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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)

Nineteen women in the follicular stage of their menstrual cycles were assessed for immunological responsiveness to a 50-min series of three psychological tasks which reliably elicit cardiovascular and neuroendocrine stress responses. Ten follicular-stage women not subjected to stress served as controls. Stress decreased lymphocyte responsiveness to PHA and PWM, percent of CD4+ cells and the ratio of CD4 + CD8 + cells. Conversely, stress increased natural killer cell number and cytolytic activity, white blood cell, lymphocyte, T and B cell count. Except for natural killer cell number, none of these changes was exhibited by controls. Most of these stress responses are similar to those reported for men and form the basis for a continuing study of the effects of reproductive hormones and stress on cardiovascular and immunological function in women.

Recent studies have identified immunologic abnormalities in some schizophrenic subjects. This experiment replicates previous findings that serum soluble interleukin-2 receptors (SIL-2Rs) are elevated in schizophrenic patients, and is the first study to describe this phenomenon in non-Caucasian patients. Despite differences between Korean and Caucasian schizophrenic patients in absolute serum SIL-2R levels, both groups were significantly elevated when compared with their respective ethnic control groups (477 +/- 171 U/ml versus 354 +/- 172 U/ml and 763 +/- 347 U/ml versus 567 +/- 231 U/ml, respectively). Neither age, gender, medication status, nor duration of illness correlated with SIL-2R levels. These findings are further evidence that immune activation is present, regardless of ethnic origin, in some schizophrenic patients.

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.

Nicotine, the psychoactive ingredient of cigarette smoke, alters lymphocyte function in vitro. However, unlike tobacco smoke, the immunologic effects of nicotine in vivo have not been determined. In the present study a single SC administration of 0.33, 0.66, or 1.32 mg/kg (free base) of nicotine bitartrate to male rats produced a dose-dependent decrease in the in vitro proliferative response of blood lymphocytes to the T-cell mitogen Con A when sampled 1 hr after nicotine administration. These results strongly suggest that acute nicotine exposure can induce immune perturbation in vivo. Nicotine also increased plasma corticosterone (CORT) and there was a substantial negative correlation (r = −.52) between CORT levels and the extent of proliferation (DPM) for the optimal Con A dose. The correlation between nicotine's immunologic and CORT effects is discussed within the context of several other potential mediators of nicotine's effects. © 1992 Wiley-Liss, Inc.

This study examined the effects of a 30-min laboratory stressor on aspects of immune function in 24 men and whether behavioral control over the stressor moderates stress effects. The stressor consisted of mild (2.5 mA) electric shock and loud (100 dB) white noise administered in an unpredictable, intermittent fashion. During stress sessions, only half of the subjects were able to control the stressor. Subjects with control were yoked to subjects who could not control the stressor so that both groups were exposed to identical intensity and duration of noise and shock. Immunologic function was assessed across stress and nonstress conditions by measuring changes in lymphocyte proliferation to concanavalin A (Con A) and phytohemagglutinin (PHA) and by measuring changes in percentages of lymphocytes and their subpopulations, granulocytes, and monocytes. Results revealed that exposure to the uncontrollable stressor altered mood but did not affect immune function. In contrast, exposure to controllable stress did not alter mood but did result in lowered lymphocyte proliferation to Con A. Poststress percentages of monocytes were also lower in subjects exposed to the controllable stressor. Results suggest that acute stress can alter aspects of immune function in humans and underscore the importance of stressor controllability in moderating stress effects on human immunity.

Background. Studies of immune measures in schizophrenia have shown differences with control subjects on a number of measures. However, immune measures are often not detectable in the serum or CSF of human samples and in many studies it is not clear how this was dealt with in the analysis. Methods. CSF IL-6 was measured by ELIS A in 6l 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. Data were analyzed with and without non-detectable values to determine if this affected the results. Results. Using a value of “0” for non-detectable values resulted in significant differences between patients and controls in plasma interleukin-6. However, if these values were treated as missing, the difference was not significant. Conclusions. The treatment of non-detectable immune measures has demonstrable effects on the analysis and interpretation of the results.

Schizophrenia, which is a chronic but episodic disorder of unknown etiology, shares immunological features with organ specific autoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis and insulin-dependent diabetes mellitus. However, recent studies have raised the issue as to whether the reported immune disturbances in schizophrenia may be the result of a stress-induced dysregulation of CNS cytokine production, rather than a permanent immunological disorder, i.e., autoimmunity.

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.

We previously demonstrated that acute nicotine administration decreased the response of rat blood leukocytes (PBL) to concanavalin A (ConA). We now extend those findings to a comparison between the effects of acute and prolonged nicotine exposure (ten daily injections), on PBL and splenocytes (SL). A single injection suppressed the PBL response to ConA and phytohemagglutinin (PHA); tolerance developed by ten injections. In contrast, acute nicotine did not affect SL response to ConA and reduced the PHA response only at the highest concentration. Ten nicotine injections enhanced SL responsiveness to PHA. The only change in PBL subsets was an increase in CD8+ cells following ten injections.

The release of clozapine, an atypical neuroleptic which can cause agranulocytosis, has re-stimulated studies of neuroleptic effects ,on the immune system (Lieberman et al 1988). Previous immune studies demonstrated that typical neuroleptics cause morphological changes (Fieve et al 1966) and, in vitro, inhibition ofDNA, RNA, and protein synthesis (Ferguson et al 1975; Baker 1976). In vivo, neuroleptics normalized the blunted response that unmedicated patients had to mitogens (Kerepcic and Jurin 1983; Liedeman and Prilipko 1988). Recently, McAilister et al (1989a) demonstrated that acute neuroleptic changes do not alter phenotypic lymphocyte markers. In particular, the CD5 marker, elevated in 30% of Caucasian schizophrenic patients, is stable for both CD5 high (greater than 5.2% of peripheral iymphocytes being B-cells with the T-cell CD5 marker), and low patients (McAllister et al 1989b). Patients with elevated numbers of CD5 + B lymphocyte are found in the autoimmune disorders Sjogren's syndrome and rheumatoid arthritis. This study asks two questions: (l) What is

The effect and relative efficiency of cyclosporin A (CsA) and cyclosporin G (CsG) on suppressing the activation of primed autoimmune rat T-helper lymphocytes were assayed. The autoimmune T-helper cells (ThS) are a long-term line specific to the retinal soluble antigen (SAg) and can adoptively transfer experimental autoimmune uveoretinitis (EAU), after in vitro reactivation with antigen or mitogen, to naive syngeneic hosts. Antigen-driven production of interleukin-2 (IL-2) and antigen-driven proliferation were inhibited in a dose-dependent manner and to a similar extent at each of the respective cyclosporin concentrations. CsA was 8–10 times more potent than CsG, with ID50-CsA occurring at 0.5 to 2 ng/ml, and ID50-CsG at 5 to 20 ng/ml, depending on the experiment and the cyclosporin batch. Addition of exogenous lymphokines in the form of rat spleen concanavalin A (Con A)-conditioned medium (SCM) or recombinant IL-2 (but not recombinant IL-1) was able to reverse only about half of the inhibition, as measured along the linear part of the dose-response curve. Inhibition of IL-2 production was lost if a maximally inhibitory dose of cyclosporin was added to the cultures later than 8 hr after antigen stimulation, while proliferation was still suppressed to 50% by cyclosporin added as late as 12 hr and could not be restored by addition of SCM. Both cyclosporins at concentrations that blocked proliferation and IL-2 production significantly suppressed the generation of high-affinity and low-affinity IL-2 receptors by ThS in response to antigen (as assayed by direct binding of 125 I-IL-2). These results suggest that CsA and CsG inhibit antigen-induced expansion of ThS by interfering with more than one activation step. In contrast, the in vitro activation of the uveitogenic potential of ThS cells, incubated with antigen in the presence of CsA or CsG and adoptively transferred into untreated recipients, was not affected by the cyclosporins. Thus, triggering of the pathogenic potential of primed autoimmune T-helper lymphocytes can take place in the presence of cyclosporin and in the absence of cellular proliferation.

Pertussis toxin (Ptx), a component of Bordetella pertussis, is responsible for many of the biological activities of this bacterium, including its potent adjuvant capacity. In attempt to better understand the Ptx activity on the immune response in vivo, we have examined the effect of Ptx on certain lymphoid cell responses in vitro which could be targets for the adjuvant activity of this molecule. Ptx was found to stimulate a variety of cell responses which include (a) increased production and release of interleukin-1 (IL-1) by human monocytes and murine macrophages; (b) co-mitogenesis, in combination with IL-1, in cultures of murine thymocytes; (c) mitogenesis in cultures of various peripheral lymphocytes; (d) increased production of IL-2 in cultures of human blood lymphocytes and rodent splenocytes; and (e) elevated release of IL-3 in cultures of murine spleen cells. In addition to its stimulatory effects, however, Ptx was found to inhibit responses of both mononuclear phagocytes and lymphocytes to other stimuli. Most activities of Ptx in vitro were achieved at the optimal concentration range of 1-10 micrograms/ml, which is 100-1000 times higher than that showing adjuvant effects in vivo. Possible explanations for the dual effect of Ptx and for the discrepancy in doses optimal for the effects in vivo and in vitro are discussed.

Experimental autoimmune uveoretinitis (EAU), an intraocular inflammatory disease, is induced in experimental animals by immunization with a retinal specific antigen, S-antigen (S-Ag), emulsified in complete Freund's adjuvant (CFA). The induction of EAU is enhanced by treating S-Ag-immunized animals with Bordetella pertussis. This study examined the effects of a purified component of B. pertussis, pertussis toxin (Ptx), on EAU induction as well as the mode of action of this toxin. Treatment of Lewis rats with Ptx concurrent with S-Ag and CFA enhanced EAU induction as shown by an earlier onset of disease, increased severity of ocular changes, and the reduction of the threshold amount of S-Ag needed for EAU induction. Treatment with Ptx selectively enhanced delayed-type hypersensitivity responses to S-Ag but did not affect specific antibody production. The mode of action of Ptx was analyzed by using the adoptive transfer of EAU by sensitized lymphocytes. Ptx treatment of donor rats enhanced the capacity of lymphocytes to transfer EAU. However, Ptx treatment of recipient rats on the day of cell transfer resulted in a delay in the onset of disease. These results indicate that Ptx enhances the immunopathogenic processes of EAU by enhancing lymphocyte activation and/or increasing their pathogenic activities.

To analyze the role of the retinal vascular endothelial cells in the development of experimental autoimmune uveitis (EAU), we studied the presence of Ia antigen and FN in retinal vessels of Lewis rats immunized with retinal S antigen. Immunopathologic studies were performed on frozen tissues obtained during various stages of the disease. Our results show that Ia antigen was not present in the normal rat retina, and there was very little FN present in a few retinal vessels. One to two days prior to the histologic and clinical onset of EAU, FN was found to be increased in the retinal vessels. Ia antigen was found to be present in the retinal vessels coincident with the first signs of cellular infiltration. During the stage of maximal cellular infiltration, FN was present diffusely throughout the retina, as well as in the subretinal space, and Ia antigen was found diffusely in the cellular infiltrate. Therefore, FN and Ia antigen reflect the immunomodulation of vascular endothelial cells in EAU, which may be very important in the pathogenesis of retinal S antigen-induced uveitis. Two possible mechanisms for the role of the activation of the retinal vascular endothelium in the development of retinal inflammation in uveitis are discussed.

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

Vitamin K stimulated the incorporation of 14 C into proteins when microsomes from melanoma, mammary gland, mast cell and lymphoma tumors were incubated with Na 2 14 CO 3 . The 14 C label in the [ 14 C] proteins was identified as [ 14 C] γ-carboxyglutamate (Gla), which is formed by carboxylation of glutamic acid residues. Carboxylation in tumor microsomes ranged from 2 to 19% of the carboxylation in normal liver microsomes per mg of microsomal protein. Carboxylation in microsomes was completely blocked by 10 μM Warfarin. SDS-polyacrylamide gel analysis of the melanoma [ 14 C] Gla protein(s) revealed one major peak of 14 C with an apparent MW of less than 6,000.

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