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Interleukin 6 (IL-6) levels have been shown to be increased in a number of autoimmune disorders and have recently been shown to be elevated in the serum of schizophrenic patients. Given the involvement of the CNS in schizophrenia, levels of interleukin-6 in the CSF are also of interest. Thus, we examined levels of both CSF and serum IL-6 concomitantly to determine if these levels were different from control values. In addition, we examined these measures in patients both on and off antipsychotic drugs to determine if any medication or exacerbation effects may account for the difference from controls. CSF IL-6 was measured by ELISA in 61 drug-free male schizophrenic (DSM-IIIR) patients and 25 well-screened healthy male control subjects. Serum IL-6 was measured in 43 of the 61 patients, and in 16 control subjects. Serum IL-6 was significantly higher in the schizophrenic patients compared to control subjects. CSF IL-6 was also higher in the patients, but the difference was not statistically significant. Paired data showed no medication or exacerbation effects on CSF IL-6, but plasma IL-6 significantly decreased in patients that experienced an exacerbation after medication withdrawal. The results indicate that IL-6 levels may be altered in schizophrenia. The relative decrease in exacerbated patients following haloperidol withdrawal may be indicative of a compensatory response of plasma IL-6 levels to relapse.

This article presents a rationale for the hypothesis that an autoimmune mechanism might be involved in the pathogenesis of some forms of obsessive-compulsive aborder (OCO). Existing clinical studies suggesting that some individuals with OCD may have an autoimmune-mediated disorder are briefly summarized. A case example where intravenous immunoglobulin G has been successfully used to treat an adult with OCD spectrum disorder is presented. Preclinical data demonstrating that fragments from the group Αβ hemolytic streptococcus cell wall M proteins can generate antibodies that bind to rat and human tissue are also presented.

This paper reviews evidence indicating that adrenal corticosteroids modulate the responsiveness of mice and rats to nicotine. Adrenalectomy increases, and both acute and chronic corticosteroid administration decrease, some of the physiological and behavioral effects of nicotine. One function of adrenal steroids may be to regulate stress-induced changes in nicotine sensitivity. Another is to mediate the development of chronic tolerance when nicotine is given intermittently, and when the resulting tolerance has a learned component. A role of glucocorticoids in the development of tolerance to nicotine is suggested by the findings that a conditioned elevation of plasma corticosterone, which anticipates nicotine delivery, accompanies the development of chronic tolerance and that environmental cues evoke a conditioned corticosterone response, but only after they have become associated with nicotine delivery. The mechanisms by which adrenal steroids modulate nicotine sensitivity are not known, although recent in vitro evidence suggests that steroids can rapidly and reversibly reduce nicotinic receptor function. While most of the data are consistent with the hypothesis that corticosteroids reduce nicotine responsiveness, and thus promote a learned form of tolerance, there are new findings that corticosteroids increase the development of sensitization to the locomotor-activating effects of nicotine. These data suggest that formulations postulating a unidirectional effect of corticosteroids on nicotine's actions (e.g. decreased sensitivity) must be revised to take into account interacting variables such as the specific nicotine effect being studied and whether that effect normally exhibits tolerance or sensitization. Finally, research is presented which indicates that the corticosterone-elevating effects of nicotine, previously reported for experimenter-administered drug, are also produced when nicotine administration is contingent on an operant response, and at a dose which sustains the development of nicotine self-administration in rats. These findings highlight the feasibility of using self-administration models in future explorations of the relationship between adrenal steroids and nicotine function.

Although considerable work has been done on the potential health effects of smoking, little is known about the contribution of nicotine to those effects. This paper presents an overview of the immune system, and a discussion of the existing literature on the effects of tobacco smoke and nicotine on immunity. Treatment with nicotine has been shown to influence all aspects of the immune system, including alterations in humoral and cellular immunity. In addition, preliminary data suggest that gender and genetic factors impact on the immunological effects of nicotine. Finally, the possible mechanisms that might mediate the effects of nicotine are discussed.

It is clear that cytokines exert a variety of modulatory actions on the central nervous system. As part of our work exploring the relationship between immune activation and psychosis, we measured cerebrospinal fluid (CSF) IL-1 alpha and IL-2 levels in 60 medicated schizophrenic patients and in 21 normal volunteers using a competitive enzyme immunoassay. The two groups did not differ significantly in their mean cytokine levels: 1.01 (0.149) ng/ml (patients) vs. 1.28 (0.150) ng/ml (controls) for IL-1 alpha and 0.970 (0.038) ng/ml (patients) vs. 1.25 (0.086) ng/ml (controls) for IL-2. There was a significant positive correlation between CSF IL-1 alpha and IL-2 levels for all subjects (r = 0.50, n = 44, p = 0.0001).

Objective: Interleukin-2, traditionally viewed as solely involved in immunological events, has recently been shown to exert profound effects on the development and regulation of the central nervous system. This study examined the relationships between interleukin-2 in the CSF and plasma ofschizophrenic patients and clinical measures, including relapse and medication status. Plasma and CSF interleukin-1 a levels were also measured to ascertain the specificity ofchanges in cytokine levels. Method: Seventy-nine physically healthy male patients with schizophrenia (DSM-III-R) received diagnostic evaluation and behavioral ratings. Haloperidol treatment was withdrawn for up to 6 weeks and patients were evaluated for symptom recurrence. CSF and plasma were obtained by establishedprocedures before haloperidol withdrawal (N=79) and after (N=64). Results: CSF levels of interleukin-la decreased significantly after haloperidol withdrawal but showed no relation to clinical status. In contrast, levels of CSF interleukin-2 were associated with recurrence ofpsychotic symptoms. Relapse-prone patients, examined both while medicated and after drug withdrawal, had significantly higher levels of CSF interleukin-2 than patients who did not relapse. CSF interleukin-2 levelduring haloperidol treatment was a significant predictor of worsening in psychosis. Conclusions: Levels of interleukin-2, a molecule that plays both neurodevelopmental and neuroregulatory roles, may have a role in relapse in schizophrenia. Levels of CSF interleukin-2 appear to be affected by relapse mechanisms, while peripheral blood levels are not. These changes are specific to interleukin-2, since levels of interleukin-lct were affected by medication withdrawal but not by change in clinical state. (Am J Psychiatry 1995; 152:1291-1297)

There is a confusing history of immune findings associated with schizophrenia. At least some of these discrepant results may be artifacts caused by heterogeneity. In an attempt to decrease heterogeneity, we studied three groups of monozygotic twins who were either discordant for schizophrenia, concordant and ill, or concordant and well. This comparison minimizes environmental and genetic variance, and heightens differences that are actually due to the disorder. Overall, schizophrenic subjects had higher levels of serum soluble interleukin-2 receptors (SIL-2Rs) than unaffected individuals (480.8, SD 238.6 U/ml vs 380.9, SD 170.6 U/ml; F = 5.256, df = 1.61, P = 0.02). When data from discordant and concordant twin groups were analysed separately, both the discordant ill twins (P = 0.06) and concordant ill twin pairs (P = 0.08) showed trends towards higher serum SIL-2R levels than their respective control groups. These data contribute to the growing body of evidence that immune activation is associated with some forms of schizophrenia.

We evaluated if the effects of acute stress on immune parameters were apparent in only the women who showed concomitant and substantial sympathetic nervous system activation and after statistical adjustment for changes in plasma volume. Nineteen women in the follicular stage of their menstrual cycles were assessed for immunological responsiveness to a series of three 3-minute psychological tasks, which reliably elicit cardiovascular and neuroendocrine stress responses. Women were classified as high or low sympathetic reactors based on their cardiovascular and neuroendocrine responses to one of the three tasks, a public speaking task. The stress-induced decreases in CD4+ percentage and increases in natural killer cell number and cytolytic activity were only apparent among the high reactors. Further analysis adjusting for alterations in plasma volume changes showed that the increase in NK cell number remained. Stress-induced proliferative responses to pokeweed mitogen and phytohemagglutinin were not more apparent among high reactors. These results are consistent with the hypothesis that the sympathetic nervous system plays a direct role in modulating the short term response to stress of some indices of the immune system in women.

To the Editor — Immunologic factors have been implicated in both the cause Levels of soluble interleukin 2 (IL-2) receptor in the serum of schizophrenic patients and healthy controls. Soluble IL-2 receptors were measured by a sandwich enzymelinked immunosorbent assay as previously described. 7 Each point represents the value for one subject; 1 U is approximately 3 pg of soluble IL-2 receptor. Schizophrenic patients (N = 30) were diagnosed using DSMIII and Research Diagnostic Criteria. The horizontal line indicates 2 SDs above the mean value for healthy controls; asterisk, P 1 Problems in demonstrating consistent immunologic stigmata in schizophrenia may

To the Editor.— Studies of various immunological parameters in schizophrenic patients are potentially confounded by the possible effects of neuroleptic medication on the immune system. Certain neuroleptic drugs, including the phenothiazines, chlorpromazine, and thioridizine, have been associated with the development of antinuclear-and and anti—single-stranded DNA antibodies, elevated serum rheumatoid factor, and even splenomegaly.1Clozapine, a dibenzodiazepine derivative, has been reported to produce a potentially lethal agranulocytosis in a small percentage of patients,2,3and therefore may have direct effects on hematopoiesis. In this issue of theArchives, we demonstrate that a subgroup of schizophrenic patients (approximately 30%) have elevated numbers of CD5+(Leu1) B lymphocytes.4This subset of B lymphocytes has been shown by several laboratories to be elevated in patients with certain autoimmune disorders.5-7The CD5+B lymphocytes are known to spontaneously proliferate in vitro8and preferentially produce autoantibodies.5,9,10In our study,4schizophrenic