World I Biol Psychiatry (2000) 1, 173 - 179

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Cellular and Humoral Immune System in Schizophrenia: A Conceptual Re-Evaluation

Norbert Muller, Michael Riedel, Manfred Ackenheil, Markus J. Schwarz Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany

Summary Immune alterations in schizophrenia have been described for decades. However, modern immuno- logical methods and new insights into the highly developed and finctionally differentiated immune system allow an integrative view of both the older and also more recent findings of immunological abnormalities in schizophrenia. The conceptual advances in immunology require the re-evaluation of elder immunological findings in schizophrenia. In this overview, recent advances in immunological research regarding the differentiation between T- Helper-I and T-Helper-2 cells and between the so- called specific and unspecific arms of the immune system are discussed. The unspecific "innate" immune system shows signs of an over-activation in unmedicated schizophrenic patients, as increased monocytes and yti-cells point to. Increased levels of Interleukin-6 (IL-6) and the activation of the IL-6 system in schizophrenia might be the result of the activation of monocytes/macrophages, too. In contrast, several parameters of the specific cellular immune system are blunted, e.g. the decreased T- helper-1 (TH-I) related immune parameters in schizophrenic patients, both in vitro and in vivo. I t seems that a TH-1-TH-2 imbalance with a shift to the TH-2 system is associated with schizophrenia. During therapy with antipsychotics, the specific TH- 1 related immune answer becomes activated, but the B-cell system and the antibody production become activated too.

Key words: schizophrenia, immune system, psychoneuroimmunology, antipsychotics.

Correspondence: Prof. Norbert Miiller Department of Psychiatry Ludwig-Maximilians- University Nussbaumstr. 7 80336 Munich Germany Tel: + 49 89 5 160 3397 Fax: + 49 89 51 60 4548 E-mail: nmueller@psy.med.uni-muenchen.de

Introduction Immunological alterations have been described in the international literature since the be- ginning of the last century (Bruce and Peebles 1903; Dameshek 1930; Lehmann-Facius 1939). For several reasons, however, the focus of interest changed from the immune system over the last decades. One reason was the intro- duction of antipsychotics into the therapy of schizophrenia leading to the dopamine hypo- thesis as the centre of research activities. Another reason was that the components and functions of the immune system were not well understood during those times, while during the last decade major advances in immunological research could be observed.

With regard to the clinical symptomatology, the acuity of the symptoms, the course, the treat- ment response and probably also the etiology, schizophrenia is a heterogenous disorder. Besides methodological pitfalls, this heterogeneity might contribute to the heterogeneity of the results of biological investigations, which can be found in several fields of biological research in schizophrenia. A widespread heterogeneity can also be observed in the results of immunological studies in schizophrenia (Overview: Muller and Ackenheil 1998).

However, a lack in the immunological methods and in the insight of the different components of the immune system and their functional balance might also have contributed to the heterogeneity of results in schizophrenia. Today, the knowledge about the functional inter- relationship of the different components of the immune system allows more specific studies and a new classification of earlier findings in schizo- phrenia. Therefore the actual concept of immu- nity is briefly outlined first.

The concept of innate and adaptive immunity in humans The immune system has developed during evolution over millions of years. In order to guarantee successful defence against numerous varying invading, life-threatening micro-orga- nisms such as bacteria or viruses, a highly dif- ferentiated system consisting of different lines of defence was established. A widespread hetero- geneity was the consequence: two functionally different immune systems both representing different types of barriers and each consisting of cellular and humoral immune components. The

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‘innate’ immune system is the phylogenetically older, ‘primitive’ one. Its cellular arm is repre- sented by monocytes/macrophages, granulo- cytes, and natural killer (NK) cells. The humoral arm consists of acute phase proteins and the complement system. This ‘unspecific‘ immune system represents the first line of defence.

The specific part of the immune system of higher organisms, including humans, is the ‘adaptive’ immune system, consisting of the cellular arm of the T- and B-cells and the humoral arm of specific antibodies. This system includes higher functions, such as memory, and can be condi- tioned. In case of re-exposure to a specific anti- gen, this system can recognise the enemy and initiate a specific immune answer.

Table 1 Components of the unspecific “innate” and the more specific cellular “adaptive” immune systems in humans

Components Innate Adaptive

Cellular Monocytes T- & B-cells Makrophages Granulocytes NK-cells y/6-celk

binding Lectin (MBL) Humoral Complement, APP, Mannose Antibodies

The ‘innate’ and the ‘adaptive’ immune systems are functionally balanced. Within the ‘adaptive’ immune system there is another balance regar- ding the activation of the cellular and the humo- ral immune system. The cellular arm of the adap- tive immune system is mainly activated by the T-helper-1 (TH-1) system - helper cells, which produce the activating ‘immunotransmitters’ Interleukin-2 (IL-2)’ Interferon-y (IFN-y) and Tumor-necrose-factor-a) (TNF-a). The humoral arm of the adaptive immune system is mainly activated via the TH-2 system - helper cells, which produce mainly IL-4, IL-10, and IL-6.

Relationship between clinical characteristics and immune alterations Signs of an inflammatory disease process in schizophrenia have been observed in a subgroup of schizophrenic patients (Korschenhausen et a1 1996). Clinical features of this subgroup showing signs of an immunological or inflammatory disease have been studied by several groups of researchers. It was observed, however, that the symptomatolgy, e.g. paranoid symptoms or negative symptoms (Cazullo et a1 1998a; Muller and Ackenheil 1995), the acuity (Korte et a1 1998; Sperner-Unterweger et a1 1992; Wilke et a1 1996), and the drug treatment (Ozek et a1 1971; Saunders and Muchmore 1964; Maes et a1 1995;

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Masserini et a1 1990; Miiller et a1 1991; Muller et a1 1997a; Miiller et a1 1999a; Pollmacher et a1 1996) influence the immunological parameters. Also, the clinical response to treatment with neuroleptics seems to be related to immune parameters (Miiller et a1 1993). Own data show that the IgG content of CSF is especially high in patients with pronounced schizophrenic nega- tive symptoms, which are associated with an unfavourable course of the disorder and often with treatment resistance (Muller and Ackenheil 1995). Those findings fit with the suggestion that the inflammatory response system is acti- vated in patients who are treatment resistant to antipsychotic medication (Maes et a1 2000).

A clearcut differentiation between immuno- logical subgroups in schizophrenia is not yet established, however. The discussion of this rela- tionship between clinical characteristics of schizophrenia and parameters of the immune system may help to define sub-groups that are characterised by disturbances of the immune sys tem.

Activation of the innate ‘unspecific’ immune system in schizophrenia Although systematic investigations of the innate immune system are lacking in schizophrenia, there are several hints that this part of the immune system may be more activated in schizophrenic patients than in controls. There is a report that monocytes are increased in schizo- phrenic patients compared with controls (Wilke et a1 1996) and our own investigations of unmedicated schizophrenic patients also showed increased amounts of monocytes in schizo- phrenia compared with controls (unpublished results). The increase of cells of the “first immune barrier” was also found in y&CD8+ cells in un- medicated schizophrenics (Muller et a1 1998).

One of the key-cytokines, which initiates the immune answer and especially activates the B-cell system, is Interleukin-6 (IL-6). Activated monocytes and macrophages are the major sour- ces of the production and release of IL-6. Vice versa, increased levels of IL-6, as mentioned in the next paragraph, might be the result of the activation of the monocyte/macrophage system leading to an over-production of IL-6 by the innate immune system.

IL-6 in the central nervous system IL-6 is a pleiotropic cytokine, which is released from different cell types in the blood (macro- phages, monocytes, T and B cells). One function of IL-6 is to activate B-cells to synthesize anti- bodies (Plata-Salaman 1991). However, as with several other cytokines, IL-6 is not only synthesised and released in immune cells of the peripheral blood, IL-6 is also produ- ced by activated astrocytes and microglia cells in the central nervous system (CNS). Several fin- dings suggest that IL-6 may mediate the exacer-

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bation of autoimmune disorders in the CNS (Dunn 1992), e.g. IL-6 supports the differenti- ation of B cells, the local IgG synthesis in the CNS, and a blood-brain barrier disturbance (Frei et a1 1989; Muraguchi et a1 1988). In the hypo- thalamus, IL-6 can induce the release of growth hormone releasing hormone and TSH, and it stimulates in vitro the secretion of prolactin and growth hormone from pituitary cells (Spangelo et a1 1989).

A strong relationship between IL-6 and neuro- transmitter production has been reported by different studies. IL-6 can stimulate neurons in vitro to secrete dopamine and probably other catecholamines as well (Hama et a1 1991). The peripheral application of IL-6 in animal expe- riments enhanced the dopaminergic and sero- tonergic turnover in the hippocampus and frontal cortex, without affecting noradrenaline (Zalcman et a1 1994). Conversely, noradrenaline can stimulate astrocytes to release IL-6 (Dunn 1992). Both observations point to a direct in- fluence of activating cytokines, especially IL-6, to the catecholaminergic neurotransmitter system.

IL-6 and schizophrenia Several reports showed increased IL-6 levels in schizophrenia (Ganguli et a1 1994; Maes et a1 1995; Frommberger et a1 1997; Lin et a1 1998). Several authors described a relationship between increased IL-6 levels and clinical features of schizophrenia: high IL-6 levels were related to the duration of the disorder (Ganguli et a1 1994) and to treatment resistance (Lin et a1 1998). These findings suggest that IL-6 serum levels might be especially high in patients with an unfavourable course of the disease. However, methodological concerns must be considered.

Investigations of the sIL-6R (soluble IL-6 receptor) levels in the CSF, however, showed that high levels of sIL-6R can be found especially in schizophrenic patients with a more marked paranoid-hallucinatory syndrome (Muller et a1 1997b). These investigations also point to a more altered IL-6 system in patients with an un- favourable course of the disease: longer duration of illness, treatment resistance, or more marked paranoid-hallucinatory symptomatology.

Another study found reduced levels of sgpl30 in the CSF of schizophrenic patients compared with depressed patients and psychiatric healthy controls (Schwarz et a1 2000b). This result sup- ports the view of a disturbance in the IL-6 system in schizophrenia, because gp130 is part of the IL- 6 system. The soluble protein spgl30 acts as an antagonist to the gp130 receptor and mediates the inhibition of the IL-6 system (Narazaki et a1 1993). Functionally, decreased sgpl30 levels in the CSF point to a decrease in the inhibition of the IL-6 system and a functional increase in the activation.

Antipsychotic therapy and IL-6 system There are several observations that antipsychotic therapy with neuroleptics is accompanied by a functional decrease of the IL-6 system. A signi- ficant decrease of IL-6 during therapy with neuroleptics was described by Maes and co-wor- kers (1995). Two studies found a significant de- crease of sIL-6R levels during antipsychotic therapy with neuroleptics (Maes et a1 1995; Muller et a1 1997a). Studies from human CNS cell cultures also showed an inhibitory effect of different neuroleptics to the production of IL-6 after stimulation with lipopolysacharides, more marked in phenothiazines compared to buty- rophenones (unpublished results). Similar obser- vations have been described by other authors too (Lin et a1 1998).

T-Helper 2 cell activation in schizophrenia IL-6 is not only a product of macrophage/mono- cyte activation, but also of the activation of the TH-2 system. Therefore it cannot be differen- tiated whether a functional increase of the IL-6 system is a product of TH-2 activation or of the monocyte/macrophage line. However, other results point to an activation of the TH-2 system in schizophrenia.

IL-10 is a cytokine that is produced by TH-2 cells. An increase of IL-10 in schizophrenic patients compared to healthy controls was reported (Cazzullo et a1 1998). Another study observed a strong relationship between IL-10 levels and schizophrenic negative symptoms in the cere- brospinal fluid of 62 unmedicated schizo- phrenics (van Kammen et a1 1997). In medicated schizophrenics, treated with haloperidol, a significant relationship between CSF IL-10 levels and the severity of schizophrenic psychosis - measured by Bunney-Hamburg psychosis rating scale (Bunney and Hamburg 1963) - was found (van Kammen et a1 1997). These findings point out that IL-10 levels in the CSF are related to the severity of the psychosis, especially to the negative symptoms.

Another characteristic cytokine produced by TH- 2 cells is IL-4. An increase of IL-4 levels in the CSF of juvenile schizophrenic patients has recently been reported (Mittleman et a1 1997). The production of IgE is also a sign for an activation of the TH-2 immune answer. In- creased levels of IgE in schizophrenic patients compared to controls have been observed (Ramchand et a1 1994). The latter findings point out that the probable increase of the TH-2 system in schizophrenia is not only a phenome- non of the peripheral immune system, but also seems to play a role in the CNS immune system.

Earlier descriptions of elevated CD3'- and CD4' cells in unmedicated schizophrenics fit as well with the hypothesis of a shift to the TH-2 system with a diminished TH-1 immune response in

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schizophrenia (Muller et a1 1991; Sperner- Unterweger et a1 1999).

As shown in Figure 1, there is a functional balance between the TH-1 and TH-2 system. It would be expected that an over-activation of the TH-2 system is associated with an under- activation of the TH-1 system. A lot of different findings over decades of years point to a decreased activation of the TH-1 system in schizophrenia.

T-Helper-1 system and schizophrenia The key characteristics of the TH-1 system are the production of interferon-y and IL-2. One of the often replicated findings in schizophrenia is the decreased in-vitro production of IL-2 (Villemain et a1 1989; Ganguli et a1 1995; Hornberg et a1 1992; Bessler et a1 1995; Cazzullo et a1 1998). This phenomenon has often been interpreted as the consequence of an exhaustion of the lymphocytes after overproduction of IL-2 but, however, might also reflect the reduced capacity of lymphocytes to produce IL-2. The observation of a decreased production of IL-2 fits well with another finding: the decreased production of interferon-y (Wilke et a1 1996; Rothermund et a1 1998). Both findings point to a blunted production of TH-1 related cytokines and to an under-activation of the TH-1 system in schizophrenia. A lack of activation of the TH-1 related cellular immune system has also been postulated by other researchers (Sperner- Unterweger et a1 1999). Own findings of the decreased production of lymphocytes after sti- mulation with different specific antigens also might reflect the reduced capacity for a TH-1 mediated immune answer in schizophrenia. Particularly after stimulation with tuberculin, which provokes a TH-1 mediated immune ans- wer, the reaction was blunted (Muller et a1 1991).

Decreased levels of SICAM-1 in unmedicated schizophrenics Recently, decreased levels of the soluble inter- cellular adhesion molecule 1 (SICAM-1) in the serum of schizophrenic patients have been described (Wieselmann, personal communica- tion; Schwarz et a1 2000a). ICAM-1 is a molecule that mediates the adhesion of lymphocytes to other lymphocytes, to endothelial cells and to parenchymatic cells on the one hand, but it also mediates the signal for the activation of the cellular immune system. ICAM-1 is part of the TH-1 immune answer (van Seventer et a1 1990; Kuhlmann et a1 1991). Therefore, decreased le- vels of the soluble form of ICAM-1, which is shed from lymphocytes, seems to represent the state of activation of the TH-1 system. However, reduced SICAM-1 levels have been found not only in the serum, but also in the CSF of schizo- phrenic patients recently (Schwarz et al, in preparation). The latter finding points out that the blunted activation of the TH-1 system may not be restricted to the peripheral immune sys-

tem, because CSF parameters reflect more di- rectly the immune pathology of the CNS.

One of the ‘classical’ epidemiological findings in schizophrenia research is the negative associa- tion between schizophrenia and rheumatoid arthritis (Vinogradov et a1 1991). This negative association can be interpreted as two sides of the TH-UTH-Zbalance - represented by increased SICAM-1 levels in rheumatoid arthritis and decreased SICAM-1 levels in schizophrenia. SICAM-1 is also a key molecule that mediates the inflammatory reaction in rheumatoid arthritis, increased SICAM-1 levels are regularly found in rheumatoid arthritis (Neidhart et a1 1995). Rheumatoid arthritis is a disorder that is primarily mediated by the cellular TH-l-related immune system.

Blunted reaction of the cutaneous cellu- lar immune answer in schizophrenia In addition, the blunted cutaneous reaction to antigens of the Multitest MQieux which can be observed in schizophrenic patients (Miiller et al, in preparation) points to a blunted answer of the cell mediated immunity in schizophrenia. A very early description of this phenomenon, long before the era of neuroleptics, is the publication of the hyposensitivity to guinea pig serum, injec- ted intracutaneously in schizophrenic patients compared to a control group (Molholm 1942). Such a blunted reaction of a cellular mediated (TH-1) immune answer was not only observed in the cutaneous reaction to antigens, but a decreased antibody production after vaccination with salmonella was also found in unmedicated schizophrenic patients (Ozek et a1 1971). The descriptions of immune reactions before the era of neuroleptics exclude the observed pheno- mena being artefacts of effects of neuroleptics.

Antipsychotic therapy, however, is associated with different effects to the immune system. Nevertheless, these effects may counter-regulate the immune effects of the disease. Neuroleptics mainly activate the TH-1 system.

TH-1 system and antipsychotic therapy Recent findings point out that neuroleptics may have TH-1 stimulating effects. In-vitro studies show that the blunted interferon-y production becomes normalised after therapy with neuro- leptics (Wilke et a1 1996). The increase of soluble IL-2 receptors has been described by several groups (Maes et a1 1994; Pollmacher et a1 1995; Miiller et a1 1997a). Since sIL-2R are shed from activated T-cells, the increase might reflect an increase of activated, IL-2-bearing T-cells.

The increase of CD4+CD45RO cells during thera- py with neuroleptics was observed by different groups (Cazzullo et a1 1998; Miiller et a1 1997~). CD4CD45RO cells are one of the main sources of interferon-y production. The increase of this subpopulation during therapy may contribute to

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an increase of the interferon-y production. The reduced sICAM-1 levels in the serum of schizo- phrenics do not normalise during short-term neuroleptic therapy, but a statistically insig- nificant tendency to increase of sICAM-1 could be observed (Schwarz et a1 2000a). On the other hand, the leucocyte function antigen 1 (LFA-1) molecule on CD4’ cells shows an increased expression during antipsychotic therapy (Muller et a1 1999). LFA-1 is the counter molecule to ICAM-1. Moreover, the blunted reaction to vac- cination with salmonella was not observed in pa- tients treated with neuroleptics (Ozek et a1 1971). These studies point out that the TH-1 mediated immune answer increases during antipsychotic therapy. However, not only the TH-1 answer, but also the B-cell mediated immune answer, increases during antipsychotic treatment.

B-cells and antipsychotic treatment Activated B-cells are antibody producing cells. Several observations in the literature point out that B-cells are activated during antipsychotic treatment and antibody production might in- crease. As early as the 1970s, in-vitro studies showed an increase of antibody production after stimulation with phenothiazines (Gallien et a1 1977; Zarrabi et a1 1979).

A number of studies described an increased antibody production in schizophrenic patients, with those observations leading to the discus- sion of an autoimmune origin of schizophrenia (Ganguli et a1 1987). Nevertheless, the role of antipsychotic treatment has not been considered in several of these studies. Although findings have repeatedly shown that about 20-3594 of schizophrenic patients show features of an auto- immune process (Muller and Ackenheil 1998), the role of actual or former therapy with neuro- leptics may not have been sufficiently taken into considera tion.

An increase of IgG - antibodies are mainly IgG- antibodies - in the CSF has been described parti- cularly in patients with predominant negative symptoms (Muller and Ackenheil 1995). In- creased antibodies against heat shock protein 60 is one of the recent interesting findings in schizophrenia, because it may reflect a mecha- nism of loss of neuronal protection (Schwarz et a1 1998b; Schwarz et a1 1999; Kilidirias et a1 1987). However, antibodies against heat shock protein 60 are especially found in patients during neuroleptic therapy.

An increased number of patients with antibody- producing B-cells (CDS’CD19+-cells) compared to healthy controls has been described in neurolep- tic treated schizophrenic patients. Our own stu- dy shows an increase of antibody-producing B- cells during antipsychotic therapy (Miiller et al, 1997~). It seems that not only the TH-1 cell sys- tem is activated during neuroleptic therapy, but also the antibody production by activated B-cells.

During antipsychotic therapy, both arms of the specific ‘adaptive’ immune system seem to be- come activated: the specific cellular immunity of the TH-1 system, as well as the B-cell system with its humoral arm, the antibody production. An activation of the unspecific ‘innate’ immune sys- tem can be found mainly in unrnedicated schizo- phrenic patients, the latter pointing to the fact that this may reflect the disease process and not be the result of antipsychotic treatment.

Outlook Different immunological methods and different clinical features of schizophrenic patients re- garding the acuity or chronicity, the subtype, the course, or the state of medication have to be taken into account in the discussion of hetero- genous results of immunological studies. More- over, it has to be regarded that schizophrenia is not a disease entity but a syndrome. Therefore, results have to be interpreted cautiously.

However, alterations of the immune system in schizophrenia have been observed for a long time. In the context of both modern sophis- ticated immunological methods and the conti- nually growing knowledge about the different and multiple functions of immune cells, cytokines, soluble factors etc., more precise sug- gestions and explanations regarding the interrelationship of the immune functions are possible. In particular, the functional differen- tiation between innate and adaptive immune system and the T-helper-1 and T-helper-2 conceptualisation enable pinpointing of func- tional deficits in schizophrenia. This leads to a more consistent theory of the immune distur- bances in schizophrenia, the role of antipsy- chotic therapy and implications for an immune therapy in schizophrenia.

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