[International Review of Neurobiology] Neurobiology of the Immune System Volume 52 || Immunity and schizophrenia: Autoimmunity, cytokines, and immune responses

IMMUNITY AND SCHIZOPHRENIA: AUTOIMMUNITY, CYTOKINES, AND IMMUNE RESPONSES

Fiona Gaughran

Ladywell Unit, University Hospital Lewisham, London SE1 3 6LH, United Kingdom

I. Background II. A u t o i m m u n e Diseases and Schizophrenia

A. Autoantibodies in Schizophrenia B. Antineuronal Antibodies C. Imnmnoglobulin Isotype Representation in Schizophrenia

III. T and B L y m p h o c y t e s in Schizophrenia A. The Acute-Phase Response in Schizophrenia B. Cytokines and Schizophrenia

IV. H L A Antigens in Schizophrenia V. HPA Axis in Schizophrenia

VI. Effects ofkaltipsychotic Medication VII. Treatment of Schizophrenia with Immunosuppressants

VIII. Vaccine Response IX. T h 1 / T h 2 h n b a l a n c e in Schizophrenia X. S u m m a i T

References

I. Background

Schizophrenia is a psychotic illness that affects almost 1% of the population worldwide. It is c o m m o n l y diagnosed in late adolescence or young adulthood. Its geographic distribution appears to be uniform (International Pilot Study o f Schizophrenia, 1973). The diagnosis o f schizophrenia is a clinical one, relying on the presence o f clusters of clinical features. The symptoms can be divided into three classes. Positive symptoms are psychotic features such as delusions or hallucinations and thought disorganization. Negative symptoms include poor motivation, social withdrawal, day-night reversal, poor self-care, and poverty o f thought. Disturbance in aspects of cognitive funct ion such as attention, executive functions, and working memory are also consistently observed, contributing greatly to the significant f imctional disability associated with the disorder (Lewis and Lieberman, 2000). Schizophrenia is a chronic illness. Management is thus expensive and life-long, both in terms of human resources and medication.

INTERNATION.&[ REVIEW OF 275 Copyright 2002, Elsevier Science (USA). NEUROBI()LOGY, VOI,. 52 All rights reserved.

0074 7742/02 $35.00

276 FIONA GAUGHRAN

It is possible that schizophrenia, as we unders tand it, is more than one disease. It is almost certain that there is more than one cause. The etiol- og T of schizophrenia is as yet unclear. There is undoubtedly a significant genetic component , a l though this is likely to be related to a combinat ion of many genes rather than to a single "schizophrenia" gene. Other factors linked to the causation of this condition include psychosocial variables, environmental triggers, viral infection, au to immune activity, endocrinological irregularities, and neurological s t ructural /anatomical abnormalities.

Epidemiological studies have linked schizophrenia with environmental factors. An excess of obstetric complications, particularly in male patients with schizophrenia, has been noted, along with minor physical anomalies and dermatoglyphic (fingerprint) abnormalities, suggesting a possible intrauterine insult (O'Cal laghan et al., 1991, 1992; Bracha et al., 1992). The possibility of a viral or nutritional origin to these developmental anomalies has been raised. Schizophrenia is more c o m m o n in cities and occurs more frequently in lower socioeconomic groups (Kohn, 1968). First trimester famine, o c c u r r e n c e of influenza epidemics during gestation, and early perinatal viral infections are also linked with the later development of schizophrenia (Susser and Lin, 1992; Cooper, 1992;Jones et al., 1998).

By the time a person presents with schizophrenia, brain changes are often evident on an MRI scan (Nopoulos et al., 1995). The most consistent abnormalit ies are en largement of the ventricles and dilatation of the cor- tical sulci, along with reduced volume of the anter ior h ippocampus, the parah ippocampal gyrus, the frontal lobe, and the superior temporal gyrus. These findings are especially marked in the left hemisphere. Pos tmor tem investigation confirms these changes and a relative absence of gliosis, or scar tissue, suggests that these structural changes may date f rom before the third trimester of intrauterine development (Waddington, 1993).

The theory that the neuropathology predates the onset of symptoms is s t rengthened by studies of children suggesting that those who go on to develop schizophrenia are more likely to show abnormalit ies of behavior in chi ldhood (Jones et al., 1994). Men presenting with schizophrenia, in particulal; are more likely to have at tended a child guidance clinic well before the onset of their schizophrenic illness (Ambelas, 1992).

The monoamine neurotransmitters, dopamine and serotonin, are im- por tan t variables in the pathogenesis of the disorder. A glutamatergic defi- ciency model has been proposed (Carlsson and Carlsson, 1990). Dopamine agonists, such as L-dopa and amphetamine , along with glutamatergic antag- onists such as ketamine, can produce acute psychosis. All the drugs used tbr the t rea tment of schizophrenia over the last four decades of the twentieth century have in conlmon all antagonism of dopamine. The newer "atypical" neuroleptics often exhibit both dopamine- and serotonin-receptor blockade.

IMMUNITY AND SCHIZOPHRENIA 277

I m m u n e abnormali t ies have been described in schizophrenia ibr many years and predate the use of neurolept ic medication. There are two possible roles that the imm une system could play in the causation of schizophrenia. First, the early ueurodeve lopmenta l changes described may be media ted by imbalances in the immune system. Second, the immune system may modulate the ongoing clinical course of the illness. Interestingly, the new "atypical" antipsychotic medications appear to have immunomodu la to ry effects.

II. Autoimmune Diseases and Schizophrenia

There are many clinical similarities linking schizophrenia and certain torms of au to immune disease. Schizophrenic-like symptoms can be directly induced by au to immune illnesses. Such illnesses may be chronic, as in (INS lupus erythematosis, or acute, such as Sydenham's chorea. Sydenham's chorea causes psychosis, obsessional thonghts, and abnormal invohmtary movements which wax and wane in line with changes in systemic antibrain antibody titers (Swedo el al., 1993).

l~light et al. (1992) considered if au to immune mechanisms could account for the genetic predisposit ion to schizophrenia. These authors noted various similarities. For example, the remit t ing-relapsing course of au to immune illnesses (e.g., lupus) is similar to that of schizophrenia: There is a variable age of onset in both conditions; both systemic lupus erythematosis (SI,E) and thyrotoxicosis behavc like schizophrenia in displaying a correlated age of onset within families; both can be precipitated by drugs, physical injury, or infection. Schizophrenia and au to immune diseases have similar monozygotic twin discordance rates. Patients with insul in-dependent diabetes mellitus (IDDM), like those with schizophrenia, are characterized by a clustering toward winter births.

Both positive and negative epidemiological associations exist between schizophrenia and various au to immune diseases. Patients with schizophrenia have an increased risk of suffering from au to immune conditions in general (Ganguli et al., 1987). On the other hand, specific au to immune conditions such as rheumatoid arthritis and IDDM are less likely to coexist with schizophrenia than would be expected (Eaton el al., 1992; Finney, 1989). Although au to immune disorders tend to occur together, negative associations can result f rom genes having opposing effects on the risk of developing different disorders.

It also appears that the inheri tance of schizophrenia may be related to that of autoinamune disorders. Not only the sufferers themselves, but also the families of patients with schizophrenia, show an excess of au to immune conditions. People with a first-degree relative suftering from schizophrenia

278 FIONA GAUGHRAN

are more likely to also have a parent or sibling with an autoimmune disease (Wright et al., 1996). Autoimmune thyroid disease (thyrotoxicosis and myxedema) is more common in the first-degree relatives of psychotic patients, as are both insulin-dependent and non-insulin-dependent diabetes mellitus even though IDDM is negatively associated with schizophrenia (see earlier). Mothers of patients with schizophrenia have lower rates of rheumatoid arthritis than controls, mirroring the findings in the patients themselves (Gilvarry et al., 1996; Baldwin, 1979).

It has been suggested that some cases of schizophrenia may have a viral cause and that the effects of the virus on the developing brain may be immunologically mediated. Influenza epidemics have been followed by an increase in births of people who will later go on to develop schizophrenia (Cooper, 1992). It has been proposed that virus-induced maternal antibodies may cross the placenta and the immature blood-brain barrier to cross-react with fetal brain tissues. These antibodies may interfere with neurodevelopment, resulting in schizophrenia in later life. It is known that rabbits inoculated with influenza A virus produce an antibody which cross- reacts with a protein in the human hippocampus, cortex, and cerebellum leading to suggestions that certain mothers, perhaps those with enhanced antibody resistance to viral infections, are immunologically predisposed to such a reaction (Laing et al., 1996). Interestingly, relatives of patients with schizophrenia have been shown to suffer from fewer viral infections than controls (Carter and Watts, 1971).

A. AUTOANTIBODIES IN SCHIZOPHRENIA

Higher than expected levels of various antibodies to both brain and non- brain tissue have been repor ted in schizophrenia. Antibodies to non-CNS- specific antigens that were repor ted include antihistone antibodies, anti- ganglioside antibodies, rheumatoid factor, anticardiolipin antibodies, lupus anticoagulant, and antibodies to nicotinic acetylcholine receptors (Yannitsi etal., 1991; Stevens andWeller, 1992; Mukherjee etal., 1994; Chengappa etal., 1991, 1992b). Platelet autoantibodies that inhibit dopamine uptake have also been described, which may be relevant given the dopamine hypothesis of schizophrenia (Kessler and Shinitzky, 1993). Galinowski e* al. (1992) found decreased IgG, IgM, and IgA autoantibodies against a variety of au- toantigens, namely actin, tubulin, myosin, DNA, thyroglobulin, elastin, and albumin. By contrast patients with schizophrenia (including unmedicated patients) along with their well relatives show high levels of anticardiolipin antibodies (Sirota et al., 1993; Chengappa et al., 1991; Firer et al., 1994), implying a possible association with antiphospholipid syndrome, which is also characterized by anticardiolipin antibodies.


Antinuclear antibodies, strongly associated with SLE, have classically been linked to antipsychotic medication, but high levels have also been found in drug-free patients, and so it is reasonable to conclude that the elevation cannot be entirely explained by neuroleptic medication. Increased antinuclear antibodies (ANA), anti-double-strand DNA, and anti-single- strand DNA titers have been repor ted not only in patients with schizophrenia but also in their healthy first-degree relatives, with no significant difference in autoantibody systems between the patients and their relatives (Sirota et al.,

1991). Non-right-handedness is especially prevalent in schizophrenia (Gur,

1977). Chengappa et al. (1992) found that non-right-handed, neuroleptic- naive patients with schizophrenia have more autoantibodies. They suggested that non-right-handedness is a clinical marker of predisposition to autoimmunity in affected men. Handedness was not a distinguishing factor in women. If a fetus was subjected to an insult during neurodevelopment affecting the dominant hemisphere, the inmmne system could be exposed to nnusual or intracellular antigens, precipitating an antibody response. The association of non-CNS antibodies with a past history of obstetric complications in schizophrenia (Chengappa et al., 1995) may also be explained in this way.

B. ANTINEURONAL ANTIBODIES

Lehmann-Facius first found antibrain antibodies in schizophrenia as far back as 1939. In 1963, Fessel replicated this work followed shortly af- terward by Heath et al. in 1967. DeLisi et al., in 1985, noted that 18% of patients with schizophrenia had antibrain membrane-binding antibodies significantly outside the control range. However, not all researchers have repor ted these positive associations (Kelly et al., 1987).

Antibodies to various specific brain areas have been described in schizophrenia. These regions include the hippocampus, the septal region, the cingulate gyms, the amygdala, and the frontal cortex, as well as neurons, glia, and blood vessels (Ganguli et aL, 1987; Kuznetsova and Semenov, 1961). Antibodies to the septal region of the brain, in particular, have been found by a number of researchers (Heath et al., 1989; Henneberg et al., 1994). Increased antihippocampal antibody concentrat ion in schizophrenia is associated with decreased lymphocyte product ion of IL-2 (Yang et al., 1994).

Antibodies to the 60 and 70 kilodalton (kDa) human heat-shock proteins (HSP) have been described. Especially high anti-HSP70 titers are seen in never-medicated patients. High anti-HSP60 titers are mainly found in patients being treated with neuroleptics. Since heat-shock proteins are

280 FIONA GAUGHRAN

involved in diverse neuroprotective mechanisms, antibodies against them may inhibit neuroprotective processes (Schwarz et al., 1999).

Heath et al. (1967) repor ted that schizophrenic patients exhibit abnormal brain waves in electroencephalograph (EEG) recordings from the cau- date nucleus and septal area. He also recorded these abnormal waves from similar sites in monkey brains after injections o f lgG isolated from the blood of acutely ill schizophrenic patients into the monkey lateral ventricle cerebrospinal fluid (CSF). In 1980, Bergen et al. prepared IgG fractions from control sub.jects and acutely ill patients with schizophrenia and tested them in rhesus monkeys under double-blind conditions. Of 107 serums tested from 24 schizophrenic patients, 29 produced positive EEG recordings in the monkeys. From 30 control subjects they tested 80 samples and tound only 6 to be positive. This amounted to more than 1 positive reaction for every 4 tested in the schizophrenia group and approximately 1 in 13 positive from control serum fractions. This suggested a substance present in serum from patients with schizophrenia that causes an effect on brain function.

In 1989 Heath and co-workers used crossed-immunoelectrophoresis to evaluate reactivity of an IgG ti'action from serum of schizophrenic patients and controls with homogenates of tissues of the septal region, hippocampus, vermal cerebelhnn, frontal cortex, and liver of rhesus monkeys. When IgG fractions of unmedicated schizophrenic patients and schizophrenic patients who had received neuroleptic medication for less than 24 h were tested against the septal region homogenate, a precipitin arc was identified, indi- cating a positive resuh, with more than 95% of the fractions. In contrast, IgG fractions of schizophrenic patients who had received neuroleptic medication for more than 24 h were rarely positive. Fractions of all control subjects tested negatively. Potentially this illustrates a remarkable relationship between neuroleptic medicatiou and the innnune system's behavior in pro- ducing and sustaining IgG specific for antigens present in critical regions of the brain.

Pandey et al. (1981), using a tmmagglutination technique, found high titers of antibrain antibodies in sermn and CSF, no t jns t from patients but also from their relatives. These antibrain antibodies were more frequent in those with a family histo W of schizophrenia and with a past history of illness.

C. IMMUNOGLOBUIdN ISO]'YPE REPRESENTATION IN SCHIZOPHRENIA

Many studies have examined differential immunoglobulin isotype levels in schizophrenia but the results have been inconsistent. Four separate groups found no difference in serum IgG, IgM, IgA, and IgE levels overall


between patients with schizophrenia and controls (Roos et al., 1985; Rao et al., 1988; Stevens et aL, 1990; Cazzullo et al., 1998).

DeLisi's team measured imnmnoglobulin levels in schizophrenia on two occasions. In 1981 they reported decreased CSF and serum IgG, IgA, and IgM in patients with chronic schizophrenia, but when they repeated the work in acutely ill patients in 1984 only the IgM finding persisted. Bhatia's team again reported decreased serum IgA and IgG levels in 1992, although they found normal IgM levels (Bhatia et al., 1992).

In marked contrast, Legros et al. (1985) reported increased serum IgM levels in psychiatric illness overall, whereas in China, Chong-Thim et al. (1993) have also found high IgM levels in acutely ill patients along with increased IgG levels in male patients. Overall, therefore, no consistent direction of change in the representation of serum imnmnoglobulin isotype levels has been clearly demonstrated in schizophrenia.

Centrally, however, it appears that CSF IgG is positively correlated with negative symptoms in schizophrenia and, conversely, patients with these CSF alterations may be at higher risk of developing negative symptoms (Muller and Ackenheil, 1995).

Reichelt and Landmark (1995) described increased specific IgA antibodies in schizophrenia. More patients than controls showed serum IgA antibody levels above the upper normal limit to gliadin, fi-lactoglobulin, and casein. Interestingly, earlier discharge from the hospital has been reported after a milk-free, gluten-free diet, implying some association with mucosal antigen challenge and the nature of the immune response thus engendered (Dohan and Grasberger, 1973).

III. T and B Lymphocytes in Schizophrenia

Morphologically atypical lymphocytes ("P cells"), similar to those found in mononucleosis and other viral diseases, have been reported in patients with schizophrenia, including a subgroup of patients who had never taken antipsychotic medication (Lahdelma et al., 1995).

Many studies have since examined the distribution of peripheral blood lymphocytes in schizophrenia. Such studies tend to reveal abnormalities although the direction of change is inconsistent. The total T cell number is low although the percentage of T cells in the blood is increased (Coffey et al., 1983; DeLisi et al., 1982).

One of the most consistent findings is of an increase in CD4 + (T helper cell) subpopulations (Muller et al., 1991). T suppressor cell activity is low (Muller et al., 1993) although both increased and decreased T suppressor

cell numbers have been reported (Achiron et nl., 1994; DeLisi et al., 1982). Muller cl al. (1993) quoted increased CD3+ (total T cells) and CD4+ cell numbers alongwith an increased ratio ofCD4’/CD8+ cells in schizophrenia. The distribution of T lymphocyte subsets in the CSF of patients with schizo phrenia is also abnormal, with 74% of patients having a CD4+ and/or CD8+ level outside the normal range (Nikkila et al., 1995).

In Cazzullo et aZ.‘s study (1998), however, when compared to healthy controls and their own relatives, patients with schizophrenia showed a lower level of CD4+ cells, with the CD4+ 45RA+ (naive) subset being significantly higher. Conversely, the number of CD4’. 4.X4- (memory) lymphocytes was lower in the patients in comparison to their relatives and controls, while the CD8+ cytotoxic T cell percentage was significantly higher.

Decreased natural killer cell acti\$y has been reported (DeLisi et al., 1983), although again, there have been inconsistent findings (McDaniel et al., 1992). Theodoropoulou et al. (2001) described increased percentages ofactivatcd CD4+ and CD16+ natural killer cells, as well as cells expressing ICAM- adhesion molecules and IL2 specific receptors.

Patients with schizophrenia have an increased number and percentage of B lymphocytes (DeLisi et al., 1982; Masserini et al., 1990). McAllister et nl. (1989) found that CD.5+ B cells, a subset ofB cells with limited immunoglobulin diversity of low affinity, were elevated to a similar degree as in rheumatoid arthritis. However, Ganguli and Rabin (1993) were unable to replicate these findings.

Zorilla PL al. (1996) examined leukocyte counts in patients with schizophrenia and their siblings and concluded that familial vulnerability for schizophrenia was characterized hy a relative lytnphopenia in the context of a relative granulocytosis, that is, a general reduction in peripheral blood lymphocytes in relation to granulocytes.

A. THE AC’CWZ-PIWX RESPOSSE IN SCHIXOPHKENIA

Acute schizophrenia is accompanied by an acute-phase response as in- dicated by increased serum and/or plasma concentrations of a number of acute-phase protcins. Increased levels of serum cc I-antitrypsin, a8macro globulin, haptoglobin, ceruloplasmin, thyroxine-binding globulin, fibrino- gen, complement component 3, C4, arl-acid-glycoprotein, and hemopexin have been observed in patients with schizophrenia when compared to controls. Albumin, a negative acute-phase protein, transferrin, and retinol- binding pro&n levels are reduced. Hemopexin levels are increased only in acutely ill patients while complement C3 and complement hemolytic

IMMUNITY ANI) SCHIzOPHRENIA 283

activity is decreased in chronically ill patients (Maes et al., 1997; Wong et al., 1996; Spivak et al, 1993).

Interleukin (IL)-1 syncrgizes strongly with IL6 in generating the acute- phase response and both these cytokines have also been found in increased quantities in schizophrenia (El-Mallakh et al., 1993; Ganguli et al, 1994). IL-6 is particularly high in the acute illness.

Maes et al. (1997) found that differences in acute-phase reactants between normal volunteers, and schizophrenic, manic, and depressed patients disappeared following chronic treatment with psychotropic drugs. Their results suggested that schizophrenia, along with depression (see Chapter 10 in this volume) and mania, is accompanied by an acute-phase response, which may bc normalized by treatment with psychotropic medication.

B. CY~OKINES AW SCHIZOPHRENIA

Other chapters in this book have emphasized the close links between the CNS, the endocrine system, and the immune system. Cytokines in the CNS are involved in various regulatory mechanisms including:

l Initiation of an inflammatory immune response in the CNS l Regulation of the blood-brain barrier l Developmental mechanisms l Repair after in-jury l Regulation of the endocrine system in the HPA axis l Different stimulator); and inhibitory influences on dopaminergic,

serotinergic, noradrenergic, and choline+ neurotxansmission.

This communication between the brain and the immune system is a two-way process. Both microglia and astroctyes can produce and release cytokines once activated (Muller and Ackenheil, 1998). Conversely, IL-2 activates T cells, which in turn trigger the proliferation of oligodendrocytes and affect the difrcrentiation of brain cells. Cytokines also play an important role in the development of the CNS which may be strongly altered by their over- or underproduction (Merrill, 1992).

Various cytokines influence the release of a number of neurotransmitters, including glutamate, dopamine, and serotonin, and therefore may be important in the pathogenesis of schizophrenia. The subtle neuropathological abnormalities in schizophrenia such as alterations in neuronal number and density are consistent with the actions of cytokines on neuronal survival and programmed cell death.

284 FIONA GAUGHRAN

1. Effect of Therapy with Cytokines

Currently, recombinant IL-2 is used with some success in cancer im- munotherapy. Its administration, however, has been repor ted to induce symptoms similar to the positive and negative features of schizophrenia, such as visual and auditory hallucinations, paranoia, delusions, agitation, irritability, cognitive impairment, and fatigue. In one study, 65% of patients treated with high-dose r-IL-2 developed symptoms such as delusions and severe cognitive impairment (Denicoff et al., 1987). Evidence for enhanced IL-2 activity in schizophrenia is summarized in Section III.B.2.b.

Interestingly, in one study, mice treated with rqL-2 on a schedule similar to that used in humans were tested for acquisition of a passive-avoidance task and then sacrificed for histological examination. Older treated mice showed impairment of acquisition of the task, along with hippocampal degenerative changes (Nemni et al., 1992). The damage was maximal in the cA3 region. In the older treated mice, there was a loss of neurons, without the accompanying reactive astrocytosis or increases in numbers of oligoden- droglia, in the cA1, cA3, and cA4 hippocampal regions. These psychological and neuropathological changes are remarkably similar to those described in schizophrenia.

2. Specific Cytokines and Schizophrenia

a. Interleukin 1. IL-1 is a cytokine implicated in a variety of central activities, including fever, sleep, ischemic injury, and neuromodula tory responses, such as neuro immune and neuroendocr ine interactions. Brief application of IL-1/~ causes a p rofound decrease of glutamate transmission in hippocampal cA1 pyramidal neurons (Lnk et al., 1999). IL-1 enhances dopaminergic sprouting and can regulate astroglia-derived dopaminergic neurotrophic factors, such as acidic and basic fibroblast growth factor or glial cell l ine-derived neurotrophic factor. Moreover, dopaminergic neurons themselves express IL-1 receptors (Ho and Blum, 1998). IL-1/~, synergisticallywith IL-6, also modulates the serotonin response in the rat anterior hypothalamus (Wu et al., 1999).

IL-lfl serum levels are raised in acute schizophrenia (Katila et al., 1994; Theodoropou lou et al., 2001). It has been suggested that this increase of IL-1 fl in schizophrenia may be as a result of decreased REM sleep (Appelberg et al., 1997).

b. Interleukin 2. IL-2 influences neurotransmit ter release in the hippocampus and striatum (Plata-Salaman and ffrench-Mullen, 1993; Lapchak, 1992). IL-2 potentiates dopamine release evoked by a number of different stimuli in mesencephalic cell cultures. It is active at very low concentrations, a finding that indicates a potent effect of IL-2 on dopaminergic


neurons and implicates a physiological role for this cytokine in the modulation ofdopamine release (Alonso et al., 1993). Peripheral application of IL-2 also causes an increase of catacholaminergic neurotransmission in the hippocampus and frontal cortex (Zalcman et al., 1994). Moreover, it is a potent modulator of hippocampal acetylcholine release (Hanisch et al., 1993).

Serum soluble IL-2 receptor (sIL-2R) levels, a marker of immune activation, are increased in schizophrenia, although not all laboratories concur (Gaughran et al., 1998; Barak et al., 1995). Increases in sIL-2Roe (a single- chain component of the trimeric receptor molecule) in schizophrenia are present before treatment with neuroleptics and are higher in patients with tardive dyskinesia, negative symptoms, and soft neurological signs (Rapaport et al., 1994; Hornberg et al., 1995). These findings are not limited to the patients alone. Rapaport et al. (1993) found increased sIL-2R in discor- dant monozygotic twins. Unaffected siblings of patients with schizophrenia also have higher serum slL-2R levels than controls (Gaughran et al., 2002). Hornberg et al. (1995) noted that patients with increased levels of sIL-2Rc~ along with decreased mitogen-stinmlated IL-2 production in cell culture, had a worse clinical course.

Gattaz et al. ( 1 9 9 2 ) tound no abnormalities in serum concentrations of IL-2 itself in schizophrenia. Theodoropoulou et al. (2001), however, found significantly lower IL-2 serum levels in schizophrenic patients than in controls with a higher percentage of cells expressing IL-2 receptors in medicated chronic schizophrenic patients compared with drug-naive patients.

A reduction in IL-2 production in an ir~ vitro assay from stimulated peripheral blood mononuclear cells (PBMCs), a standard test of cellular im- munocompetence, in the disorder has been repeatedly reported, although, again, there have been some dissenters (Kim et al., 1998; Cazzullo et al.,

2001). Decreased IL-2 production, in this assay system, in schizophrenia is associated with serum antihippocampal antibodies (Yang et al., 1994). In one patient, tollowed over 33 weeks, Ganguli et al. (1995a), found that relapse could be predicted with a great degree of certainty by the IL-2 production levels in the in vitro assay of the previous week.

Licinio et al. (1991) found elevated IL-2 in the CSF of drug-free schizophrenic patients although other groups did not concur, with Barak et al.

(1995) reporting low sIL-2R CSF levels. High CSF levels of IL-2 have been suggested to predict schizophrenic relapse (McAllister et al., 1995).

Muller et al. (1997) observed that sIL-2Rce levels increased in patients after clinical improvement, although this has not been a uniform finding (Gaughran et al., 2001). He attributed the symptoms of schizophrenia to excess intracranial IL-2 and suggested that the symptoms decrease because of a neutralization of this effect with treatment, mediated by sIL-2R0t. Plasma sIL-2Rc~ binds its ligand, IL-2, thereby competing for the binding of fi-ee

286 FIONA GAUGHRAN

IL-2 to cellular IL-2R on the responding cells. Increased sIL-2R~ therefore mediates an immunosuppressive effect due to its capacity to reduce IL-2 availability.

Muller postulated that once bound to sIL-2R(~, less IL-2 crosses the b lood-bra in barr ier (BBB), as it is then a larger molecule. Alternatively, increased serum sIL-2Ra could result in increased CSF sIL-2R0t levels, as the diffusion of proteins across the BBB depends on serum concentrations. Higher CSF sIL-2Ra will then bind more IL-2 and mediate a decrease of free CSF IL-2 levels. Another proposed mechanism was that, as neuroleptics seem to increase the permeabil i ty of the BBB for certain compounds , more sIL-2Ru cross the BBB during t rea tment and inhibit fur ther central activation by IL-2.

The reduced IL-2 product ion by in vitro assay f rom sampled PBMCs repor ted in schizophrenia is also seen in certain au to immune disease (Caruso et al., 1993) and has been explained by in vivo overproduct ion of IL-2 causing T-cell exhaustion and the consequent in vitro hyporesponsiveness of stimulated peripheral b lood mononuc lea r cells. Consistent with this ex- planation is the finding of low serum cholesterol levels in schizophrenia (Boston et al., 1996). IL-2 causes a decrease in cholesterol, especially HDL, along with an increase in serum triglycerides (Penttinen, 1995).

c. Interleukin 6. IL-6 affects the levels of monoamine neurotransmit ters in the brain. It modulates the serotonin response in the rat hypothalamus (Wu et al., 1999). Systemic administration of IL-6 induces reductions of interstitial dopamine levels (Song et al., 1999).

Elevated serum IL-6 and sIL-6R have been repor ted and have been associated with t reatment resistance (Lin et al., 1998). Levels of IL-6 are maximal during acute episodes of schizophrenia (Frommberger et al., 1997) and are associated with duration of illness (Ganguli et al., 1994). High CSF levels of sIL-6R are found in patients with more marked positive symptoms of the illness (Muller et al., 1997). It is of interest to compare the evidence of increased cellular immune activity and activation of the acute-phase response outlined earlier with the parallel literature evidencing similar associations with immune dysregulation in relation to depression (see Chapter 10 in this volume).

d. InterJerons. Interferon-y (INF-v) is lowered in the acute phase of schizophrenia (Arolt et al., 1997) al though Becker et al. (1990) found no d i f ference in serum interferon in first psychotic attacks. Decreased product ion of in ter feron-~ (INF-~) and INF-y has been repor ted (Moises et aL, 1985), although Cazzullo et al. (2001) described higher product ion of INF-v in drug- free and drug-naive patients. Inglot et al. (1994) found that patients with chronic schizophrenia with a high interferon response had predominately

IMMUNITY AND S C H I Z O P H R E N b \ 287

positive symptoms, while those with a low interferon response had mainly negative symptoms. In Preble and Torrey's 1985 study, high tilers of interferon were found in serum from 24.4% of patients with psychosis and from 3.1% of controls. Interferon-positive patients were more likely to have had a recent onset or exacerbation of their illness and to be on low-dose or no medication. No interferon was detected in the CSF of 65 patients or 20 control subjects. Patients with decreased INF-F product ion have a worse clinical course (Hornberg et al., 1995).

e. Other cytokines. TNF-ce levels and IL-3 like activity are high in schizophrenia (Theodoropoulou et al., 2001; Sirota et al., 1995). There is no difference in IL-4 and IL-10 product ion in drug-free patients (Cazzullo et al.,

2001). Serum 1L-18, however, a Th 1 pro-inflammatory cytokine produced by macrophage-like cells, is increased (Tanaka et al., 2000). Increased plasma IL-1 receptor antagonist (IL-1Ra) and lower levels of Clara cell protein (CC16), a natural anti-cytokine, were described by Maes et al. (1996), who went oil to suggest that schizophrenia may be accompanied by in v ivo activation of the monocytic arm of cell-mediated immunity.

The regulated expression of neural cell adhesion molecule (NCAM) isoforms in the brain is critical for many neurodevelopmental processes including axonal outgrowth, and the establishment of neuronal connectivity. Barbeau et al. (1995) investigated the expression of the major adult isoforms of NCAM and its embryonic isofbrm (PSA-NCAM) in the hippocampal region of postmortem brains from 10 schizophrenic and 11 control individuals. They observed a 20-95% reduction in the number of hilar PSA- NCAM immunoreactive cells in the dentate gyrus of the great majority of schizophrenic brains. The expression of this embryonic form of NCAM appears to be related to synaptic rear rangement and plasticity. Therefore, the decrease in hippocampal PSA-NG~M immunoreactMty in schizophrenia may suggest altered plasticity of the hippocampus in a large proport ion of people with schizophrenia.

Schizophrenia is associated with both obstetric complications and mater- hal exposure to infection (O'Callaghan et al., 1991, 1992). Cytokine levels, including levels of IL-lfi, IL-6, and TNF-0~, are altered in amniotic fluid or neonatal cord blood in pregnancies complicated by infection (Gilmore and Jarskog, 1997). Given that maternal cytokines can cross the placenta, birth trauma, associated with a disturbed BBB, could facilitate invasion of immune-activating agents into the developing CNS (Muller and Ackenheil, 1998). This could, in them T, result in neurodevelopmental changes, ulti- mately presenting as schizophrenia.

As a note of caution Haack and colleagues (1999) cast doubt on the cytokine abnormalities repor ted in schizophrenia. They measured circulating

288 FIONA GAUGHRAN

IL-1Ra, sIL-2R, TNF-c~, soluble TNF receptors (sTNF-R p55, sTNF-R p75), and ILo6 and found that the levels were affected by age, body-mass index (BMI), gender, smoking habits, ongoing or recent infectious diseases, or prior medication. Cytokine or cytokine receptor levels were significantly increased in patients treated with clozapine (sIL-2R, sTNF-R p75), lithium (TNF-0~, sTNF-R p75, IL-6), and benzodiazepines (TNF-a, sTNF-R p75). Taking these confounding factors into account, they found no evidence for disease-related alterations in the levels of IL-1Ra, sIL-2R, sTNF-R p75, and IL-6, whereas levels of sTNF-R p55 were slightly decreased in schizophrenia compared to healthy controls. They concluded that, if confounding factors are carefully taken into account, plasma levels of the previously mentioned cytokines and cytokine receptors yield little evidence for immunopathology in schizophrenia.

IV. HLA Antigens in Schizophrenia

HLA antigens have been linked to several immunologically mediated disorders, and there have been a number of studies examining their distribution in patients with schizophrenia. According to Wright et al . 's (2001) review of the subject, early studies were limited by their use of unstandard- ized diagnostic criteria. Although the earlier studies focused mostly on class I antigens in schizophrenia, more recent ones have examined the frequen- cies of class II antigens. Two or more groups have reported associations of HLA A9 (or its A24 subspecificity), A28, A10, DRBI*01, and DRw6 with schizophrenia.

The same authors have previously reported negative associations of schizophrenia with HLA DQBI*0602, an allele which may protect against insulin-dependent diabetes mellitus (IDDM), which itself is negatively associated with schizophrenia. They also examined the HLA DRB1 gene locus on chromosome 6p21.3 in 94 patients with schizophrenia and 92 unrelated mothers of different schizophrenic patients. The HLA DRBI*04 gene is positively associated with rheumatoid arthritis. They found decreased HLA DRBI*04 gene frequency both in the patients and in the unrelated mothers. This is consistent with the epidemiological findings of a negative association between schizophrenia and rheumatoid arthritis. This provides some evidence that the HLA DQBI*0602 and DRBI*04 alleles (or alleles at linked loci) may protect against schizophrenia.

Wright et al. (2001) suggest possible mechanisms for this. First, some property of the HLA molecules encoded by these alleles may directly protect against schizophrenia. There is already evidence that the HLA DQbeta


chain with aspartate at position 57 protects against IDDM. Second, a negative genetic association with HLA DQBI*0602 and DRBl*04 may be secondary to a positive association at a linked locus such as DPB1 or DQA1. Third, pedigrees with a schizophrenic m e m b e r may have a propensi ty for autoimmune diseases and the presence or absence of DQBI*0602 and DRBI*04 alleles in some member s of such a pedigree may influence whether IDDM, rheumato id arthritis, or schizophrenia develop.

They acknowledge that two well-designed studies have failed to find associations between HLA types and schizophrenia so the cumulative evidence thus far remains weak. Genetic linkage studies have tound limited evidence of a susceptibility locus to t schizophrenia on the short arm of ch romosome 6 near the HLA region at 6p21.3. Although there have been negative studies, linkage has been tound for D6S274, D6S296, and D6S291, which map close to the HLA region.

V. HPA Axis in Schizophrenia

The precise relationship of the HPA axis to schizophrenia is, as yet, un- certain. Marx and Lieberman (1998) have reviewed the subject extensively and note that studies have focused oil basal cortisol secretion, cortisol or ACTH responses to stressors, dexamethasone suppression tests (DST), and cortisol responses to pharmacological probes.

Basal cortisol level studies in patients with schizophrenia have shown an inconsistent pattern, with most finding no differences between patients with schizophrenia and controls, a l though there have been individual reports of high basal cortisol secretion in schizophrenia, with others of low levels in medicated schizophrenic patients. No differences in basal ACTH secretion in CSF or serum have been reported. Following neuroleptic t rea tment of schizophrenia, plasma cortisol levels decrease. It is speculated that this in- hibition could be related to reduced noradrenergic activity (Wik, 1995).

Patients with schizophrenia have reduced cortisol, ACTH, and growth h o r m o n e responses to stressors such as lumbar puncture, suggesting a disturbance of the flexibility of the HPA axis in the disorder. Increased severity of psychosis is associated with a b lunted ACTH response to lumbar puncture, a l though cortisol and ACTH responses to hypoglycemia appear normal (Breier et al., 1988; Kathol et al., 1992). Patientswith schizophrenia, however, have an exaggerated ACTH response to acute metabolic stress induced by 2-deoxy-l>glucose (Elman et al., 1998).

Tile rates of dexamethasone suppression test (DST) nonsuppression cited in schizophreniavary greatly, with figures between 5 and 44% reported.

290 FIONA GAUGHRAN

Some groups have found an association between DST nonsuppression and negative symptoms, but others found no such link. Cognitive impairment is correlated with 8 a.m. postdexamethasone cortisol concentrations in unmedicated schizophrenic patients (Newcomer et al., 1991). Depressed patients with schizophrenia, do not have higher rates of DST nonsuppression compared to nondepressed patients (Garyfallos et al., 1093). HPA axis activation is elicited by cytokines such as IL-1, IL-6, and TNF-~e. These cytokines are increased in schizophrenia and therefore the hypercortisolemia recorded could be induced by their pro-inflammatory activity (Altamura et al., 1990).

ACTH and cortisol responses to apomorphine are reduced in schizophrenia, suggesting dysfunction in the dopaminergic systems (Mokrani et al., 1995). There is no difference in the cortisol response to D-fenfluramine challenge however (Abel et al., 1996).

VI. Effects of Antipsychotic Medication

Antipsychotic medications have long been associated with the production of autoantibodies. Antinuclear antibodies have classically been linked to antipsychotic medication. Other antibodies linked to the prescription of neuroleptics include rheumatoid factor, antihistone antibodies and anticardiolipin antibodies (Gallien et al., 1977; Chengappa et al., 1991, 1992b; Canoso et al., 1990) mimicking to some extent the autoantibody profiles characteristic of SLE and antiphospholipid syndrome.

Some authors have described immunosuppressive effects of neuroleptics (Saunders and Muchmore, 1964; Baker et al., 1977). Others found no suppression of the immune system (Muller et al., 1991) and some in vitro investigations have even demonstrated an immune-activating function ofan- tipsychotic drugs (Zarrabi et al., 1979). These contradictory results suggest that both in vitro and in v ivo effects, as well as short- and long-term effects, must be considered when interpreting studies.

There appears to be, following short-term treatment at least, a difference in effects on the immune system between "typical" and "atypical" antipsychotics. Taking IL-9 as an example, haloperidol, a typical neuroleptic, does not alter slL-2R~ levels (Pollmacher et al., 1997), although clozapine does (Pollmacher et al., 1905). The findings of increased slL-2R0~ levels more with atypical neuroleptics may be related to their mixed D2 and 5HT2a receptor blockade or, as previously stated, their ability to modulate the HPA axis. No difference in slL-2R~ levels is found, however, between patients on typical and atypical neuroleptics after 6 months of t reatment (Ganguli et al., 1995b).


There have also been several reports that antipsychotic therapy in schizophrenia is associated with a decrease of IL-6 or SIL-6R levels. Overall it appears that the signs of immune activation seen in schizophrenia and depression normalize after 1-2 months of neuroleptic, mood stabilizer, or antidepressant therapy (Muller and Ackenheil, 1998).

Clozapine, the drug used for treatment-resistant schizophrenia, is widely accepted to have immunomodula tory properties. It increases the plasma levels of TNF-0e, soluble TNF receptors p55 and p75, and slL-2r. Increased TNF-0e and slL-2r levels are more p ronounced in patients with clozapine- induced fever who also have increased plasma IL-6 levels and granulocyte counts. Plasma IL-1 receptor antagonist levels and monocyte and lymphocyte counts are not affected by clozapine t reatment (Pollmacher et al.,

1996).

VII. Treatment of Schizophrenia with Immunosuppressants

Given the links with autoimmune disease and the evidence of T-cell activation in the condition, some researchers have been curious about the effects of immunosuppressive therapy in the t reatment of schizophrenia. Smidt et al,, in 1985, treated twelve patients with chronic schizophrenia with glucocorticoids in combination with neuroleptic drugs. Two were discontin- ued due to aggravation of psychiatric illness. Seven had a greater than 50% reduction in first-rank symptoms. The patients who responded to steroid t reatment were younger, with a shorter history of illness, and were more likely to have a positive family history of schizophrenia, hnmunological investigations, including 0e-l-antitrypsin levels, haptoglobins, orosomucoid, and serum IgA, IgM, and IgG levels failed to differentiate between gluco- corticoid responders and nonresponders .

Levine et al. (1997) treated fourteen patients with schizophrenia who had high antiplatelet antibodies with azothiaprine. Only two of eleven com- pliant patients showed a reduction in psychiatric symptomatology but the t reatment was generally well tolerated.

VIII. Vaccine Response

There is evidence of impaired responsiveness to routine vaccination schedules in schizophrenia. In 1942, Molholm described decreased delayed hypersensitivity to guinea pig serum in schizophrenia and Vaughan et al.

292 FIONA GAUGHRAN

(1949) recorded decreased responsivity to pertussus vaccine in the disorder. Ozec et al. (1971) found lower antibody product ion after vaccination against salmonella in unmedicated patients with schizophrenia. Psychiatric patients also demonstrate a reduced antibody response to hepatitis B vaccine (Russo et al., 1994). The response to influenza vaccination in institutionalized elderly patients with schizophrenia and dementia is like- wise significantly less than in healthy community populations (Edgar et al., 2000).

IX. Thl/Th2 Imbalance in Schizophrenia

Muller et al. (1999) proposed a T h l / T h 2 imbalance with a shift to the Th2 system in schizophrenia. Both the unspecific "innate" and the specific arm of the immune system are involved in the dysfunction of the immune system in the illness. The "innate" immune system shows signs of overac- tivation in unmedicated schizophrenic patients, with increased monocytes and y6T-cells (a primitive form of T cell which contributes toward innate defense). The increased levels of IL-6 and the activation of the IL-6 system seen in schizophrenia might also be the result of the activation of monocytes/macrophages.

In addition, several parameters of the specific cellular immune system are blunted, for example, the decreased Thl-related immune parameters in schizophrenic patients both in vitro and in vivo. Muller suggests that the role of neuroleptic therapy may not have been taken seriously into con- sideration when interpreting studies showing increased antibody levels in schizophrenia. He proposes that neuroleptic therapy results in activation of both arms of the acquired immune system, both the cellular (Thl ) and the humoral (Th2). He cites papers showing normalization of IFN-y production, the increase of 1L-2 receptors with treatment, and the fact that the blunted antibody response to vaccination with salmonella was not observed in patients that were treated with neuroleptics (Wilke et al., 1996; Ozek et al.,

1971). The reduced in vitro product ion of IL-2 by stimulated PBMCs, well de-

scribed in schizophrenia, has been traditionally interpreted as due to cell exhaustion. However, another possibility is that it may reflect the reduced capacity of lymphocytes to produce IL-2, consistent with a shift away from Thl-media ted immunity. Furthermore, the response to stimulation with tuberculin, which is mediated through Th l activity, is blunted in schizophrenia (Muller et al., 1991).


Neopter in levels, another indicator of the activity in the T h l cellular immune system, are lowest at baseline and increase significantly during the first week of t reatment of acute schizophrenia. The baseline levels are significantly lower in comparison to healthy controls, suggesting normalization of cellular immunity during t reatment (Sperner-Unterweger et al., 1989).

The soluble intercellular adhesion molecule-1 (slCAM-1) is also a marker for the activation of the T h l cellular immune system. Patients with schizophrenia showed significantly decreased serum levels of slCAM-1 both without antipsychotic medication immediately after admission to the hospital, and after clinical improvement (Schwarz et al., 2000). Muller and Ackenheil (1998) postulate that the negative relationship between schizophrenia and rheumatoid arthritis ment ioned earlier may be an illustration of this T h l / Th2 divide. Rheumatoid arthritis is associated with high slCAM-1 levels and schizophrenia has low slCAM-1 levels. Rheumatoid arthritis is a disorder that is primarily mediated by the Thl-re la ted immune system.

Functionally, in 1942, before neuroleptics were invented, Molhohn demonstrated hyposensitivity to foreign protein (guinea pig serum) in patients with schizophrenia, also implying blunting of T h l immune reactions.

Schwarz et al. (2001) also hypothesize a shift to Th2-1ike inmmne reactivity in a subgroup of schizophrenic patients. Besides the immunological abnormalities, this subgroup appears to suffer with more p ronounced negative symptoms and a poorer therapy outcome. It is suggested that the type of schizophrenia affecting this subgroup may be related to a prenatal viral infection. The increase in CD3 + and CD4 + cells seen ill schizophrenia is also consistent with a Th2 shift in the illness.

Therefore , a pattern of aberrations in the T-cell cytokine system that is typical for Th2-skewed autoimmune disorders, such as SLE, and consistent with a shift to Th2 domination, namely decreased IL-2 product ion and increased IL-2 receptors along with lowered product ion of IFN-v has been repor ted in patients with schizophrenia. These findings are not affected by clinical variables but may be associated with acute exacerbations of the illness (Arolt et al., 2000).

Against the theory ofa T h l / T h 2 imbalance with a shift to the Th2 system in schizophrenia is that increased slL-2R0e levels are described not just in the patients but also in their first-degree relatives. The increased lymphocyte proliferation and the increased levels of IL-2 in the CSF also suggest activation of the Th l system. Rothermnndt et al. (2000) examined IL-2 and IFN-v product ion in unmedicated schizophrenia patients before and during 4 weeks of neuroleptic t reatment and found no change in cytokine production. These results do not support the notion that neuroleptic medication in v ivo might influence Th l cytokine production in schizophrenia.

294 FIONA GAUGHRAN

X. Summary

As is ev ident f rom the p resen t account , there is no single or persua-

sive a r g u m e n t that signals e m a n a t i n g f rom the i m m u n e system are directly involved in the etiology of schizophrenia . We do no t even know if we are dea l ing with a single d isorder with a single causality; a lmost certainly we are not. The precise etiology of schizophrenia , as with so many neuro log-

ical disorders, r emains obscure. However, there is a b u n d a n t evidence in sch izophren ia of mu tua l dysregulat ion of n e u r o n a l f unc t i on a nd i m m u n e system activity. A l though this evidence is no t always consistent , a pa t t e rn emerges suggest ing aspects of i m m u n e activity be ing involved in the pathol- ogy of n e u r o n a l d e v e l o p m e n t that characterizes schizophrenia . Exposure to

infective agents, HLA associations, a u t o i m m u n e associations, d is turbances in lymphocyte popula t ions , a n d cytokine imbalances with a skew toward Th2

activity are support ive of this view. Tha t the evidence is no t always consis tent is a t es tament to the complexi ty and he te rogene i ty of the disorder, to con-

f o u n d i n g by antipsychotics that themselves are i m m u n o m o d u l a t o r y , a nd to the muhi face ted na ture , with all its checks an d balances, of the i m m u n e system itself.

References

Abel, K., O'Keane, V., and Murray, R. (1996). Enhancement of the prolactin response to d-tenfluramine in drug-naive schizophrenic patients. Bt: J. t~uhiatry 168, 57.

Achiron, A., Noy, S., Pras, E., Lereya, J., Hermesh, H., and Laor, N. (1994). T-cell subsets in acute psychotic schizophrenic patients. Biol. Ps~chiat~), 35, 27-31.

Alonso, R., Chadieu, I., Diorio,J., Krishnamurthy, A., Quirion, R., and Boksa, P. (1993). Intct~ leukin modulates evoked release of [:+H] Dopamine in rat cultm'ed mesencephalic cells. J. Neurochem. 61(4), 1284-1290.

Altamura, A. C., Boin, E, and Maes, M. (1999). HPA axis and cytokines dysregulation in schizophrenia: Potential implications for the antipsychotic treatment. Eut: Neurop,sychopha*~ macol. 10(1), 1-4.

Ambelas, A. (1992). Schizophrenia in an evolutionary perspective. B~: J. Psychiat U 1609, 401-404.

Appelberg, B., Katila, H., and Rimon, R. (1997). Plasma Interleukin 1/3 and sleep architecture in schizophrenia and other non-affective psychoses. Psychosom+ Med. 59(5), 529-532.

Aroh, V., Weitzsch, C., Wilke, I., Nolte, A., Pinnow, M., Rothermundt, M., and Kirchner, H. (1997). Production of interferon ?/in families with multiple occurrence of schizophrenia. Psychiatry Res. 66(2-3), 145-152.

Arolt, V., Rothermnndt, M., Wandinger, K. E, and Kirchner, H. (2000). Decreased in vitro production ofintertieron g and interleukin 2 in whole blood of patients with schizophrenia during treatment. Mol. l~s),chiat~[v 5(2), 150-158.

IMMUNITY AND SCItlZOPHRENIA 295

Baker, G. A., Santalo, R., and Blumenstein, J. (1977). Effect of psychotropic agents on the hlastogenic response of human T-lymphocytes. Bid. Psychiatry 12(2), 159-169.

Baldwin,J. A. (1979). Schizophrenia and physical disease. Psychol. Med. 9, 611-618. Barak, V., Barak, Y., Levine,J., Nisman, B., and Roisman, I. (1995). Changes in interleukin IB

and solub5e interleukin 2 receptor levels in CSF and serum of schizophrenic patients. J. Basic Clin. Physiol. Pharma,ol. 6 ( 5 ), 61- 69.

Barbeau, D., Liang, J. J., Robitali51e, Y., Qnirion, R., and Srivastava, I . K. (5995). Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains. Proc. Nat. A*Y~d. Sci. USA 92(7), 2785-2789.

Becket', D., Kritschmann, E., Floru, S., Shlomo-David, Y, and Gatlieb-Stematxky, ~E (5990). Serum interferon in first psychotic attacks. Br.J. Psychiat*?i 157, 13(%538.

Bergen@ R., Grinspoon, L., Pyle, H. M., Martinez, J. L.J., and Pennell, R. B. (5980). Innnuno- logic studies in schizophrenia and control subjects. Biol. Psychiatry 15, 3(59-379.

Bhatia, M. S., Dhar, N. K., Agrawal, E, Khurana, S. K., Bohra, N., and Malik, S. C. (1992). 5mnnmog5obulin profile in schizophrenia. Indian]. Med. Sei. 46(8), 239-242.

Boston, R E, Dnrsun, S. M., and Reverly, M. A. (5996). Cholesterol and mental disorder. B~[ t3~ychiat~y 169(6), 682-689.

Bracha, H. S., ~l~rrey, E. E, Gottesman, 5. I., Bigelow, L. B., aim Culmiff, C. (1992). Second- trilnester markers of fetal size in schizophrenia: A study of monozygotic twins. Am. J. I'sychiatry 149(10), 1355-61.

Breier, A., Wolkowitz, O,, Doran, A., Bellar, S., and Pickar, D. (5988). Neurobiological effects ot hnnbar puncture stress in psychiatric patients and healthy vohmteers. Ps~&iatric Resemvh 25, 187.

Canoso, R. T., de Oliveira, R. M., and Nixon, R. A, (1990). Neuroleptic-associated autoantibodies. A prevalence study. Biol. Psychiatry 27(8), 863-870.

Carlsson, M., and Carlsson, A. (1990). Interactions between glutainatergic and monoaminergic systems within the basal ganglia: hnplications for schizophrenia and Parkinson's disease. Trends Neurosci. 13, 272-276.

Carter, M., and Watts, C. A. H. (1971). Possible biological advantages among schizophrenic relatives. BrJ. t3sychiat~y 118, 453-460.

Carnso, C., Candore, G., Cigna, D., Collucci, A. T., aim Modica, M. A. (1993). Biological significance of soluble l L-2 receptor. Mediators Inflamm. 2, 3-21.

Cazzullo, C. L., Saresella, M., Roda, K., Calw), M. G., Bertrando, R, Doria, S., Clerici, M., Salvaggio, A., and Ferrante, P. (1998). Increased levels nfCD8 + and CD4 + 45RA + lymphocytes in schizophrenic patients. Schizoph,: Res. 31 (1), 49-55.

Cazznllo, C. L., Sacchetti, E., Galluzzo, A., Panariello, A., Colombo, E, Zagliani, A., and Clerici, M. (2001). Cytokine profiles in drng-naive schizophrenic patients. Schizophr Res. 47 (2-3), 293-298.

Chengappa, K. N., Ganguli, R., Yang, Z. W., Brar, J. S., Li, L., and Rabin, B. S. (1992a). Left- handed first-episode, neuroleptic-naive schizophrenic patients have a higher prevalence of autoantibodies. Schizophr Res. 8 (1), 75-80.

Chengappa, K. N., Carpenten, A. B., Keshavan, M. S., Yang, Z. W., Kelly, R. H., Rabin, B. S., and Ganguli, R. (1991 ). Elevated IgG and lgM anticardiolipin antibodies in a subgronp of medicated and unmedicated schizophrenic patients. Biol. Psychiat D" 30(7), 731-735.

Chengappa, K. N., Nimgaonkar, V. L., Bachert, C., Yang, Z. W., Rabin, B. S., and Gangnli, R. (1995). Obstetric complications and autoantibodies in schizophrenia. ActaPsychiatr Scan& 92(4), 270-273.

Chengappa, K. N., Betts Carpenter, A, Yang, Z. W., Brar, J. s., Rabin, B. S., and Gangu5i, R. (1992b). Elevated IgG anti-histone antibodies in a subgroup of medicated schizophrenic patients. Schizophr. Res. 7, 49-54.

296 FIONA GAUGHRAN

Chong-Thim, W., Wing-Foo, T., and Nilmani, S. (1993). Serum immunoglobulin levels in Chinese male schizophrenics. Schizophr. Res. 10, 61-66.

Coffey, C. E., Sullivan,J, and Rice,J. (1983). T lymphocytes in schizophrenia. Biol. Psychiatry, 18(1), 113-119.

Cooper, S.J. (1992). Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. B~: J. Psychiatry 161,394-396.

DeLisi, L. E., Weinberger, D., Potkin, S., Neckers, L., Shiling, D., and Wyatt, R. (1981). Quan- titative determination of immunoglobulins in CSF and plasma of chronic schizophrenic patients. Br.J. P~?chiat~y 139, 513-518.

DeLisi, L. E., Goodman, S., Neckers, L., and Wyatt, R. (1982). An analysis of lymphocyte subpopulations in schizophrenic patients. Biol. Psychiatry 17(9), 1003-1009.

DeLisi, L. E., Ortaldo, J. R., Maluish, A. E., and Wyatt, R.J. (1983). Deficient natural killer cell activity and macrophage fnnctioning in schizophrenic patients. J. Neural Transm. 58, 99-106.

DeLisi, L. E., King, C., and T~argum, S. (1984). Serum immunoglobulin concentrations in patients admitted to an acute psychiatric inpatient service. B~:J. Psychiatry 145, 661-666.

DeLisi, L. E., Weber, R.J., and Pert, C. B. (1985). Are there antibodies against brain in sera from schizophrenic patients? Review and prospectus. Biol. Psychiatrv 20, 94-115.

Denicoft, K. D., Rubinoff, D., Papa, M. Z., Simpson, C., Seipp, C. A., Lotze, M. T., Chang, A. E., Rosenstein, D., and Rosenberg, S. A. (1987). The neuropsychiatric effects of treatment with Interleukin 2 and lymphokine activated killer cells. Ann. Intern. Med. 107, 293-300.

Dohan, E C., and Grasberger, J. C. (1973). Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-fl'ee diet. Am. ~ Psychiat~ 130 (6), 685-688.

Eaton, W. W., Ha)~vard, C., and Ram, R. (1992). Schizophrenia and rheumatoid arthritis: A review. Schizoph~: Res. 6, 181-192.

Edgar, S., Gaughran, E, Macdonald, A., Oxford,J. S., and Lambkin, R. (2000). Response to influenza vaccine in an elderly institutionalised population with schizophrenia or dementia. Royal College of Psychiatrists Annual Meeting, Edinburgh.

El-Mallakh, R. S., Suddath, R. L., and Wyatt, R. J. (1993). lnterleukin 1-(~ and interleukin 2 in cerebrospinal tluid of schizophrenic subjects. P~vg. Neuro-P.~ychopharmacol. Biol. Psychiatry 17(3), 383-391.

Elman, I., Adler, C. M., Malhotra, A. K., Bir, C., Pickar, D., and Breier, A. (1998). Effect of acute metabolic stress on pituitary-adrenal axis activation in patients with schizophrenia. Am..]. Psychiatr~ 155(7), 979-981.

Fessel, %'. J. (1963). Antibrain factor in psychiatric patients' sera: Further studies with haemag- glutinin technique. Arch. Gen. Ps),dziatry 8, 614.

Finney, G. O. H. (1989).Juvenile onset diabetes and schizophrenia? Lancet 2(8673), 1214- 1215.

Firer, M., Sirota, E, Schild, K., Elizur, A., and Slor, H. (1994). Anticardiolipin antibodies are elevated in drug-ti-ee, muhiply affected families with schizophrenia.J. Clin. Immunol. 14 ( 1 ), 73-78.

Frommberger, U. H., Bauer, J., Haselbauer, E, Fraeulin, A., Riemann, D., and Berger, M. (1997). Interleukin 6 plasma levels in depression and schizophrenia: Comparison between the acute state and after remission. Eur. Arch. t%,chiatry Clin. Neumsci. 247(4), 228-233.

Galinowski, A., Barbouche, R., Truffinet, R, Louzir, H., Poirrier, M. E, Bouvet, O., Loo, H., and Avrameas, S. (1992). Natural autoantibodies in schizophrenia. Acta Ps)'chiat~: Stand. 85 (3), 240-242.

Gallien, M., Schnetzler, J. P., and Morin,J. (1977). Antinuclear antibodies and lupus cells in 600 hospitalised, phenothiazine treated patients. Ann. Med. Psychol. Med. 1,237-248.

Gangtfli, R., and Rabin, B. S. (1993). CD5 + B lymphocytes in Schizophrenia: No aheration in numbers or percentage as compared with control subjects. Psychiatry Res. 48, 69-78.


Ganguli, R., Brar,J., Chengappa, K. N. R., Deleo, M., Yang, Z., and Rabin, B. (1995a). Mitogen- stimulated interleukin 2 production in nevei~medicated, first episode schizophrenic patients: The influence of age of onset and negative symptoms. Arch. Gen. P~ychiatry 52(8), 668-672.

Ganguli, R., Brar,J. S., and Rabin, B. S., Reply to Pollmachei, T., Hinze-Selch, D., Mullington, J., and Holsboet, E (1995b). Clozapine induced increase in plasma levels of soluble interleukin 2 receptors. Arch. ge~n. Ps'~chiatry 52, 878.

Ganguli, R., Rabin, B. S., Kelly, R. H., Lyte, M., and Ragu, U. (1987). Clinical and labora- tory evidence of autoimmnnity in acute schizophrenia. Ann. }~\ E A~ad. Sci. 496, 676- 685.

Ganguli, R., Yang, Z. W., Shurin, G., Chengappa, R., Brat, J. S., Gubbi, A. B., and Rabin, B. S. (1994). Serum Interleukin 6 concentration in schizophrenia: Elevation associated with duration of illness. Psychiatry Res. 51 (1), 1-10.

Garyfallos, G., Lavrentiadis, G., Amoutzias, D., Monas, K., and Monos, N. (1993). Negative symptoms of schizophrenia and the dexamethasone suppression test. Acta Psychiat~ Stand. 88, 425.

(,attaz, W. E, Dalgalarrondo, R, and Schroder, H. C. (1992). Abnormalities in serum concentration of Interleukin 2, Inter~bron-~ and Interferon-v in schizophrenia not detected. Schizoph~: Res. 6, 237-241.

Gaughran, E, O'Neill, E., Cole, M., Collins, I52, Daly, R.J., and Shanahan, E (1998). Increased soluble interlenkin 2 receptor levels in schizophrenia. Schizoph~: Rea. 29, 263-267.

Gaughran, E, O'Neill, E., Sham, R, Daly, R.J., and Shanahan, E (2001). Soluble interleukin 2 receptor levels in acute and stable schizophrenia. Schizoph~: Res. 82(1-2), 143-144.

(;aughran, E, O'Neill, E., Sham, E, and Daly, R. J, (2002). Shanahan E Soluhle interleukin 2 receptor levels in tmnilies of people with schizophrenia. Schizoph): Res. 56(3), 235- 239.

Gihnore, J. H., and Jarskog, L. E (1997). Exposure to inlection and brain development: Cytokines in the pathogenesis of schizophrenia. Schizoph): Res. 24(3), 365-367.

Gilvarry, C. M., Sham, R C., Jones, R B., Cannon, M., Wright, P., Lewis, S., Bebbington, E, Toone, g. K., and Murray, R. M. (1996). Family history of autoimnmne disease in psychosis. Schizoph): Res. 19, 33-40.

Gur, R. E. (1977). Motoric laterality imbalance in schizophrenia. Arch. (;en. Psychiatry 34, 33-37. Haack, M., Hinze-Selch, D., Fenzel, T., Kraus, T., Knhn, M., Schuld, A., and Pollmacher, T.

(1999). Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: Eftects of confounding factors and diagnosis. J. Psychiat): Res. 33(5), 407-418.

Hanisch, U. K., Seto, D., and Quirion, R. (1993), Modulation of hippocampal acelylcholine release: A potent central action of interleukin-2. J. Neurosci. 13(8), 3368-3374.

Heath, R. G., Krupp, I. M., Byers, L. W., and Lijekvist, J. 1. (1967). Schizophrenia as an inmmno- logic disorder. 3. Efliects of antimonkey and antihuman brain antibody on brain fimction. Arch. Gen. Ps~chiatt 3, 16(1), 24-33.

Heath, R. G., McCarron, K, L., and O'Neil, C. E. (1989). Antiseptal brain antibody in lgG of schizophrenic patients. Biol. Psychiatry 25, 725-733.

Henneberg, A. E., Horter, S., and Ruffert, S. (1994). Increased prevalence of antibrain antibodies in the sera from schizophrenic patients. Schiz@h~ Res. 14, 15-22.

Ho, A., and Blum, M. (1998). Induction of interleukin-I associated with compensator dopaminergic sprouting in the denervated striatum of young mice: Model of aging and nenrode- generative disease. J. ~\Mlrosci. 18(15), 5614-5629.

Hornberg, M., Arolt, V., Wilke, I., Kruse, A., and Kirchner, H. (1995). Production ofinterferons and lyinphokines in leukocyte cultures of patients with schiznphr. Schizopht: Reg. 15(3), 237-242.

298 FIONA GAUGHRAN

Inglot, A. D., LeszekJ., Piasecki, E., and Sypula, A. (1994). Interferon responses in schizophrenia and major depressive disorders. BioL Psychiat U 35, 464-473.

International Pilot Study of Schizophrenia. (1973). World Health Organization, Geneva. .]'ones, E, Rodgers, B., and Murray, R. (1994). Child development risk factors for adult

schizophrenia. Lancet 344, 1398-1402. Jones, E, Rantakallio, E, Hartikainen, A. L., Isohanni, M., and Sipila, E (1998). Does schizophre-

nia result from pregnancy, deliveD, , and perinatal complications? A 28-year study in the 1966 North Finland Birth Cohort. Presented at the 8th Congress of the Association of PsychopharmacoloD,.

Kathol, R. G., Gehris, T. L., Carroll, B. T., Samuelson, S. D., Pitts, A. K, Meller, W. H., and Carter,J. L. (1992). Blunted ACTH response to hypoglycemic stress in depressed patients but not in patients with schizophrenia.a~ P~ychiat~: ICes. 26(2), 103-116.

Katila, H., Appelberg, B., Hurnm, M., and Rimon, R. (1994). Plasma levels of interleukin-lB and Interleukin-6 in schizophrenia, other psychoses, and affective disorders. Schizophr l@s. 12, 29-34.

Kelly, R. H., Ganguli, R., and Rabin, B. S. (1987). Antibody to discrete areas of the brain in normal individuals and patients with schizophrenia. Biol. Psychiatry 22 (12), 1488-1491.

Kessler, A., and Shinitzky, M. (1993). Platelets from schizophrenic patients bear autoimmune antibodies that inhibit dopamine uptake. Psychobiology 21 (4), 299-306.

Kim, C. E., Lee, M. S., and Suh, K. Y (1998). Decreased interleukin 2 production in Korean schizophrenic patients. Biol. l~ychiatry 43(9), 701-704.

gafight,J., Knight, A., and Ungwari, G. (1992). Can Autoimmune mechanisms account for the genetic predisposition to schizophrenia? BrJ. Psychiat U 160, 533-540.

Kohn, M. L. (1968). Social class and schizophrenia: A review./. Psy&iatr. Res. 6, 155-173. Kuznetsova, Ni., and Semenov, S. E (1961). Determining antibodies to the brain in the serunl

of patients with neuropsychiatric disease. Zh. Nevr@atol. P~ikhiatr 61,869-874. Lahdelma, R. L., Katila, H., Hirata-Hibi, M., Andersson, L., Appelberg, B., and Rimon, R.

(1995). Atypical lymphocytes in schizophrenia. Eu~: P~ychiat*~y 10(2), 92. Laing, E, I~fight, J. G., ~Mght, E, and Irving, W. L. (1996). Disruption of fetal brain develop-

ment by maternal antibodies as an aetiological factor in schizophrenia. In "Neural Devel- opment in Schizophrenia: Then D' and Research" (S. A. Mednick, ed.). Plenum, New York.

Lapchak, P. A. (1992). A role for interleukin 2 in the regulation of striatal dopaminergic fimction. Neuroreport 3, 165-168.

Legros, S., Mendlewicz,J., and Wybran,J. (1985). hnlnunoglobulins, autoantibodies and other serum protein fractions in psychiatric disorders. Era: Arch. Ps~chiat~)' Neurol. Sci. 235(1), 9-11.

Lehmann-Facius, H. (1939). Serologischanalytische veruche it liqouren und seren von schizophrenien. Alg. Z Psychiatr. 110, 232-243.

Levine,J., Gtmnan,J., Feraro, R., Le W, R, Kihmi, R., Leykin, l., Deckmann, M., Handzel, Z. T., and Shinitzky, M. (1997). Side effect profile of azothioprine in the treatment of chronic schizophrenic patients. Neuropsychobiology 36 (4), 172-176.

Lewis, D. A., and Lieberman,J. A. (2000). Catching up on schizophrenia: Natural History and Neurobiology. Neuron 28(2), 325-334.

Licinio,J., K~Tstal,J., 8eihyl,J., Altemus, M., and Charney, D. (1991). Elevated central levels of interleukin 2 in drug fl'ee schizophrenic patients. Schizophr Res. 4, 372.

Lin, A., Kenis, G., Bignotti, S., Tura, G.J., De Jong, R., Bosmans, E., Pioli, R., Altanmra, C., Scharpe, S., and Maes, M. (1998). The intlammatory response system in treatment resistant schizophrenia increased serum interleukin 6. Schizophr. Res. 32 (1), 9-15.

Luk, W. E, Zhang, Y, White, T. D., Lue, E A., Wu, C., Jiang, c. G., Zhang, L., and Moldofsky, H. (1999). Adenosine: A mediator of interleukin-lfl-induced hippocampal synaptic inhi- bition..]. Neurosci. 19(11), 4238-4244.


Maes, M., Bosmans, E., Ranjan, R., Vandoolaeghe, E., Meltzer, H. Y, De Ley, M., Berghmans, R., Starts, G., and Desnyder, R. (1996). Lower plasma CC16, a natural anti-inflammatoo' protein, and increased plasma interleukin 1 receptor antagonist in schizophrenia: Effects of antipsychotic drugs. Schizoph~: Res. 21 (1), 39-50.

Maes, M., Delange,J., Ranjan, R., Mehzer, H. Y, Desnyder, R., Cooremans, W., and Scharpe, S. (1997). The acute phase protein response in schizophrenia, mania and major depression: Effects of psychou'opic drugs. Psychiatry Res. 66 (1), 1-11.

Marx, C. E., and Lieberman, J. A. (1998). Psychoneuroendocrinolo~" of schizophrenia. P.~;chiat~: Clin. North Am. 21 (2), 413-434.

Masserini, C., Vita, A., Basile, R., Morselli, R., Boato, E, Peruzzi, C., Pugnetti, L., Ferrante, E, and Cazzullo, C. L. (1990). Lymphocyte subsets in schizophrenic disorders. Relationship with clinical, neuromorphological and treatment variables. Schizoph~ Res. 3(4), 269-275.

McAllister, C. G., Rapaport, M. H., Pickar, D., Podruchny, T. A., Christison, G., Alphs, L. D., and Paul, S. M. (1989). Increased numbers of CD5 + B tymphocytes in schizophrenic patients. Arch. Ge*z. P~vchiatry 46(10), 890-894.

McAllister, C. G., van Kammen, D. E, Rehn, T.J., Miller, A. L., Gurklis,J., Kelley, M. E., Yao,J., and Peters,.]. L. (1995). Increases in CSF levels of interleukin 2 in schizophrenia: Ettiects of recurrence of psychosis and medication status. Am../. P~ychiatry 152, 1291- 1297.

McDaniel, .]. S., Jewart, R. D., Eccard, M. B., Pollard, W. E., Caudle, J., Stipetic, M., Risby, E. D., Lewine, R., and Risch, S. C. (1992). Natnral killer cell activity in schizophrenia and schizoattective disorder: A pilot study. SchizoDh~. Res. 8(2), 125-128.

Merrill, J. E. (1992). Tumor necrosis factor ce, interleukin 1 and related cytokines in hrain development: Normal and pathological. Dev. Neu*r,~ci. 14, 1-10.

Moises, H. W., Schindlcr, L., Leroux, M., and Kirchner, H. (1985). Decreased production of interferon oe and interfieron g in leucocytes cultures of schizophrenic patients. Acta Psychiah: &and. 72(1), 45-5/).

Mokrani, M., Duval, E, Crocq, M., Bailey, E E., and Macher, J. R (1995). Muhihormonal responses to apomorphine in mental illness, t~ychoneuroendocdnolog 7 20, 365.

Molhohn, H. B. (1942). HyposensitMty to foreign protein in schizophrenic patients, t4~ychiah: Q. 16, 565-571.

Mukhmjee, S., Mahadik, S. E, Korenovsky, A., Laev, H., Schnur, D. B., and Reddy, R. (1994). Serum antibodies to nicotinic accD'lcholine receptors in schizophrenic patients. Schizophr. Res. 12, 131-136.

Muller, N., and Ackenheil, M. (1995). Immunoglobulin and albumin content ofcerebrospinal fhfid in schizophrenic patients: Relationship to negative symptomatolo~'. Schizoph~: [Lo~. 14, 223-228.

Muller, N., and Ackenheil, M. (1998). Psycho-neuro-immunolo~, and the cytokine action in the CNS: hnplications for psychiatric disorders, Pro~. ~\?ur~P.sychopharmacol. Biol. P~),~iffatry 22(1), 1-33.

Muller, N., Ackenheil, M., Hofschuster, E., Mempel, W., and Eckstein, R. (1991). Celhflar immunity in schizophrenic patients before and during neuroleptic treatment. 14~ychiat U Res. 37, 147-160.

Muller, N., Hotschuster, E., Ackenheil, M., and Eckstein, R. (1993). T-cells and psychopathologD' in schizophrenia: Relationship to the outcome of neuroleptic therapy. Acta P~ychiat~: Stand. 87(1), 66-71.

Muller, N., Empl, M., Riedel, M., Schwar~, M., and Ackenheil, M. (1997). Neuroleptic treatment increases soluble II~2 receptors and decreases soluble IL6 receptors in schizophrenia. Eu~: Arch. Psychiat U Clin. Neurosci. 247(6), 308-313.

Muller, N., Riedel, M., Ackenheil, M., and Schwarz, M.J. (1999). The role of immune fimction in schizophrenia: An overview. Eu~ Arch. P.s2~chiat U Clin. Neurosci. 249(Supply 4), 62-68.

300 FIONA GAUGHRAN

Nemni, R., lannaccone, S., Quattrini, A., and Smirne, S. (1992). Effiect of chronic treatment with recombinant interleukin 2 on the central nervous system of adult and old mice. Brain Res. 591 (2), 248-252.

Newcomer, J. w., Faustman, W. O., Whiteford, H. A., Moses, J. A. Jr., and Csernansky, J. G. (1991). Symptomatology and cognitive impairment associate independently with postdexamethasone cortisol concentrations in unmedicated schizophrenic patients. Biol. P,y- chiatry 29(9), 855-864.

Nikkila, H., Muller, FL, Ahokas, A., Miettinen, K., Andersson, L. C., and Rimon, R. (1995). Abnormal distributions ofT lymphocyte subsets in the cerebrospinal fluid of patients with schizophrenia. Schizophr. Res. 14, 215-221.

Nopoulos, E, Torres, I., Flaum, M., Andreasen, N., Ehrhardt, J. C., and Yuh, W. T. C. (1995). Brain morphology in first episode schizophrenia. Am.J. PsychiaO 7 152, 1721-1723.

O'Callaghan, E., Larkin, C., Kinsella, A., and Waddington, J. (1991). Familial, obstetric and other clinical correlates of minor physical anomalies in schizophrenia. Am. J. Psychiatry 148, 479-483.

O'Callaghan, E., Gibson, T., Colohan, H. A., Buckley, R, Walshe, D. G., Larkin, C., and Waddington,J. L. (1992). Risk of schizophrenia in adults born alter obstetric complications and their association with early onset of illness: A controlled study. BMJ 305, 1256-1259.

Ozek, M., Toreci, K., Akkok, I., and Guvener, Z. (1971). [Influence of therapy on antibody- tormation.] [German] Pss, chopharmacologia 21(4), 401-412.

Pandey, R. S., Gupta, A. K., and Chaturvedi, V. C. ( 1981 ). Autoimnmne model of schizophrenia with special reference to antibrain antibodies. BioL Psychiatry 16, 1123-1136.

Penttinen, J. (1995). Hypothesis: Low sermn cholesterol, suicide and interleukin 2. Am. J. Epidemiol. 141,716-718.

Plata-Salaman, C. R., and ffrench-Mullen,J. M. (1993). Interleukin-2 modulates calcium cm~ rents in dissociated hippocampal CAI neurons. Neuroreport4(5), 579-581.

Polhnacher, T., Hinze-Selch, D., Mullington,J., and Holsboer, E (1995). Clozapine induced increase in plasma levels of soluble interleukin 2 receptors. Arch. Gen. Psychiatry 52, 877-878.

Polhnacher, T., Hinze-Selch, D., and Mullington, J. (1996). Effects of clozapine on plasma cytokine and soluble cytokine receptor levels..]. Clin. Pw:hopharmacol. 16(5), 403-409.

Pollmacher, T., Hinze-Selch, D., Fenzel, T., Kraus, T., Schuld, A., and Mullington, J. (1997). Plasma levels of cytokines and soluble cytokine receptors during treatment with haloperidol. Am.]. Psychiatry 154(12), 1763-1765.

Preble, O. T., and Torrey, E. E (1985). Serum interferon in patients with psychosis, Am. J. Psychiat~)" 142(10), 1184-1186.

Rao, N. IV, Gopinath, E S.,Jayasimha, N., and Subhash, M. N. (1988). Immunochemical profiles in schizophrenia. NIMHANSJ. 6(1), 27-28.

Rapaport, M., and Lohr, J. B. (1994). Serum interleukin 2 receptors in neuroleptic naive schizophrenic subjects with and without tardive dyskinesia. Acta Psychiatr. Scand. 90, 311- 315.

Rapaport, M. H., Fuller Torrey, E., McAllister, C., Nelson, D. L., Pickar, D., and Paul, S. M. (1993). Increased sermn soluble interleukin 2 receptors in schizophrenic monozygotic twins. Eur. Arch. Psychiatry Clin. Neurosci. 243, 7-10.

Reicheh, FL L., and Landmark, J. (1995). Specific IgA antibody increases in schizophrenia. Biol. P~ychiat~y 37, 410-413.

Roos, R. E, Davis, K., and Meltzner, H. Y (1985). hnmunoglobulin studies in patients with psychiatric diseases. Arch. Gen. Psychiatry 42, 124-128.

Rothermundt, M., Aroh, V., Leadbeater, J., Peters, M., Rudolf, S., and Kirchner, H. (2000). Cytokine in unmedicated and treated schizophrenic patients. Neuroreport 11(15), 3385- 3388.

IMMUNITY AND SCHIZOPftRENIA 301

Russo, R., Ciminale, M., Ditommaso, S., Siliquini, R., Zotti, C., and Ruggenini, A. M. (1994). Hepatitis B vaccination in psychiatric patients. Lancet 343, 346.

Saunders,J. C., and Muchmore, E. (1964). Phenothiazine effect on human antihody synthesis. B~ J. Psychiat D, 110, 84-89.

Schwarz, M.J., Riedel, M., Gruber, R., Ackenheil, M., and Muller, N. (1999). Antibodies to heat shock proteins in schizophrenic patients: hnplications for the mechanism of the disease. A m. ji Psvchiatry 156(7), 1103-1104.

Schwarz, M.J., Riedel, M., Ackenheil, M., and Muller, N. (2000). Decreased levels of soluble intercellular adhesion molecule-I (sICAM-1) in unmedicated and medicated schizophrenic patients. Biol. Psychiat~y 47(1), 29-33.

Schwarz, M. J., Muller, N., Riedel, M., and Ackenheil, M. (2001). The Th2-hypothesis of schizophrenia: A strategy to identify a subgroup of schizophrenia caused by immune mechanisms. Med. tIypotheses 56(4), 483-486.

Sirota, R, Schild, K., Firer, M., Tanay, A., Elizur, A., Meytes, D., and Slor, H. (1991). Autoanti- bodies to DNA in multicase tamilies with schizophrenia. Biol. Ps~chiat,~; 29, 131A.

Sirota, E, Firer, M., Schild, K., Zurgil, N., Barak, Y, Elizur, A., and Slor, H. (1993). Increased anti-Sm antibodies in schizophrenic patients and their tamilies. Prog. Neuro-PD'chopharmacol. Biol. Psychiatry 17, 793-800.

Sirota, R, Schild, K., Elizur, A., Djaldetti, M., and Fishman, R (1995). Increased interleukin 1 and interleukin 3 like activiu¢ in schizophrenic patients. IS-og. Neuropsych@harmacol. Biol. PE';chiat~?; 19, 75-83.

Smidt, E., Axelsson, R., and Steen, G. (1985). Treatment of chronic schizophrenia with glucocorticoids in combination with neuroleptic drugs: A pilot stud}: Curt. Therapeut. Res. 43, 842-850.

Song, C., Merali, Z., and .Mfisman, H. (1999). Variations of nucleus accumbens dopamine and serotonin tollowing systemic interleukin-l, interleukin-2 or interleukin-6 treatment. 1N?uroscie~zce 88(3), 823-836.

Sperner-Unte~eger, B., Barnas, C., Fleischhacker. W. W., Fuchs, D., Meise, U., Reibnegger, (;., and Wachter, H. (1989). ls schizophrenia linked to aheration in celhflar immunily? Schizophr. Res. 2(4-5), 417-421.

Spivak, B., Radwan, M., Brandon,J., Baruch, Y., Stawski, M., Tyano, S., and Wcizman, A. (1993). Reduced total complement haemolytic activity in schizophrenic patients. Psychol. Med. 23(2), 315-318.

Stevens, A., and Weller, M. (1992). Ganglioside antibodies in schizophrenia and major depression. Biol. t~chiat~y 32(8), 728-730.

Stevens, J., Papadopoulos, N. M., and Resnick, M. (1990). Oligoclonal bands in acute schizophrenia: A negative search. Acta t~s),chiatr. Stand. 81 (3), 262-264.

Susser, E. S., and Lin, S. R (1992). Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945. A~rh. Gen. t~D, chiat~:v 49, 983-988.

Swedo, S., Leonard, H., Schipiro, M., Casey, B.J., Mannheim, G. B., Lenane, M., and Rettew, D. C. (1993). Sydenham's Chorea: Physical and psychological symptoms of St. Vitus Dance. Pediatri~ 91,706-7] 3.

Tanaka, K. E, Shintani, E, Fujii, ~_~, ~:hgi, G., and Asai, M. (2000). Serum interleukin-18 levels are elevated in schizophrenia. P~3,chiatry Res. 96 (1), 75-80.

Theodoropoulou, S, 8panakos, G., Baxevanis, C. N., Economou, M., Gritzapis, A. 1)., Papamichail, M. E, and Stefanis, C. N. (2001). Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic paticnts. Schizoph~: Res. 47 (1), 13-25.

Vaughan, W. T., Sullivan,J. c., and Ehnadjian, E (1949). hninunity and schizophrenia, l~vcho sore, Med. 11,327-333.

302 FIONA GAUGHRAN

Waddiugton, J. (1993). Schizophrenia: Developmental neuroscience and pathobiology. Lancet 341,531-536.

Wik, G. (1995). Ettects of neuroleptic treatment on cortisol and 3-methoxy-4-hydroxy- phenylethyl glycol levels in blood, j( Endocrinol. 144(3), 425-429.

Wilke, l., Arolt, V., Rothermundt, M., Weizsch, C. H., Hornberg, M., and Kirchner, H. (1996). Investigations of cytokine production in whole blood cuhures of paranoid and residual schizophrenic patients. Eu~: Arch. P~ychiat~y Clin. Neurosci. 246, 279-284.

Wong, C. T., Tsoi, W. E, and Saha, N. (1996). Acute phase proteins in male Chinese schizophrenic patients in Singapore. Schizc*ph,: Res. 22(2), 165-171.

Wright, E, Sham, E C., Gilvarry, C. M.,Jones, E B., Cannon, M., Sharma, T., and Murray, R. M. (1996). Autoimmune diseases in the first degree relatives nf schizophrenic and control subjects. Schizoph~: Res. 20, 261-267.

Wright, E, Nimgaonkar, V. L., Donaldson, E T., and Murray, R. M. (2001). Schizophrenia and HLA: A review. SchizophT: Res. 47(1 ), 1-12.

Wu, Y, Shaghaghi, E. K., Jacqnot, C., Pallardy, M., and Gardier, A. M. (1999). Synergism between interleukin-6 and interleukin-1/3 in hypothalamic serotonin release: A reverse in vivo microdialysis study in F344 rats. Eu~: Cytokine Netw. 10 ( 1 ), 57- 64.

"Fang, Z. W., Chengappa, R., Shurin, G., Brat,.]. S., Rabin, B. S., Gubbi, A. B., and Ganguli, R. (1994). An association between anti-hippocampal antibody concentration and lymphocyte production of IL-2 in patients with schizophrenia. Ps~;choI. Med. 24, 449-455.

Yannitsi, S. G., Mannussakis, M. N., Mavridis, A. K., Tzioutas, A. G., Lonkas, S. B., and Plataris, G. K. (1991). Factors related to the presence of auto-antibodies in patients with chronic mental disorders. Biol. Psychiatry' 30, 731-735.

Zalcman, S., Green-|ohnson, J. M., Murray, L., Nance, D. M., Dyck, D., Anizman, H., and Greenberg, A. H. (1994). Cytokine specific central monoamine alterations induced by interleukin-l, -2 and -6. Brain Res. 643, 40-49.

Zarrabi, M. H., Zncker, S., Miller, T., Derman, R. M., Romeno, G. S., and Hartnett, J. A. (1979). Immunologic and coagulation disorders in chlorprmnazine treated patients. Ann. Intern. Med. 91,194-199.

Zorilla, E. E, Cannon, T, D., Gur, R. E., and Kessler, J. (1996). Leukocyte and organ-non- specific auto-antibodies in schizophrenics and their siblings: Markers of vulnerabilig, or disease? Biol. Psychiatry 40, 825-833.

Documents

[International Review of Neurobiology] Neurobiology of the Immune System Volume 52 || Immunity and schizophrenia: Autoimmunity, cytokines, and immune responses