, no significantcorrelations between stress and variousparameters of humoral immunity werefound. Natural killer activity provides aparticularly interesting index of im-

munocompetence for several reasons.First, although its precise function is un-known, it is thought to provide a generalhost defense in combating host cells un-dergoing malignant transformation andalso against viruses (58). Secondly, whatis measured is a natural property of thecell rather than an artificially inducedmeasure, such as response to mitogens.For these reasons, it appears to have par-ticularly important implications for resis-tance to disease. Its disadvantage is that itis not as yet as well standardized as mito-gen stimulation techniques. Although allof these studies reporting suppressed cel-lular immunity in human subjects understress are intriguing, none has been repli-cated at this point, although no attemptshave yet been reported, either.

Giving further credibility to thesehuman studies, there have been severalanimal studies in which stress has alsobeen associated with diminished lympho-cyte response to mitogens (59, 60), lym-phocyte cytotoxicity (59), and lymphocyteresponse to antigenic stimulation (61). Inrelated animals studies, suppression ofcellular immunity secondary to stress hasbeen reflected in diminished skin homo-graft rejection in mice (62), diminishedgraft-versus-host response (63), and di-minished delayed hypersensitivity reac-tion (64).

Whereas most studies have thus con-curred in the immunosuppressive effectsof stress on cellular immunity, a few havefound conflicting results, in which stressappears to have augmented cellular im-mune function (59, 65, 66). For example,one study reported that stress increaseddelayed hypersensitivity. Although thediscrepancy may be explained in part onthe basis of differences in the experimen-tal animals and the type of stress used, theduration of stress and the length of the


REVIEW ARTICLE

time interval between the stress and theimmunological measurements are of cen-tral importance. For example, Monjan andCollector subjected mice to the stress ofloud noise on a chronic basis and found abiphasic response (59). For the first 2weeks or so of stress, they found a 50%decrease in response to mitogens andlymphocyte cytotoxicity. After 3 weeks,however, there was a striking increase inthese same functions. These investigatorsattribute the initial decrease to the in-creased steroid levels occurring over thesame period. They attribute the longer-term increase to one or more circulatingfactors, such as somatotropic hormone.Similarly, Folch and Waksman demon-strated that either a noise stress, a waterdeprivation stress, or an injection of hyd-rocortisone may all result in loss of rats'suppressor T-cells adhesiveness to glasswool (a measure of suppressor T-cell ac-tivity) in the short run, i.e., around 5 days.However, at 2—3 weeks, there is a returnto normal levels, followed by a marked in-crease in suppressor cell activity. LikeMonjan and Collector, they attribute theshort-term effect to elevated steroids, butwonder whether the subsequent increaseis due to altered levels of thymus hor-mone(s) or a redistribution of lympho-cytes (66).

Humoral Immunity

A variety of experimental stresses,especially overcrowding, have also beenshown to reduce antibody responses toflagellin, a potent bacterial antigen, bothon primary and secondary immunization(67-69). If the stress is applied prior to orimmediately subsequent to immuniza-tion, it is immunosuppressive, and only ifsmall doses of antigen are used. However,if stress is applied several days after in-oculation, it is ineffective (70).

Early Experience and Immunity

The effect of stress in early life experi-ence has also been associated with alteredimmunological responses later in life.Adult rats which had been handled in in-fancy have been shown to have higherantibody titers in response to both pri-mary and secondary immunization withflagellin than a control group (71). In con-trast, handling 1 week prior to immuniza-tion has been found to depress antibodyresponses to immunization. Once againthat reenforces the concept that the timingof the stress is crucial. Early infectionsand nutritional stresses can also modifythe developing immune system and leadto permanent alterations in both the im-munological responses and host sub-stances as summarized in a recent articleby Dutz and colleagues (72). Residualimmunologic alterations persisting longafter proper nutrition was resumed weredescribed in phagocytosis, complementlevels, cyclic AMP, accelerated thymic at-rophy, and an accelerated decline incell-mediated immunity.

CONDITIONING AND THEIMMUNE SYSTEM

Another link connecting the psycheand immune system has been the demon-stration of behaviorally conditioned im-munosuppression. In 1975, Ader andCohen described the phenomenon of be-haviorally conditioned immunosuppres-sion in rats using a taste aversionparadigm (73). Saccharin (the conditionedstimulus) was paired with cyclophos-phamide (the unconditioned stimulus), asubstance producing gastrointestinal dis-tress as well as immunosuppression. In acarefully controlled study, subsequent



exposure to saccharin was found to exertan immunosuppressive effect as measuredin lower antibody titers raised to immuni-zation with sheep red blood cell antigen.We have been able to replicate thephenomenon of behaviorally conditionedimmunosuppression (74). The reason forthis effect remains a mystery. However, itdoes not seem to be due to a nonspecificstress. When lithium chloride is substi-tuted for cyclophosphamide, no im-munosuppressive effect is seen. Further-more, in the same paradigm, adrenocor-ticoid levels are equally raised by expo-sure to saccharin regardless of whetherlithium chloride or cyclophosphamide isused as the unconditioned stimulus (75).

HYPNOSIS AND THE IMMUNESYSTEM

Hypnosis has been found to alter theclinical manifestations of delayed hyper-sensitivity. Black and his associates wereable to inhibit the Mantoux reaction(tuberculin skin test) by direct suggestionunder hypnosis in subjects known to bepositive reactors (76). Although the typi-cal swelling and erythema were absent,skin biopsies did reveal the expected de-gree of cellular infiltration. In otherstudies, direct suggestion under hypnosishas been shown to inhibit immediatehypersensitivity reactions in allergicdermatitis [77), allergic responses to food[77), and in urticarial eruptions (78).There have as yet been no adequate at-tempts to replicate these interestingstudies.

BRAIN STIMULATION AND THEIMMUNE SYSTEM

By directly stimulating the brain, dif-ferent investigators have produced altera-

tions in the immune response. Lesions inthe dorsal hypothalamus of rabbits havebeen shown to suppress both humoral andcellular immunity (79). The same Russianauthors have described the effect ofmesencephalic stimulation in enhancingantibody responses (80). Fessel and For-syth demonstrated a doubling of gammaglobulin levels by electrical stimulation ofthe lateral hypothalamus in rats (81).Bilateral hypothalamic lesions in guineapigs have been observed to protect againstlethal anaphylaxis (82, 83). In furtherstudies, it was found that anterior but notposterior lesions protect againstanaphylaxis (84). In addition to demon-strating the protective effect of anteriorhypothalamic lesions against anaphy-laxis, Macris and his colleagues foundthat they lowered antibody titers and de-creased cutaneous delayed hypersensiti-vity by this technique (85). Stein's reviewin Science (3) contains a more detaileddiscussion of the effect of hypothalamiclesions on immunological reactions andevidence for the role of hormonal media-tion of these effects.

THE QUESTION OFMECHANISMS

There seems little doubt that differentpsychological states and CNS stimulationcan influence the immune system. Thequestions now are really what themechanisms are, and how clinically sig-nificant they might be.

The predominant hypothesis has beenthat CNS change leads to immunologicchange through the mechanism ofhypothalamic-pituitary hormonaJ stimu-lation. There is considerable evidence, di-rect and indirect. Already mentioned arethe variety of hormones which directly af-

158 Psychosomatic Medicine Vol. 41, No. 2(March 1979)

REVIEW ARTICLE

feet immunity. Adding those interactionswith our growing knowledge ofpsychoendocrinology (86) providesstrong indirect evidence for the impor-tance of this mechanism. Not surpris-ingly, adrenocorticoids have been focusedon the most. In at least two studies involv-ing stress and immunity, simultaneouselevations in corticosterone have beenmeasured which correlate with the im-munological depression (49, 60). Thyroidhormone has also been implicated.

Another mechanism may involve theautonomic nervous system. The use ofhypnosis to inhibit the Mantoux responseaffected the vascular component of thereaction. Clearly the autonomic nervoussystem is exquisitely sensitive to emo-tional states and may at least affect manyof the secondary aspects of the immuneresponse. Adrenergic nerve endings canbe found in the spleen and in the thymusand may have a more direct relationshipon immunologic reactivity. In fact, a re-cent study by several Japanese inves-tigators reports a suppression in a primaryimmune response (in both antibody titerand number of plaque-forming cells) afterchemical sympathectomy in mice by theuse of 6-hydroxydopamine (87). There isalso the possibility, since lymphocyteshave /3-adrenergic receptors, that sympa-thetic release of adrenalin can modify cel-lular immunity. A recent report providesevidence that chronic /3-adrenergic stim-ulation over a period of several daysdecreases the number of /3-adrenergic re-ceptor sites on polymorphonuclear leuko-cytes (88).

Finally there is the possibility of a sepa-rate mechanism of action. The phenome-non of behaviorally conditioned im-munosuppression provides some supportfor this. The fact that the taste aversionconditioned stimulus, saccharin, has an

immunosuppressive effect cannot be fullyexplained by changes in corticosteroids.Further, the data from Besedovsky'sstudy, showing an increased rate ofneuronal firing in the hypothalamus im-mediately after antigen antibody interac-tion and prior to any change in thyroid orcorticosteroid hormone, are also sugges-tive of a direct link between an immunereaction and the CNS (25). In the lattercase, it appears to be an afferent link be-ginning with the immune reaction some-how sending a message to thehypothalamus. The investigation intopossible mechanisms is clearly only in itsinfancy. Hopefully, our colleagues in im-munology will share our enthusiasm inthe pursuit of these questions.

METHODOLOGIC ISSUES

In reviewing the data already availableand in considering future approaches toresearch in this field, several points aboutmethodology need emphasis.

First, since the term "stress" in alllikelihood will continue to be used to de-scribe diverse phenomena, overgenerali-zation is to be avoided. Instead, carefulattention should be given to what it actu-ally refers to in any given situation andhow it is quantified. In attempting to de-lineate mechanisms of action we need tobe aware that what is defined as stress,even psychological stress, may often in-clude direct physical stimulation that isinherently noxious. Further psychologicalstress may change the behavior of an or-ganism such that other physical stimulicome into play which may produce inter-nal physiological change through sepa-rate mechanisms. For example, it wouldbe hard to find a person in an extremestate of stress whose pattern of daily liv-

Psychosomatic Medicine Vol. 41, No. 2 (March 1979) 159


ing is not in some way altered in responseto the stress.

That raises the question as to whether avariety of behaviors can influence thefunctioning of the immune system. Thereare no data at present about the effect ofchanges in sleep, diet (short of gross mal-nutrition), or exercise on immunity. How-ever, there is suggestive evidence thatsmoking (89) and alcohol consumption(90) can impair some functions of immu-nity. Beyond that, many experiences likepregnancy and anesthesia (91), for exam-ple, and a wide range of drugs includingchlorpromazine (92), diphenylhydantoin(93), and some antibiotics (94) may tem-porarily depress cellular immunity. Thelist of substances and circumstanceswhich can produce immunosuppressionis impressive as even a rapid perusal ofthe Index Medicus can attest. From amethodological point of view, the influ-ence of these other factors, aside frompsychological stress, needs to be con-trolled and in some cases investigated intheir own right.

The issue of time and timing is impor-tant. At what time does the psychologicalstress occur? How long does it last? Interms of the life cycle of the host, is itduring early developmental periods, inmid-life, or in old age? At what point dur-ing a diurnal cycle, during which thereare known to be wide variations in certainproperties of the immune response? Themore information that develops about thenormal regulation of the immunologicalactivity, the more sophisticated ourhypotheses linking psychological changeand immunological change need to be.Illness may occur as a result of a disrup-tion of a normal rhythmic balance ratherthan an absolute lowering of the variousmeasurements of immune components.There may be biphasic changes depend-

ing on the time at which immunologiclevels are taken. The discoveries de-scribed above require that the hour orperhaps the day in which immunologicalmeasurements are made need to be kept asconstant as possible, and perhaps singlemeasurements are woefully inadequate.

Finally, we have to deal with the im-mune system as the complex network thatit is, in which psychological stress mightbe either immunosuppressive or enhan-cing of some aspects of the immune re-sponse, depending on the time of mea-surement and depending on the functionsmeasured. We know that there are subsetsof T lymphocytes, both helper T cells andsuppressor T cells, and new subsets beingidentified all the time. Psychologicalchange may produce different effects onthese subsets, as hydrocortisone is knownto do. Suppression of suppressor cellsmay enhance certain functions of immu-nity. Furthermore, higher levels do notnecessarily mean a stronger, healthier re-sponse. The immune system itself is care-fully regulated. Processes are initiatedand turned off by feedback mechanisms.Most important is the concept of thehomeostasis of the system and the healthyregulation of immunity which gives us abetter parameter for susceptibility to dis-ease than the magnitude of a single iso-lated immune function.

SUMMARY

We have reviewed various sources ofevidence which indicate that the immunesystem, and hence susceptibility to a widevariety of diseases, is subjected to the in-fluence of stress and other psychologicalstates. We have emphasized as well thatthe immune system is influenced also bygenetics, aging, and a variety of environ-


REVIEW ARTICLE

mental experiences. The impact of psy-chological stress must be evaluatedwithin this broader context and there is aneed to know a great deal more about thedynamics and base line of the immunesystem and its components.

Considerable evidence indicating theclose interrelationship between the endo-crine and immune system has been pre-sented. Both play key roles in maintainingan organism's integrated adaptation to theenvironment. It is likely that stress exertsmost, but perhaps not all, of its influenceon the immune system through themechanism of endocrinologic change.The autonomic nervous system and pos-sibly other brain-immune system connec-tions may mediate these effects.

The importance of periodicity as one ofthe most fundamental and ubiquitousproperties of all dynamic living systems

has also been emphasized. An individu-al's response to environmental stimuliwill vary in a predictable manner accord-ing to the amplitude, phase, or even thefrequency of various biological rhythms.Stress may disturb the coordinated coupl-ing of such rhythms more than any singledimension.

In future investigations of the effect ofstress on immunity, measurements ofimmunologic function will need to cap-ture the dimensions of time and rhythmmore carefully, as well as to control for themany other factors which may cause per-turbations in the immune system.

The authors wish to express theirgratitude to Professor Edmond Yunis,Chief, Division of Immunogenetics, Sid-ney Farber Cancer Institute, Boston, forhis helpful criticism and suggestions.

REFERENCES

1. Weiner H: Presidential Address: Some comments on the transduction of experience by the brain:Implications for our understanding of the relationship of mind to body. Psychosom Med 34:355-380,1972

2. Amkraut AA, Solomon GF: From the symbolic stimulus to the pathophysiologic response: Immunemechanisms. Int J Psychiat Med 5:541-563, 1974

3. Stein M, Schiavi RC, Camerino M: Influence of brain and behavior on the immune system. Science191:435-440, 1976

4. Austen KF: Homeostasis of effector systems which can also be recruited for immunologic reactions.Presidential Address, American Association of Immunologists, Atlanta, Georgia, June 6, 1978

5. Austen KF: Introduction to clinical immunology, in Harrison's Principles of Internal Medicine (8thedition, edited by GW Thorn, RD Adams, E Braunwald, KJ Isselbacher, RG Petersdorf). New York,McGraw-Hill Book Comp., 1977

6. Roitt I: Essential Immunology (2nd edition). Oxford, England, Blackwell Scientific Publications, 19747. Haller O, Hansson M, Kiessling R, Wigzell H: Role of non-conventional natural killer cells in resistance

against syngeneic tumor cells in vivo. Nature (Lond) 270:609-611, 19778. Buckley CE, Dorsey FC: The effect of aging on human serum immunoglobulin concentrations. J Im-

munol 105:964-972, 19709. Purilo DT, Hallgren HM, Yunis EJ: Depressed maternal lymphocyte response to phytohaemagglutinin

in human pregnancy. Lancet 1:769, 197210. Fabris N: Immunological reactivity during pregnancy in the mouse. Experientia 29:610—612, 197311. Makinodan T, Yunis E (editors): Immunology and aging, in Comprehensive Immunology (Series editors

RA Good, SB Day). New York, Plenum Medical Book Company, 1977



12. Roberts-Thomson IC, Whittingham S, Youngchaiyud U, Mackay IR: Aging immune response, andmortality. Lancet 11:368-370, 1974

13. Allansmith M, McClellan B, Butterworth M: Stability of human immunoglobulin levels. Proc Soc ExpBiol Med 125:404-407, 1967

14. Grundbacher FJ: Heritability estimates and genetic and environmental correlations for the humanimmunoglobulins, G, M, and A. Am J Hum Genet 26:1-12, 1974

15. Smolensky MH, Reinberg A (editors): Chronobiology in Allergy and Immunology. Springfield, 111.,Charles C. Thomas, American Lecture Series, 1977

16. Besedovsky H, Sorkin E: Network of immune-neuro-endocrine interactions. Clin Exp. Immunol 27:1-2,1977

17. Ahlqvist J: Endocrine influences on lymphatic organs, immune responses, inflammation, and autoim-munity. Acta Endocrinol [Suppl] (kbh) 206, 1976

18. Wolstenholme GE, Knight J (editors): Hormones and the Immune Response, Ciba Study Group, No. 36.London, Churchill, 1970

19. Goldstein AL, Guha A, Zatz MM, Hardy MA, White A: Purification and biological activity of thymosin:A hormone of the thymus gland. Proc Natl Acad Sci USA 69:1800-1803, 1972

20. Selye H: Stress and disease. Science 122:625-631, 195521. Ambrose CT: The essential role of corticosteroids in the induction of the immune response in vitro, in

Hormones and Immune Response, Ciba Study Group, No. 36 (edited by GEW Wolstenholme, J Knight).London, Churchill, 1970

22. Fabris N: Hormones and aging, in Comprehensive Immunology (edited by T Makinodan, E Yunis;Series editors RA Good, SB Day). New York, Plenum Medical Book Company, 1977, pp 73-89

23. Krug V, Krug F, Cuatrecasas P: Emergence of insulin receptors on human lymphocytes during in vitrotransformation. Proc Natl Acad Sci USA 71:1330-1333, 1974

24. Bourne HR, Lichtenstein LM, Melmon KL, Henney CS, Weinstein Y, Shearer GM: Modulation of in-flammation and immunity by cyclic AMP. Science 84:19-28, 1974

25. Besedovsky H, Sorkin E, Felix D, Haas H: Hypothalamic changes during the immune response. Eur JImmunol 7:323-325, 1977

26. Pierpaoli W, Maestroni GJ: Pharmacologic control of the hormonally modulated immune response. III.Prolongation of allogenic skin graft rejection and prevention of runt disease by a combination of drugsacting on neuroendocrine functions. J Immunol 120:1600-1603, 1978

27. Bahnson CB (editor): Second conference on the psychophysiological aspects of cancer. Ann NY AcadSci 164:307-634, 1969

28. Day G: The psychosomatic approach to pulmonary tuberculosis. Lancet 1:1025-1028, 195129. Imboden JB, Canter A, Cluff LE: Convalescence from influenza: A study of the psychological and

clinical determinants. Arch Int Med 108:393-399, 196130. Engel GL: Studies of ulcerative colitis: III. The nature of the psychologic processes. Am J Med

19:231-256, 195531. Rimon R: A psychosomatic approach to rheumatoid arthritis: A clinic study of 100 female patients. Acta

Rheumatol Scand (Suppl) 13, 196932. Engels WD, Wittkower ED: Psychophysiological allergic and skin disorders, in Comprehensive

Textbook of Psychiatry, II. (edited by AM Freedman, HJ Kaplan, BJ Sadock) Baltimore, Williams &Wilkins Book Comp., 1975, pp 1685-1694

33. Pettingale KW, Greer S, Tee DE: Serum IgA and emotional expression in breast cancer patients. JPsychosom Res 21:395-399, 1977

34. Hendrie HC, Paraskevas F, Baragar FD, Adamson JD: Stress, immunoglobulin levels, and early polyar-thritis. J Psychosom Res 15:337-342, 1971

35. Gunderson EK, Rahe RH (editors): Life Stress and Illness. Springfield, 111., Charles C. Thomas, 197436. Parkes CM, Brown RJ: Health after bereavement—a controlled study of young Boston widows and

widowers. Psychosom Med 34:449-461, 197237. Cobb S: Physiological changes in men whose jobs were abolished. J Psychosom Res 18:245—258, 197438. Cobb S: Social support as a moderator of life stress. Psychosom Med 38:300-314, 197639. Rasmussen AF Jr, Marsh JT, Brill NQ: Increased susceptibility to herpes simplex in mice subjected to

avoidance-learning stress or restraint. Proc Soc Exp Biol Med 96:183-189, 1957


REVIEW ARTICLE

40. Johnsson T, Rasmussen AF Jr: Emotional stress and susceptibility to poliomyelitis virus infection inmice. Arch Gesamte Virusforsch 18:392, 1965

41. Johnsson T, Lavender JF, Hultin E, Rasmussen AF Jr: The influence of avoidance-learning stress onresistance to Coxsackie B virus in mice. J Immunol 91:569—574, 1963

42. Rasmussen AF Jr: Emotions and immunity. Ann NY Acad Sci 164:458-461, 196943. Jensen MM, Rasmussen AF Jr: Stress and susceptibility to viral infections. II. Sound stress and suscepti-

bility to vesicular stomatitis virus. J Immunol 90:21-23, 196344. Davis DE, Read CP: Effect of behavior on development of resistance in trichinosis. Proc Soc Exp Biol

Med 99:269-272, 195845. Brayton AR, Brain PF: Proceedings: Effects of differential housing and glucocorticoid administration on

immune responses to sheep red blood cells in albino TO strain mice. J Endocrinol 64(1):4P—5P, 197546. Hamilton DR: Immunosuppressive effects of predator induced stress in mice with acquired immunity to

Hymenolepsis nana. J Psychosom Res 18:143-150, 197447. Friedman SB, Ader R, Grota LJ: Protective effect of noxious stimulation in mice infected with rodent

malaria. Psychosom Med 35:535-537, 197348. Marsh JT, Lavender JF, Chang SS, Rasmussen AF: Poliomyelitis in monkeys: Decreased susceptibility

after avoidance stress. Science 140:1414-1415, 196349. Riley V: Mouse mammary tumors: Alteration of incidence as apparent function of stress. Science

189:465-467, 197550. Ader R, Friedman SB: Differential early experiences and susceptibility to transplanted tumor in the rat.

J Comp Physiol Psychol 59:361-364, 196551. Levine S, Cohen C: Differential survival to leukemia as a function of infantile stimulation in DBA/2

mice. Proc Soc Exp Biol Med 102:53-54, 195952. Amkraut AA, Solomon CF, Kraemer HC: Stress, early experience and adjuvant-induced arthritis in the

rat. Psychosom Med 33:203-214, 197153. Bartrop RW, Lazarus L, Luckhurst E, et al: Depressed lymphocyte function after bereavement. Lancet

1:834-836, 197754. Rimsey SL, Ritzman SE, Mengel CE, et al: Sky-lab experiment results: Hematology studies. Acta As-

tronautica 2:141-154, 197555. Palmblad J, Cantell K, Strander H, et al: Stressor exposure and immunologic response in man: interferon

producing capacity and phagocytosis. J Psychosom Res 20:193-194, 197656. Greene WA, Betts RF, Ochitill HN, et al: Psychosocial factors and Immunity: Preliminary report. Annual

Meeting, American Psychosomatic Society, Washington, D. C, March 31, 197857. Locke SE, Hurst MW, Heisel JS, et al: The influence of stress on the immune response. Annual Meeting,

American Psychosomatic Society, Washington, D. C, April 1, 197858. Behelak Y, Banerjee D, Richter M: Immunocompetent cells in patients with malignant disease: The lack

of naturally occurring killer cell activity in the unfractionated circulating lymphocytes from patientswith chronic lymphatic leukemia (CLL). Cancer 38:2274-2277, 1976

59. Monjan AA, Collector MI: Stress-induced modulation of the immune response. Science 1.96:307-308,1977

60. Gisler RH: Stress and hormonal regulation of the immune response in mice. Psychother Psychosom23:197-208, 1974

61. Joasod A, McKenzie JM: Stress and the immune response in rats. Int Arch Allergy Appl Immunol50:659-663, 1976

62. Wistar R, Hildemann WH: Effect of stress on skin transplantation immunity in mice. Science131:159-160, 1960

63. Amkraut AA, Solomon GF, Kasper P, et al: Stress and hormonal intervention in the graft-versus-hostresponse. Adv Exp Med Biol 29:667-674, 1972

64. Pitkin DH: Effect of physiological stress on the delayed hypersensitivity reaction. Proc Soc Exp BiolMed 120:350-351, 1966

65. Mettrop PJ, Visser P: Exteroceptive stimulation as a contingent factor in the induction and elicitation ofdelayed-type hypersensitivity reactions to l-chloro-2 & 4 dinitrobenzene reactions in guinea pigs.Psychophysiology 5:385-388, 1969

66. Folch H, Waksman BH: The splenic suppressor cell: Activity of thymus dependent adherent cells:

Psychosomatic Medicine Vol. 41, No. 2 (March 1979) 1 63


Changes with age and stress. J Immunol 113:127-139, 197467. Solomon GF: Stress and antibody response in rats. Int Arch Allergy Appl Immunol 35:97-104, 196968. Versey SH: Effects of grouping on levels of circulating antibodies in mice. Proc Soc Exp Biol Med

115:252-255, 196069. Petrovskii IN: Problems of nervous control in immunity reactions. II. The influence of experimental

neuroses on immunity reactions. Zh Mikrobiol Epidemiol Immunobiol 32:1451, 196170. Solomon GF, Amkraut AA, Kasper P: Immunity, emotions, and stress. Ann Clin Res 6:313-322, 197471. Solomon GF, Levine S, Kraft JK: Early experience and immunity. Nature (Lond) 220:821-822, 196872. Dutz, W, Kohout E, Rossipal E, Vessal K: Infantile stress, immune modulations, and disease patterns.

Pathol Annu 11:415-454, 197673. Ader R, Cohen N: Behaviorally conditioned immunosuppression. Psychosom Med 37:333—340, 197574. Rogers MP, Reich P, Strom TB, Carpenter CB: Behaviorally conditioned immunosuppression: Replica-

tion of a recent study. Psychosom Med 38:447-451, 197675. Ader R: Conditioned adrenocortical steroid elevations in the rat. J Comp Physiol Psychol

90:1156-1163, 197676. Black S, Humphrey JH, Niven JS: Inhibition of Mantoux reaction by direct suggestion under hypnosis.

Br Med J 6:1649-1652, 196377. Ikemi Y, Nakagawa S: Psychosomatic study of so-called allergic disorders. Jap JMedProgr 50:451—474,

196378. Kaneko Z, Takaishi N: Psychometric studies on chronic urticaria. Folia Psychiatr Neurol Jap 17:16—24,

196379. Korneva EA, Khai LM: Effect of destruction of hypothalamic areas on immunogenesis. Fiziol Zh SSSR

49:42-48, 196380. Korneva EA, Khai LM: Effect of stimulating different mesencephalic structures on protective immune

response patterns. Fiziol Zh SSSR 53:42-47, 196781. Fessel NJ, Forsyth RP: Hypothalamic role in control of gamma globulin levels. Arthritis Rheum

6:771-772, 1963 (Abstr.)82. Freedman DX, Fenichel G: Effect of mid-brain lesion in experimental allergy. Arch Neurol Psychiatr

79:164-169, 195883. Szentivanyi A, Filipp G: Anaphylaxis and the nervous system. Part II. Ann Allergy 16:143-151, 195884. Luparello TJ, Stein M, Park DC: Effect of hypothalamic lesions on rat anaphylaxis. Am J Physiol

207:911-914, 196485. Macris NT, Schiavi RC, Camerino MS, Stein M: Effect of hypothalamic lesions on immune processes in

the guinea pig. Am J Physiol 219:1205-1209, 197086. Sachar EJ: Topics in Psychoendocrinology. New York, Grune and Stratton, 197587. Kosohara K, Taraka S, Ito T, et al: Suppression of the primary immune response by chemical sym-

pathectomy. (Research communication.) Chem Pathol Pharmacol 16:687-694, 197788. Galant SP, Duriseti L, Underwood S, Insel PA: Decreased /3-adrenergic receptors in polymorphonuclear

leukocytes after adrenergic therapy. N Engl J Med 299:933-936, 197889. Holt PG, Keast D, MacKenzie JS: Immunosuppression in the mouse induced by long-term exposure to

cigarette smoke. Am J Pathol 90:281-284, 197890. Lundy J, Raaf JH, Deakins S, et al: The acute and chronic effects of alcohol on the immune system. Surg

Gynecol Obstet 141:212-218, 197591. Duncan PG, Cullen BF: Anesthesia and immunology. Anesthesiology 45:522-538, 197692. Mitrova E, Mayer V: Phenothiazine-induced alterations of immune response in experimental tick-borne

encephalitis: Morphological model analysis of events. Acta Virol (Praha) 20:479—485, 197693. Yabuki S, Nakaya K: Immunoglobulin abnormalities in epileptic patients treated with diphenylhydan-

toin. Folia Psychiatr Neurol Jap 30:93-109, 197694. Munster AM, Loadholdt CB, Leary AG, et al: The effect of antibiotics on cell mediated immunity.

Surgery 81:692-695, 1977


Documents

REVIEW ARTICLES The Influence of the Psyche and the ......REVIEW ARTICLES The Influence of the Psyche and the Brain on Immunity and Disease Susceptibility: A Critical Review MALCOLM