Human psychoneuroimmunology today

Journal of Clinical Laboratory Analysis 4:22-38 (1 990)

Human Psychoneuroimmunology Today Massimo Biondi and Giorgio D. Kotzalidis

Third Psychiatric Clinic, University of Rome, “La Sapienza, ” Rome, Italy

Studies in human psychoneuroimmunology began around 1919, but a systematic approach wasn’t used until the work of Solomon in the 1960s. Recently, the new specialty has achieved relative independence due to considerable data acquisition.

Stress research has revealed relationships between neuroendocrine and immune changes. In parallel, increasing evidence of immunological alterations in psychiatric diseases has expanded the field; presently, immunological correlates of psychosomatic diseases and personality are sought. On the

other hand, while immunological disease has been psychologically assessed for many years, a clear-cut link between psyche and immunological changes has yet to be shown. This fact, along with the therapeutic implications of advancing knowledge, will influence strongly the future trends of psychoneuroimmunology. Concepts emerging from the study of this field will be of heuristic value to both psychiatry and immunology and will help define new and expanded limits for both disciplines.

Key words: Psychoneuroimmunology, mind-endocrine-immune interactions, schizophrenia, depression, stress, psychosomatic disease, personality, cancer, immunity

INTRODUCTION

Psychoneuroimmunology examines the analogies and recip- rocal influences, direct or indirect, between the nervous system and the immune system. The observation that psychic activity can influence immune phenomena dates back to 19 18 (1) and was a consequence of the discovery of conditioned reflex. During the late 1920s, immunological alterations were demonstrated in mental diseases (2), and during the mid- 1950s, a clear relationship was described among brain activity, endocrine organs, and immune function (3). The term psychoimmunology did not appear in Solomon and Moos’ 1964 article (4), as is often reported; however, this article contained many of the ideas that subsequently contributed to some of the basic tenets of psychoneuroimmunology , a term coined in the early 1980s (5,6). Since there was no one journal specifically devoted to the new field, relevant papers ended up in more than 200 journals. At present, the journals Mind, Brain, and Immunity and Progress in Neuroendocrinim- munology and the increasing number of textbooks on the topic bear witness to its great fascination for scientists.

Although it has long been evident that immune activity influences neuronal function, a molecular basis for a com- plete neuro-endocrine-immune loop was not suggested until it was demonstrated that interleukin-1 is able to influence the pituitary (7) and the hypothalamus (8-10).

The direct influence of neural tissue on immune cells has been substantiated by anatomical studies ( 1 1 - 16); the endocrine nature of immunocyte subpopulations became apparent when it was shown that lymphocytes are able to synthesize

0 1990 Wiley-Liss, Inc.

and secrete adrenocorticotropic hormone (ACTH) and beta- endorphin (17,18) and other opioids (1 9). Furthermore, lymphocytes possess receptors for neurotransmitters and hormones (20) and are particularly susceptible to the effects of stress (21). Soon after its discovery, epinephrine became one of the first hormones to be thought of as a mediator of psychological influences on immune reactivity (l), and the immunodepressant effect of cortisol has been known since the pioneering work of Selye on stress (3). The impact of stress research on the development of psychoneuroimmunological conceptual frameworks can hardly be overemphasized, as will become apparent in the next section.

IMPACT OF STRESS RESEARCH

Selye’s studies were the first series of systematic observa- tions on the effects of stressors on immunity. After exposing animals to stress, he observed lymphatic organ involution, lymphocytopenia, and reduced resistance to infectious agents (22). Subsequent animal studies showed stress to induce delays and decreases in immunoglobulin (Ig) production; reduced B lymphocyte reactivity associated with booster effect suppression and secondary response impairment; reductions in T cell responses to mitogens; reductions in helper function, cytotoxic activity, and natural killer (NK) function; altered delayed hypersensitivity and graft-versus-host reactions; and

Received March 29, 1989. Accepted June 22, 1989.

Address reprint requests to Massimo Biondi, M.D. , I11 Clinica Psichiatrica, Universita di Roma, “La Sapienza,” 00185 Roma, Italy.

Human Psychoneuroimmunology 23

to be lower during between-test periods (32); the elevation in salivary IgA tended to correlate with salivary norepinephrine and to be higher (31) and more persistent in high-power inhib- ited individuals (32). Medical students showed decreased plasma levels but not salivary IgA levels (33), lower NK cell activity (33-33, lower OKT4 + cell percentages, and a lower OKT4/OKT8 ratio (34) on the day of a test compared with 1 mo earlier. They also showed decreased interferon production on the day of the test compared with 6 wk earlier (35). Increased monocytes and decreased OKT4, OKT8, and interleukin-2 (IL-2)-receptor-positive cells were observed in students of psychology on the day of examinations compared with 6 wk earlier and compared with controls not taking examinations (36). T cell response to antigens, mitogens, and allo- geneic cells in the same subjects were decreased from 6 wk before the examinations to 2 wk after.

Preoperative stress was shown to affect the response to phy- tohemagglutinin (PHA) and pokeweed mitogen (PKW) unfa- vorably in individuals particularly sensitive to stress, thus influencing postoperative outcome (37). Nine months of unemployment negatively affected the response of T cells to PHA in women (38), and airplane flight induced nonspecific, stress- related alterations in T and B cell responses to mitogens and in T and B cell cooperation (39). Novelty induced a parallel increase in anxiety, plasma cortisol, OKT4 + cell percentage, and OKT4/OKT8 ration in medical students (40). Decreased mitogen proliferation responses were found in an oral mental arithmetic stress setting (41). In this study, it was shown that type A subjects (those with coronary disease-prone behavior patterns) had significantly higher proliferative responses to PHA than did type B subjects (those with low- coronary-risk behavior patterns). This result is surprising since the former tend to have chronic sympathetic activation, leading to decreased immune responsivity (42). However, similar studies should be done before conclusions are made.

Stressful life events have been shown to affect immunocompetence in a variety of stress paradigms. High life event scorers showed decreased blastogenic responses to PHA and PKW in a presurgical stress context (37) and decreased NK activity in academic stress (33) and bereavement contexts (43). Another study found no significant correlation between life stress scores and NK activity but did find NK activity to be a measure of good coping (44). Anxiety and depression correlated inversely with NK activity in that study (44).

reduced graft rejection and interferon production. [For a review, see Monjan (23)].

Commonly assessed immunological parameters in both stress-related and non-stress-related contexts are listed in Table 1. Immune assessment during stress in humans has been done using several paradigms, including academic stress, preoperative and forced wakefulness stress, existential stress accu- mulation, frustration, bereavement, unemployment, and marital discord and divorce (Table 2). [For a review, see Palmblad (24) or Biondi and Pancheri (25).]

Stressful Life Events

Bereavement (loss of spouse) was shown to be associated with prolonged depression of T cell (26,27) and B cell reactivity to mitogens (27) in longitudinal prospective studies and with decreased NK activity (28) in a tangential study. In the latter study (28), the marital loss and anticipated loss groups showed significantly lower NK activity in comparison with the control group, whereas cortisolemia was significantly higher in the bereaved as compared with the other groups. Renormalization of T cell proliferative response to mitogens did not occur prior to 6 mo after the loss event (27).

Divorce affects immunity in a more complex way. Divorced men show an abnormal antibody response to Epstein-Barr virus (EBV) and a lower OKT4/OKT8 ratio compared than controls (married men); however, in men who initiated the sepa- ration, the immune impairment was less severe (29). Divorced women showed a decreased antibody response to EBV, decreased OKT4 + cells, decreased Nk activity, and greater psychic depression with than did controls (married women) (30). Immune dysregulation correlated to both depression and attachment to the exspouse (30).

Academic stress induced an increase in the salivary IgA secretion rate, which tended to decrease after a test (31) and

TABLE 1. Stress-Sensitive Immunological Parameters

Number of circulating lymphocytes Number of circulating monocytes B cell/T cell ratio Killer (suppressor)/helper (inducer) ratio Helper (inducer) percentage Antibody response (plasma, saliva, skin) Response to mitogens (PHA, con-A, PKW) E-rosette formation NK cell activity Surface receptors Steroid receptors

TABLE 2. Stressful Life Events Probably Related to Immunodepression

Death of spouse Divorce Test taking Waiting for surgery

Coping and Personality

Reaction patterns to everyday life stress are probably related to the coping style of an individual and appear to be important determinants of stress-induced immunodepression. Sub- jects scoring high on the repression-denial scale of the Reaction Pattern Test (45) had low proliferative responses to PHA and reduced E-rosette formation and skin test hyporeactivity com-

Lacking or losing job pared with low deniers in a preoperative setting (46). In a

24 Biondi and Kotzalidis

female sample with breast disease, subjects who showed a poor mitogenic response to PHA were high deniers and scored higher on the depression scale of the MMPI (47).

Loneliness has been reported to correlate to self-perceived stress (48). High scorers on the UCLA Loneliness Scale had significantly lower NK activity levels (33,48) and antibody response to viral challenge [EBV, herpes simplex 1, and cytomegalovirus (49)J than did low scorers.

Whereas high stress agonizes immunodepression in humans, relaxation acts as an inverse agonist. Frequent relaxation practice resulted in an increase in the percentage of OKT4 + cells (34); different types of relaxation resulted in increased levels of salivary IgA not dependent on cortisolemia (50). Transcen- dental meditation reduced lymphocyte high-affinity beta- adrenoceptor binding, thus rendering lymphocytes less sensitive to the actions of stress (5 1).

Stress and Infection

Altered immunity increases susceptibility to various patho- gens. In healthy individuals, the action of infectious agents is specifically blocked by the immune system, which starts countering the disease as soon as it contacts a pathogen. The brain is influenced by even the mildest infection (52) and influences and organizes the immune response (53-56). A heav- ily stressed brain does not contribute to healing responses in an ideal manner (57-59); hence, it might be that stress’s ability to modulate susceptibility to infection (a largely documented fact [60-621 occurs via both brain and endocrine effects.

While brain effects are difficult to assess due to high individual differences, endocrine effects have been investigated adequately. In particular, it was shown that catecholamine activity (42,63,64) and plasma corticosteroid levels (63) are increased prior to the onset of disease. Plasma catecholamines and cortisol induce alterations in immune competence, so that it may be theorized that increased stress increases adrenal activity with a consequent rise in epinephrine and cortisol; the two hormones subsequently act on lymphocytes to decrease immune competence, enabling an infectious agent to invade the organism relatively undisturbed and cause illness at a clinical level. This explanation of the effects of stress is based on fragmentary though sound experimental evidence. It has yet to be proven convincingly in a single prospective experiment involving subjective stress quantification, serial measurement of plasma cortisol and catecholamines, and serial evaluation of immune function. Also, this simplistic explanation does not take into account that there are other stress hormones that also have definite, although poorly defined, effects on immunity. [For a review, see Calabrese et al. (65).] Also not accounted for is that cortisol is not always and exactly an immunosuppressive agent, but rather it is an inhibitor of excessive and unspecific immune reactions (66). However, glucocorticoids have been shown to suppress human NK cell activity in vitro (67). A study by Dorian et al. (68), which

unfortunately did not include hormonal evaluations, showed that, among the various immune parameters tested, NK activity impairment predicted susceptibility to viral illness. Highly stressed individuals were likely to present more psychopa- thology and less NK activity in this study.

Among viral infections, the acquired immunodeficiency syndrome (AIDS) poses the most formidable problems. When AIDS first appeared, it was not possible to assess the stress exerted on the affected individual, nor was it possible to assess premorbid perceived stress. Now, however, it is possible to assess perceived stress in human immunodeficiency virus (HIV)-positive individuals (those experiencing a life- threatening condition) and to compare them with patients with full-blown AIDS (who are almost certain of their fate). Anx- iety and distress are higher in the HIV-positive patients, who report the onset of AIDS almost with relief (69). Controlled studies are warranted to examine whether stress is a factor in determining HIV-seropositivity or progression to AIDS. The reader will profit from referring to a recent book on the neuropsychiatric aspects of AIDS (70), although conclusions cannot be made at this point.

Stress and Neoplasia

A mechanism similar to that proposed for infections could be responsible for stress effects on tumorigenesis, a process that is presently thought to be associated with decreased immunosurveilance. As with infectious diseases, the loss of N K cell competence has been associated with malignant growth (71). Lymphocytes damaged by exposure to high corticoid levels may fail to control either latent viruses or malignant mutant cells (72); in healthy people, mutations are corrected by DNA-repairing methyltransferase, a stress- sensitive enzyme (73). Corticoids also act at a nuclear level, thus directing DNA-dependent RNA synthesis; an excess of nuclear steroid receptor occupancy could have mutagenic consequences. Highly stressed individuals exhibit poor DNA repairing capacity (74), thus being more susceptible to malig- nancy. Recent life change stress was found to be related to lung cancer in the young (75). Low levels of cooperative coping style combined with pessimism, somatic anxiety, and life threat are related to progression of benign tumor of the cervix to squamous-cell carcinoma (76). Psychic depression has been found to correlate with cancer mortality (77) but not morbidity (78); however, orality-dependency was found to be unrelated to cancer risk (79). Cancer heterogeneity and the involvement of nonpsychological factors render the data on psychological influences difficult to interpret (80). At present, the hypotheses on psychic and immune interactions in determining disease susceptibility have to focus on phenomena impinging on the function of the hypothalamic-pituitary-adrenal (HPA) axis, namely stress, anxiety, and depression (65-83).

In conclusion, although there is sufficient evidence that emotional stress affects the immune system (84), there is no


been debated on scientific grounds. Depression was found to correlate (77,88) or not to correlate (78,89) with cancer. Schizophrenia, on the other hand, has been correlated inversely with cancer (90,91); however, this finding should be interpreted with caution. Most schizophrenics are first diagnosed during adolescence and early adulthood (92), whereas cancer is usually diagnosed later in life, and schizophrenics have a risk of death more than double of that of the general population (92)-partly because of a higher suicide rate (93). In view of these facts, studies showing a positive or no relationship between the schizophrenia and cancer [reviewed by Baldwin (94)] should be read in terms of positivity.

Cancer was found to occur more often in high deniers (95,96), in Eysenck’s extroverts (97), in Sjobring’s substable women (98), and in persons who excessively either express or suppress their emotions (99). These results have led to the theorization of a cancer-prone behavior pattern (type C); according to this theory, an overcooperative, appeasing, unas- sertive, harmonizing patient who is alexithymic toward negative emotions, compliant with external authority, and anxious and defensive toward stress has more probability to develop cancer than someone without these traits ( 1 00,lO 1). Work on this promising construct is in progress (102).

Although denial has been assumed to be a positive predic- tor of cancer incidence (95), it has been shown to prolong life after cancer onset (103). On the other hand, a negative prognostic behavioral pattern for cancer survival has been reported to be passivity-helplessness (103- 105). However, methodological discrepancies limit the validity of these data.

clear evidence that it promotes disease in unpredisposed individuals. At present, most studies do not distinguish between acute and chronic stress or between effectively and ineffec- tively coped-with stress. They also do not take into account the adaptation potential of organisms (85). As for life stresses, methodological problems prevent us from drawing firm conclusions (86). Stress events should be examined in relation to the status of the organism at the starting moment of the pathogenetic process. However, the “incubation” time var- ies in different diseases, and this difference is sufficient to create problems of questionnaire standardization.

PSYCHIATRY AND IMMUNOLOGY

Frequently, infectious diseases present with psychiatric symptoms. Also, specific behavioral changes are often present in medical diseases for which an immunological causa- tion has been supposed or immunological alterations found. The psychic and the immune may interact at any organ of the body, including the brain.

A leading American textbook of psychiatry (87) includes in its chapter on psychosomatic medicine gastrointestinal disorders, obesity, anorexia nervosa, cardiovascular disorders, respiratory disorders, endocrine disorders, skin disorders, rheumatoid arthritis, accident proneness, headache, and immune disorders; cancer is briefly treated in the latter section, whereas sexual disorders are surprisingly absent (they are dealt with in another section of the book). Every section in this chapter, except those on accident proneness and cardiovascular and eating disorders, discusses immunological mechanisms. How- ever, only the sections on immune disorders tried to present an integrated view of mind-brain-immune interactions. In ulcer- Acquired immunodeficiency Syndrome ative colitis, Crohn’s disease, bulimia, coronary-prone behavior pattern (not actually a disease-probably a myocardial infarc- tion-promoting factor), asthma, APUDomas, autoimmune thy- roiditis, Grave’s disease, diabetes mellitus, Cushing’s disease, alopecia areata, rheumatoid arthritis, systemic lupus erythematosus (SLE), progressive systemic sclerosis, cluster headache, and allergy, both immunological and psychiatric abnormalities occur; whether these abnormalities are interde- pendent or bear a causal relationship remains to be established.

In our opinion, connective tissue diseases, APUDomas, and alopecia areata deserve special attention, as they have been poorly assessed from a psychological viewpoint. Our preliminary results on alopecia areata suggest a possible link with affective disorders, although caution is advised since links of the latter with panic disorders and chronic pain, advanced on purely pharmacotherapeutic grounds (ex adiu- vantibus criterion), proved to have a tenuous biological sub- strate (Teodori, Paga, and Biondi, unpublished results).

Neoplasia

Patients with AIDS quite often present with psychiatric symptoms. High levels of anxiety are usually present, and onset is frequently characterized by marked depression. Symp- toms suggesting schizophrenia may also be observed. Delu- sions may be a feature of presentation. The premorbid personality of the AIDS patient has not yet been fully assessed, so the possibility of psychic disease pre- or coexistence or facilitation has not been ruled out. Dementia is the only psychiatric symptom associated with AIDS that is known to be a sequela.

The external envelope protein of HIV- 1, gp 120, bears structural homologies to neuroleukin (106,107) and vasoactive intestinal polypeptide (VIP) (108-1 1 1). Neuroleukin is a growth factor that was first isolated in the nervous system and that also has a lymphokine role. In particular, neuroleukin can stimulate T-dependent monocyte proliferation, probably as an autocrine effect (1 12). The stimulated monocytes can then induce a polyclonal B cell activation, thus causing hyperimmunoglobulinemia, a frequently observed finding in people with AIDS (PWAs). A neuroleukin receptor has yet

Galen observed cancer to occur more frequently in melan- cholic women; after about 18 centuries this observation has

to be isolated and localized in the nervous and immune tissue; furthermore, the role of neuroleukin in adult brain has


not been assessed and there is no evidence that central nervous system (CNS) symptomatology is induced through gp 120 agonism or antagonism of neuroleukin function (I 13).

VIP is an amine precursor uptake and decarboxylation (APUD) family peptide, synthesized and secreted by neurons and, probably, immunocytes. Within the brain, VIP is widely distributed, but it is most prominent in the hypothalamus, the cerebral cortex, and the hippocampus ( 1 14,115), sites involved in neuroendocrine regulation, biological intelligence, information processing, and emotions. VIP receptors are found in the CNS (1 16- 1 18), on nonadherent peripheral lymphocytes (119,120), and in monocytes (120,121) and can be of both type 1 and type 2 subtype (122). VIP binding to its lymphocyte receptors induces decreased concanavalin-A (con-A) (1 23,124) and PHA ( 123) responses; besides these actions, VIP inhibits NK cell activity (123 , increases con-A-driven Ig synthesis (122,123, and enhances lymphocyte release in the lymphatic fluid ( 126).

HIV- 1 envelope protein gp 120 binds to CD4, a differenti- ation antigen common to lymphocytes, macrophages, and, among others, neurons with a cortical and subcortical distribution (1 27). CD4 has been attributed the role of HIV- 1 receptor (128); hence, that peptides binding CD4 may inhibit HIV activity (108,129) has been interpreted in terms of receptor specificity. This interpretation has prompted a search for an endogenous substance with a structural homology with a gp 120 amino acid sequence. VIP 1-12 was found to have both structural homology with gp 120 and CD4 binding ability (108-1 10,129). It was thus hypothesized thatHIV-1 interferes with the normal actions of VIP to produce AIDS symptomatology (1 11).

The cortical and subcortical distribution of VIP binding sites fits the existence of dementia, affective symptoms, and psychosis. There have also been suggestions that VIP mechanisms may be implicated in depression (130) and in schizophrenia (1 3 1,132), although mechanisms of either hyperactivity or hypoactivity can be implicated. In the rat brain, VIP stimulates postsynaptic dopaminergic mechanisms ( 133); should this also be found to be true in humans, it would associate VIP hyperactivity with psychosis and hypoactivity with depression. The effects of VIP on the immune system are consistent with an hyperVIPergic effect of HIV rather than with inhibition. It is interesting that the Verner-Morrison syndrome, a pancreatic or gastrointestinal APUDoma characterized by watery diarrhea, hypokalemia, and hypochlorhydria, involves VIP hypersecretion and that AIDS most commonly

to be answered. However, the answer to Pert and Dienstfrey’s question-how can a virus produce such great damage by inhibiting the peptides’ good work in few sites? (1 1 I)--could be that this is not the only thing the virus does.

Psychiatric Aspects of Immunological Activity

It recently became apparent that immune products influence behavior. Immune complexes are capable of inducing eating ( I 35) in the rat, an effect that is complement-dependent and mediated through a hypothalamic action (136). SLE may present dementia, lethargy, and psychotic features, either schizophrenia-like or depressive (1 37), and such symptoms have been partly attributed to immune complex deposits (1 38) in the cerebrospinal fluid of patients with SLE (139). In order to relate immune complex deposition to SLE psychiatric manifestations, such deposits should be found in cortical or limbic regions.

The hypothesis of a relationship between Igs and schizophrenic symptomatology has not been confirmed (140). Gen- erally, autoimmune hypotheses of psychiatric diseases are based on findings of circulating autoimmune complexes, which might well be iatrogenic. Also, they are inconsistent, except in bipolar illness, where antinuclear antibodies are present before pharmacological treatment (141).

Interferons (IFs) have behavioral effects consistent with central, partly morphinomimetic, antidopaminergic, antisero- tonergic, and steroid mechanisms (142-147). IF-alpha is neurotoxic, inducing behavioral depression, retardation, asthe- nia, and irritability (148), symptoms usually associated with fever. These symptoms tend to occur in a milder form with IF-gamma (149), which has been shown to activate the HPA axis (142,143). In turn, memory-related hormones released by acute stress tend to switch off IF-gamma release from lymphocytes (150,151). Memory disturbance associated with slow wave electroencephalographic (EEG) activity has been observed with IF-alpha (152) but not gamma (147). Farkkila et al. (147) found that cerebrospinal fluid serotonin turnover was reduced by IF-gamma, an effect that could result in reduced coricotropin-releasing factor secretion. IF-alpha increased psychiatric symptomatology in patients with pre-existing psychiatric problems such as phobia and obsessive thought (153). The greatest psychic unbalance was shown by HIV-positive patients (153). It might be speculated that, in patients with impaired tolerance to stress, psychiatric symptoms tend to reemerge more easily after IF-alpha treatment.

presents with diarrhea. Although the T peptide sequence from gp 120 does not bind enterohepatic VIP receptors (134), lmmunopsychopharmacology

patients with Verner-Morrison syndrome should receive psychiatric and psychologic assessment to check for eventual similarities between the clinical picture of this histologically benign but prognostically unfavorable tumor and that of AIDS. Whether T peptide interacts with brain and lymphocytic VIP receptors and which is the subtype involved are questions yet

Drugs used in common psychiatric practice have immunological effects. Contrary to the common belief that benzo- diazepines cause immunosuppression, there is indirect evidence that they can actually enhance immune function (154,155). Antipsychotics have a biphasic effect on T helper and total T cell numbers; they increase both at low doses and


not to be consistent with time (176). These cells might in part represent NK cells, a cell type that tends to be reduced in a particular subpopulation of schizophrenics (179). A decrease in macrophage function has also been described (179). Whether these abnormalities represent a result of neu- roleptic medication is still controversial (176).

The T suppressorlhelper ratio has been described as increased (180) or decreased ( 1 8 I ), and this discrepancy has been attributed to schizophrenic population heterogeneity (176). Theophylline-sensitive T lymphocytes, representing OKT8 + , Fc-receptor positive T suppressors, were found to be reduced in a recent study (182). B cell counts were found to be increased in one study (183). NK, B cell, and T cell reduced responsiveness has been reported in several studies (179,183,184), butwhether it isacause, aneffect, o radrug treatment epiphenomenon has not been settled (176).

A finding of hyper-Igemia would suggest active infection, exaggerated B cell reactivity (of which there exists no consistent evidence), or autoimmunity. Igs have been found to be increased (1 85- 187), decreased ( 188), or unchanged ( 189) in schizophrenics; moreover, Ig levels did not differ between schizophrenic and nonschizophrenic family members (190).

Self-directed antibrain antibodies were found in schizophrenics (180,186), but similar findings may be seen in normals and are thought to be nonspecific. The subtype of schizophrenia could be important in trying to establish differences in autoantibodies between schizophrenics and controls; antimyelin basic protein antibodies were found increased in catatonics compared with other schizophrenics compared with normals (191), but the sample was small so that inferences cannot be made. An eventual antibody raised against dopaminergic receptors would be consistent with the dopamine hypothesis of schizophrenia, but the search for such a molecule has yielded no positive results (192).

Viral hypotheses involve the herpes class of viruses (193), cytomegalovirus (194), and retroviruses (195), but negative results have been reported (1 96,197). That a viral infection or autoimmunity is present in schizophrenia is suggested by the presence of higher interferon levels in schizophrenics than in normals (198), but alternative explanations are possible. The observation that populations fed with gluten-free diets show a low incidence of schizophrenia led to the theory that persons with a genetic deficit in gluten-metabolizing capacity could develop antibodies against gluten; therefore, either gluten (199) or immune complexes could induce psychotic behavior (200). This hypothesis has found no experimental support (200).

Other approaches seeking a link between brain and immune correlates of schizophrenia are the immunogenetic and the lymphocyte surface receptor investigations. HLA studies showed a great variety of associations (201). Recent studies have showed either negative results (202) or a weak association with A1 and B37 and a somewhat stronger association with a combination of the two (203). Tritiated spiroperidol

diminish them at high doses (156). This biphasic effect and methodological inaccuracies partly account for discrepancies observed in the past and reviewed by Kaufmann and cowork- ers (1 57). Response to viruses can be affected bidirectionally by antipsychotics, depending on the virus (158). Mechanisms involving phenothiazine effects on lymphocytic RNA (158, 159), independent of dopaminergic blockade (159), are thought to mediate these effects. However, chlorpromazine dose-dependently inhibits DNA synthesis in human lymphocytes in vitro (1 60).

Lithium induces an abnormal thyroid-stimulating hormone (TSH) response to protirelin (TRH) (161) and increased antithyroid Ig formation (162). Another drug used in bipolar illness, carbamazepine, is myeloplegic and induces autoimmunity (141). Tricyclic antidepressants have not been investigated extensively with regard to their influence on the immune system. However, since they are likely to bind to a lymphocytic muscarinic acetylcholine receptor ( 163), probably of the M2 subtype (164), they may improve immune function. It is remarkable that levamisol, an immunomodulating drug, induced a reversal of tricyclic resistance in a small sample of depressed patients, along with improvement in immune parameters and mood (165). For readers at ease with Italian, the topic is dealt with more comprehensively in Cerbo et al. (166).

Immunocyte receptors are not exactly the same as CNS drug receptors ( 1 67- 169), and different types of interaction are possible between the same molecules in the immune versus nervous circuitry. An example of this is that lymphocytes process the ACTH-beta-endorphin precursor differently than do the pituitary and the hypothalamus (170). Whereas CNS activity of pro-opiomelanocortin fragments can be uni- directional, immunomodulating effects can be bidirectional ( 17 1). To account for bidirectional effects of opioids on immunity, a receptor-specific model has been proposed (172). Fur- thermore, local autocrine phenomena are likely to play as important a role as do long and short feedback loops, in the sense that double servomechanisms are available at a hypothalamic and pituitary level. For example, IL-1 effects on ACTH secretion can be mediated either tonically directly at the pituitary (173) or phasically, and more rapidly, at the hypothalamus (174), probably through a neuronal IL-lergic pathway (174,175).

Psychoneuroimmunology and Psychiatric Disease

Schizophrenia

Immunological abnormalities in schizophrenia were believed to exist as early as the late 19th century, but the matter was approached more systematically in the 1950s and 1960s [see DeLisi (1 76) for a review]. Technological progress has contributed to the understanding of immune function disturbance in schizophrenia. Initial studies revealed an increase in atyp- ical circulating lymphocyte numbers (177,178), found later


binding studies showed an increase in the lymphocyte binding sites in schizophrenic patients (204,205), but whether this represents upregulation of true dopamine receptors is a matter of speculation.

The putative immunological alterations of schizophrenia are summarized in Table 3. Taken together, these data suggest that something is wrong with immunity in schizophrenics, but individual variability and disease heterogeneity prevent the picture from being clear. This result is similar to responses to various neuroendocrine challenges, which can be abnormal in many ways in the same population, thus yielding no consistent pattern. It is possible that immunity and responses to neuroendocrine challenges are related somehow. Evidence for immune ego disintegration is lacking or incomplete.

Depression

Depression is the psychiatric condition that has been most thoroughly investigated from the immunological standpoint. Depressed patients show decreased circulating lymphocyte numbers (206-210) but no B/T cell (206) or helper/suppressor ratio differences (210,211) compared with controls. Neutro- phi1 counts tend to be elevated in depressives (207) and man- ics (212).

Depressed patients show decreased lymphocyte proliferation responses to all mitogens (206,2 1 1,2 13-2 17). Major depressives had significantly lower mitogenic responses than minor depressives (2 17). However, caution is needed in inter- preting these results unidirectionally (208,218,219); mitogenic responses are not always different from those of controls (2 18), and inpatients behave differently from outpatients (206,208). Manic patients showed decreased responses to PHA and con-A but not to PKW, a result consistent with a T cell impairment (220).

The somewhat increased incidence of autoantibodies in depressives is nonspecific (221,222). It is interesting that an IgG directed against beta-endorphin has been detected in the plasma of depressive patients more frequently than in healthy controls (222), but the significance of this finding is presently unclear.

Given the high frequency of altered dexamethasone-induced cortisol suppression and blunted TSH response to TRH in depressed patients, whether the immunological abnormali-

TABLE 3. Putative Immunological Abnormalities in SchizoDhrenia

Probable Decreased NK and phagic activity Abnormal helper (inducer)/killer (suppressor) ratio

Decreased suppressor (OKT8 + ) number Increased B cell count Upregulation of dopamine high-affinity binding sites Aberrant immunocytic cooperation

Possible

ties found in depression correlated with neuroendocrine impairment has been investigated. Results concerning the HPA axis were negative. Plasma cortisol (215,223) and the dexamethasone suppression test (214,217) did not correlate with immune phenomena. Interestingly, the TRH-stimulated TSH output of monocytes from depressed patients was decreased compared with that from normal controls in a recent study (224).

Acute depressive illness induces lymphocyte glucocorticoid receptor downregulation (225); however, this effect is subject to tolerance (226). Recovered patients are found to have normal lymphocyte glucocorticoid receptors (227). Beta-adrenergic receptors were found to be decreased on lymphocytes from unipolar and bipolar patients (228,229), unchanged on lym- phoblasts from bipolars (230), and with decreased affinity in monocytes from endogenous depressives (23 1). Mimicry or symmetrical behavior with respect to the brain and adaptation to stress have been invoked to explain these findings.

Immune abnormalities reported to occur in depression are summarized in Table 4. Globally, depressives tend to have a dull immune responsivity more often than do normals, as in their tendon reflexes or in dealing with life. Since depressed patients are demonstrably more stressed than normals, the lack of correlation between stress and immune indices might mean that there are other pathways of brain activity control- ling the immune response which bypass the HPA and hide the effect of the latter.

The protective role of the pineal in carcinogenesis has been recently demonstrated (232,233). Among pineal products, the peptide epithalamin and the indole melatonin have shown anti- tumor activity (232,234). Melatonin is the hormone that plasma levels are most potently influenced by photoperiod. The normal periodicity of melatonin secretion appears to be protective against tumor growth (235). The role of chronobiological factors and melatonin in immune modulation is being increasingly recognized (236-239). Recently, the pathophysiology of seasonal affective disorder has been related to melatonin, and a photoperiodically based therapeutic method has been developed to treat it (240). Since melatonin rhythm affects the sensitivity of cells to stress hormones (241), it would be possible to view the relationships among depression, cancer, immunity, stress, pineal, and biorhythms in a more integrative way. Chronobiological considerations should therefore always be made when dealing with neuroimmunomodulation.

TABLE 4. Putative Immunological Abnormalities in Depression

Probable Decreased circulating lymphocytes Neutrophilia Decreased response to mitogens Decreased lymphocyte beta-adrenoceptors

Decreased TRH-induced lymphocytic TSH release Possible


tion time is extremely difficult; considerable shifts between the endocrine and immune consequences of psychoneural events are possible. Such difficulties are increased in human stress research.

Other Psychiatric Conditions

There have been few studies dealing with the psychoneuro- immune aspects of other psychiatric conditions. One study found decreased polymorphonuclear and monocytic phago- cytosis in phobic patients (242), while another showed autis- tic children not to have more antibrain antibodies than depressed subjects or normal controls (243). Lymphocytic beta-adrenoceptors were found to be decreased in patients with panic disorders (244) and of increased responsiveness, unrelated to high plasma norepinephrine levels, in bulimic women (245). These results suggest that noradrenergic regulation is altered in these disorders (244,245). At least in panic, this alteration bears no relationship to depression (244). That addiction to opiates is mediated partly through an immune response (145,246,247) is a suggestive proposal that needs to be experimentally tested in humans.

Psychoneuroimmunology and Personality

Studies involving the evaluation of personality parameters in relation to immune parameters have been scanty and meth- odologically imperfect. Two studies investigated only salivary IgA levels, finding them to be decreased in chronically frustrated power-motivated males (64) and stressed high- internal-locus-of-control individuals (248). Two other studies attempted to correlate MMPI parameters to immunological parameters; one used an MMPI special allergy scale but no laboratory parameter and found a positive correlation with both hypomania and schizophrenia scales (249). The other (250) investigated only NK cell function in healthy young adults and found it to correlate inversely with psychopathol- ogy; all MMPI scales except hysteria and social isolation correlated with NK function.

The validity of current psychoneuroimmunologic data is restricted by methodological limitations. Psychologists, psy- chiatrists, and endocrinologists employ primitive immunological assessment methods, and immunologists use simple and inadequate neuroendocrine tests (25 1). Gross methods are apt to detect bold links, but if such links were present in the neural, the immune, and the endocrine tissues, they would have been found by the less sophisticated technology of the past. It is conceivable that the relationships between the nervous and the immune system are subtle, and the effects of each system on the other might not be apparent. It is evident that the two systems are relatively independent, and each can respond to environmental stimuli with no aid from the other. However, these systems exchange information, which can be quantitatively unimportant with regard to a given effect but can have a weight in the presence of a given environmental setting. Alternatively, subliminal information might sensitize a target if contact is permitted with sufficient frequency, kindling the effect after some time. The corollaries of these considerations are that a large number of variables should be taken into account in designing a study and that deciding evalua-

THE FUTURE

The data now available through clinical and basic research have established psychoneuroimmunology as a separate domain. Data are now being gathered in lymphocyte subset alterations, in NK cell activity, in lymphocyte response, and in neurotransmitter and peptide binding. These data are from disease groups such as the anxiety disorders, the affective disorders, and the psychoses. It is possible that such disease groups will eventually be subclassed on immunological grounds or that distinct diseases within a group will present distinctive and characteristic immunological features.

It is hoped that studies on the effects of psychopharmacological agents on immune function will be performed more intensely and systematically in the future to cover all drug classes used in psychiatric practice. The evidence for the existence of a benzodiazepine receptor on the monocyte plasma membrane (252) should spark research for benzodiazepine agonist and antagonist effects on immune responsivity, but the other drug classes should by no means be overlooked, since receptors known to be affected by their action are found on lymphocytes. It is to be expected that studies investigating psychoactive drug effects on immunity will have a major impact on drug selection and on preclinical screening of future drugs.

The involvement of other than pro-opiomelanocortin- derived peptides in immune regulation has been recently recognized (122,253,254). This should prompt the assessment of immunocyte binding of all peptides of the brain-gut axis, especially the most recently discovered (for example, galanin- and diazepam-binding inhibitor). Conversely, lymphocytes should be assessed for neuroendocrine peptide production; the new DNA cloning techniques may help this assessment. Should these assessments give positive results, than some new lymphocyte subpopulations could be seen to be part of the integrated diffuse neuroendocrine system. The endocrine nature of some thymic cells has been known for some time (255) , but only recently has it been understood that neuro- hormone-secreting cells of the diffuse neuroendocrine system reside within the thymus (256). In parallel, the map of brain distribution of immune system-related molecules will eventually be completed and their physiology at that site elu- cidated. Furthermore, in view of recent evidence (257), the relationship between the immune system and platelets should be investigated, so that the mass of data on platelet markers of psychiatric disease can be integrated within a psychoneuroimmunologic frame.

The relationship of personality to patterns of immune responsiveness will be another issue to settle. Methods of


assessing personality other than the MMPI should be tested in future studies, and the immune parameters to correlate to personality parameters should take into account the progress in immune biology. This is a field in which immunogenetics and behavior genetics may establish some changes.

Also in the future, the psycho-neuroendocrine-immune ring will be closing. It will only be a matter of time, as research is already entrained in this direction. The only differences will be in the extent of the explored domain, in the sense that some more neglected areas will receive due consideration. Psychosomatic disease treatment will undoubtedly benefit from immune function monitoring, and psychotherapeutic techniques will influence the course of diseases associated with immunological impairment in a more specific way than has been possible up to now. It is worth mentioning that new psychotherapeutic techniques are already being tried in the treatment of cancer; these techniques take into account an immunological basis for the pathogenesis of cancer (258). Furthermore, interesting parallels will be made re- garding immune impairment and schizophrenia and psychosomatic disorders.

It has been hypothesized that schizophrenia could be associated with left-handedness (259), but conclusive evidence is lacking (260), although an increased frequency of left- handedness was found in schizophrenia with a particular clinical course (261). Likewise, left-handedness was found more frequently in immune disorders (53,262,263), and differen- tial interhemispheric regulation of immune parameters has been shown in the mouse cerebral cortex (264-269). Abnor- mal lateralization in schizophrenic patients involves increased oxygen consumption in the left brain (270) and is consistent with a relative increase in dopaminergic function within right rostra1 cortical or subcortical structures (271). It is important for neurons to be present and functioning in adequate numbers and at an adequate firing rate, but what is more important is that they establish the right contacts; otherwise, the processing of information leads to faulty and multiple meanings-and this is one of the things that happen in schizophrenics. In the mouse, left frontal and prefrontal cortex lesions decrease and right symmetric lesions increase proliferation responses to mitogens and NK cell activity (264-268). Right parietal and occipital lobe lesions induce decreased mitogen proliferation responses, whereas bilateral lesions are nec- essary to decrease suppressor function (269).

Increased prefrontal and limbic dopaminergic activity has been postulated to exist in acute schizophrenia (272) and to be localized in the right brain (271). Comparing the effects of cortical lesions in the mouse on immunity with immune dysfunction in schizophrenia (Table 3), we noted that decreased NK and B cell function could be consistent with a relative hypofunction of the left frontal cortex, whereas decreased (1 82) or increased (180) suppressor function may be due to impaired left-to-right hemisphere cooperation, should cortex in humans modulate immunity the same way it does in the mouse. Dis-

crepancy in suppressor cell evaluation might be due either to differences in patient populations (176) or to differences in laboratory methods (182,273). It would be interesting to assess the role of dopamine in the modulation of immunity in mouse paradigms. An eventual confirmation that pathological alterations in the CNS responsible for schizophrenic symptomatology also lead to immune system impairment would leave open the question of how such lesions are produced. It is possible that cortex information processing and immune map distribution (similar to that of somatotopic sensory and motor maps) are both altered in schizophrenia due to a basic common defect more caudad in the brain.

What seems to be most exciting in future developments in psychoneuroimmunology is not the hope to cure the depressed with immune enhancers or the cancer patient with psycho- therapy. Such utopistic trends are not considered by even the most optimistic workers in the field of psychoimmunology. Instead, excitement focuses on the conceptual impact of three apparently unrelated medical disciplines. Endocrinology, psychiatry, and immunology focus on systems dealing with communication, with translation of externally derived stimuli into information bits for internal system use. The similarities of functioning, apart from molecular homologies, are not many, but the analogies are striking. Such analogies have long been recognized [for a review, see Jankovic (274)], and their inter- disciplinary and cybernetic implications are now being increasingly recognized.

The fact that neural cell adhesion molecules (N-CAMS) contributing to neuron morphology are homologous to Igs does not mean that neurons and lymphocytes are closer rela- tives than other bodily cells (275), but rather that they used a common molecule with morphogenetic properties to achieve their features and, subsequently, to respond to environmental challenge. Both use an early narcissistic pattern to ego development, to use psychological terms, and use parts of it in a subsequent mature interaction with the outside world. Both make images of the external world by using their own counterimages, demonstrating themselves to be strongly autopoietic. These two useful metaphors, which are based on one biological observation, could be of heuristic value when trying to extrapolate on system development and orga- nization. Recently, an immunological metaphor has been used to better understand combat stress reactions (276).

Other lessons we may be taught by studying closely the neuroendocrine and immune reactions to external challenge are relevant to the process of learning. Learning capacity is the property of a system to respond to a stimulus and thus to reduce the entropic impact of the stimulus or to enhance its organizing properties; learning is demonstrated when the system changes its behavior when faced with the same stimulus at different times in such a way that either its response is more effective or quicker. To demonstrate learning, a system should have memory of the stimulus, that is, a trace of it stored within the system. Learning and memory are proper-


4. Solomon GF, MOOS RH: Emotions, immunity, and disease. A specu- lative theoretical integration. Arch Gen Psychiatr I 1:657-674, 1964.

5. Ader R (ed.): Psychoneuroimmunology. Academic Press, New York, 1981.

6. Solomon GF, Amkraut AA: Psychoneuroendocrinological effects of the immune response. AnnRev Microbiol35:155-184, 1981.

7. Besedovsky H, del Rey A, Sorkin E, Dinarello CA: lmmunoregulatory feedback between interleukin- 1 and glucocorticoid hormones. Science 233:652-654, 1986.

8. Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W: Interleukin- I stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238522-524, 1987.

9. Berkenbosch F, van Oers J, del Rey A, Tilders F, Besedovsky H: Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science 238524-528, 1987.

10. Rettori V, Jurkovicova J, McCann SM: Central action of interleukin-1 in altering the release of TSH, growth hormone, and prolactin in the male rat. JNeurosciRes 18:179-183, 1987.

1 1 . Bulloch K: Neuroanatomy of lymphoid tissue: A review. In Neural Modulation of Immunity, R Guillemin, M Cohn, T Melnechuk, eds. Raven Press, New York, 1985, pp 1 1 1-141.

12. Felten DL, Felten SY, Carlson SL, Olschowka JA, Livnat S: Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol I3S(suppl):755S-765S, 1985.

13. Bulloch K, Cullen MR, Schwartz RH, Longo DL: Development of innervation within syngeneic thymus tissue transplanted under the kid- ney capsule of the nude mouse: A light and ultrastructural microscope study. JNeurosciRes 18:16-27, 1987.

14. Felten DL, Ackerman KD, Wiegand SJ, Felten SY: Noradrenergic sympathetic innervation of the spleen: I . Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. JNeurosciRes 18:28-36, 1987.

15. Felten SY, Olschowka J: Noradrenergic sympathetic innervation of the spleen: 11. Tyrosine hydroxylase (TH)-positive nerve terminals form synapticlike contacts on lymphocytes in the splenic white pulp. J Neurosci Res 18:37-48, 1987.

16. Ackerman KD, Felten SY, Bellinger DL, Felten DL: Noradrenergic sympathetic innervation of the spleen: 111. Development of innervation in the rat spleen. JNeurosci Res 18:49-54, 1987.

17. Smith EM, Blalock JE: Human lymphocyte production of corticotropin and endorphin-like substances: Association with leukocyte interferon. Proc NutlAcadSci USA 18:7530-7535, 1981.

18. Lolait SJ, Clements JA, Marwick AJ, Cheng C, McNally M, Smith AI, Funder JW: Pro-opiomelanocortin messenger ribonucleic acid and posttranslational processing of beta endorphin in spleen macrophages. JClinlnvest 77:1716-1779, 1986.

19. Martin J, Prystowsky MB. Angeletti RH: Preproenkephalin mRNA in T-cells, macrophages, andmastcells. J NeurosciRes 18:82-87, 1987.

20. Wybran J: Enkephalins, endorphins. substance P, and the immune system. In Neural Modulation of Immunity, R Guillemin, M Cohn, T Melnechuk, eds. Raven Press, New York, 1985, pp 157-161.

21. Stein M: Bereavement, depression, stress, and immunity. In Neural Modularion oflmmuniy, R Guillemin, M Cohn, T Melnechuk, eds. Raven Press, New York, 1985, pp 29-44.

22. Selye H.: Stress. Acta, Montreal, 1950. 23. Monjan AA: Stress and immunologic competence: Studies in animals.

In Ps?choneuroimmunologv, R Ader, ed. Academic Press, New York,

24. Palmblad J: Stress and immunologic competence: Studies in man. In: Psychoneuroimmunology, R Ader, ed. Academic Press, New York.

25. Biondi M, Pancheri P: Mind and immunity. A review of methodology in human research. In Research Paradigms in Psychosomaric Medi- cine, GA Fava, TN Wise, eds. Karger, Basel, 1987, pp 234-25 I.

1981, pp 185-228.

1981, pp 229-256.

ties of living and nonliving matter as well, but in the nervous and immune system they show particular characteristics because of the potential novelty of the stimulation these systems are apt to receive and the dynamic nature of the within- system interactions.

Neural learning as related to the immune response has been studied systematically in various conditioning paradigms; behaviorally conditioned immunosuppression (277-282) and immunoenhancement (283,284) have been demonstrated. The mechanism remains obscure (282), and there is still considerable debate on the nature of the phenomenon (251). How- ever, conditioning paradigms have been used to conceptualize defensive phenomena, both neural and immune, as system- specific expressions of the same adaptive process (285).

Immunocytes seek each other when they have something to communicate, and they establish strict relationships until the message is received; neurons send their axons to establish synapses with appropriate neurons, and they maintain the synapse as long as it is useful. Once the message passes to the receiver of information, it gives rise to substance buildup that promotes responne to the environment (antibody formation, action); this substance is part of the memory and promotes a quicker response upon restimulation (secondary immune response, better performance). The molecules involved in intracellular message formation and storage in the two systems can be identical, thus pointing to an interesting parallel between nervous and immune system functions (286).

The learning phenomenon associated with sensitization can lead in the nervous system to the phenomenon of kindling (287). This phenomenon has been used as a model of epilepsy (288,289), alcoholic withdrawal syndrome (290), depression (291), psychoses (292), and recovery from long-term illness (293) and involves alterations in plasticity (294). Kin- dling is a mechanism whereby biological organisms adapt in the long run and in a stepwise manner, and it is present in nature more than it is actually realized. Autoimmune disease and cancer could be good candidates to test a kindling model, and the influence of psychosocial factors, particularly stressful events, should be investigated.

The above are but a few of the possible paradigms that can be transferred from the immune domain to the neural one and vice versa. We believe that as data from animal and human studies accumulate, conceptual frameworks of psychoneuroimmunology and the contributing disciplines will continue to change gradually. Sudden transformations will take place when the data are be sufficient to catalyze progress in scientific thinking.

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