the immune system and schizophrenia: an integrative view

456

The Immune System and Schizophrenia

An Integrative View

NORBERT MÜLLER,

a

MICHAEL RIEDEL, RUDOLF GRUBER, MANFRED ACKENHEIL, AND MARKUS J. SCHWARZ

Psychiatric Hospital, Ludwig-Maximilian University, Munich, Germany

A

BSTRACT

: Immune alterations in schizophrenia have been described fordecades. Modern immunological methods and new insights into the highlydeveloped and functionally differentiated immune system allow an integrativeview of both the older and the recent findings of immunological abnormalitiesin schizophrenia. Both the unspecific and the specific arms of the immunesystem seem to be involved in the dysfunction of the immune system in schizo-phrenia. The unspecific, “innate” immune system shows signs of overactiva-tion in unmedicated schizophrenic patients, as indicated by increasedmonocytes and

��

-cells. Increased levels of interleukin-6 (IL-6) and the activa-tion of the IL-6 system in schizophrenia might be the result of the activation ofmonocytes/macrophages, too. On the other hand, several parameters of thespecific cellular immune system are blunted, such as, for example, thedecreased T helper-1 (TH-1)–related immune parameters in schizophrenicpatients both

in vitro

and

in vivo.

It seems that a TH-1–TH-2 imbalance with ashift to the TH-2 system is associated with schizophrenia. During antipsychotictherapy with neuroleptics, the specific TH-1–related immune answer becomesactivated, but in addition the B cell system and antibody production increase.

INTRODUCTION

Immunological alterations in schizophrenia have been described in the interna-tional literature since the beginning of the last century.

1–3

However, for several rea-sons, the focus of interest moved away from the immune system. One reason was theintroduction of neuroleptics into the therapy of schizophrenia, leading to the dopam-ine hypothesis as the center of research activities. Another reason was that the com-ponents and functions of the immune system were not well understood during thosetimes.

Schizophrenia is a heterogenous disorder in its clinical symptomatology, the acu-ity of its symptoms, its course, its treatment response and probably also its etiology.Besides causing methodological pitfalls, this heterogeneity might contribute to theheterogeneity of the results of biological investigations, which can be found in sev-eral fields of biological research in schizophrenia. Widespread heterogeneity can

a

Address for correspondence: Prof. Dr. med. Dipl.-Psych. Norbert Müller, Psychia-trische Klinik der Ludwig-Maximilians-Universität, Nußbaumstr. 7, 80336 München,Germany. Voice: 089-5160-3397; fax: 089-5160-4548.

[email protected]

457MÜLLER

et al.

: IMMUNE SYSTEM AND SCHIZOPHRENIA

also be observed in the results of immunological studies in schizophrenia (overviewin Ref. 4).

RELATIONSHIP BETWEEN CLINICAL CHARACTERISTICS AND IMMUNE ALTERATIONS

Signs of an inflammatory disease process in schizophrenia have been observed ina subgroup of schizophrenic patients.

5

Clinical features of this subgroup showingsigns of immunological or inflammatory disease have been studied by several groupsof researchers. It was observed that the symptomatolgy—for instance, paranoidsymptoms or negative symptoms,

6,7

the acuity,

8–10

and the drug treatment

11–18

influ-ence the immunological parameters. Also, the clinical response to treatment withneuroleptics seems to be related to immune parameters.

19

The discussion of this relationship between the clinical characteristics of schizo-phrenia and parameters of the immune system may help to define subgroups charac-terized by disturbances of the immune system. Moreover, a critical review has to takeinto consideration these results in order to classify the immune alterations withregard to clinical features of schizophrenia on the one hand and to the function of theimmune system on the other. Therefore, a short description of the immune system isnecessary for further understanding its dysfunction in schizophrenia.

THE CONCEPT OF INNATE AND ADAPTIVE IMMUNITY IN HUMANS

The immune system developed over millions of years of evolution. In order todefend against a variety of invading life-threatening microorganisms, such as bacte-ria and viruses, a highly differentiated system consisting of different lines of defensewas established. A widespread heterogeneity was the consequence: two functionallydifferent immune systems both representing different types of barriers and each con-sisting of cellular and humoral immune components. The “innate” immune systemis the phylogenetically elder, “primitive” one. Its cellular arm is represented bymonocytes/macrophages, granulocytes, and natural killer (NK) cells. The humoralarm consists of acute-phase proteins and the complement system. This “unspecific”immune system represents the first line of defense.

The specific part of the immune system of higher organisms including humans isthe “adaptive” immune system, consisting of the cellular arm of the T and B cellsand the humoral arm of specific antibodies. This system includes higher functions,such as memory, and can be conditioned. In case of reexposure to a specific antigen,this system can recognize the enemy and initiate a specific immune response (seeT

ABLE

1).The innate and adaptive immune systems are functionally balanced. Within the

adaptive immune system is another balance involving the activation of the cellularand humoral immune systems. The cellular arm of the adaptive immune system ismainly activated by the T helper–1 (TH-1) system—helper cells that produce theactivating “immunotransmitter” interleukin-2 (IL-2), interferon-

γ

(IFN-

γ

), andtumor necrosis factor–

α

(TNF-

α)

. The humoral arm of the adaptive immune system

458 ANNALS NEW YORK ACADEMY OF SCIENCES

is activated mainly via the TH-2 system—helper cells that produce mainly IL-4,IL-10, and IL-6.

ACTIVATION OF THE INNATE UNSPECIFIC IMMUNE SYSTEM IN SCHIZOPHRENIA

Although systematic investigations of the innate immune system in schizophreniaare lacking, there are several hints that this part of the immune system may be moreactivated in schizophrenic patients than in controls. There is a report that monocytesare increased in schizophrenic patients compared to controls,

10

and our own investi-gations of unmedicated schizophrenic patients also showed increased amounts ofmonocytes in schizophrenia compared to controls (unpublished results). An increasein the number of cells of the “first immune barrier” was also found in

γδ

+

CD8

+

cellsin unmedicated schizophrenics.

20

One of the key cytokines that initiates the immune response and especially acti-vates the B cell system is interleukin-6 (IL-6). Activated monocytes and macrophag-es are the major sources of the production and release of IL-6. Vice versa, increasedlevels of IL-6, as mentioned in the next paragraph, may be the result of the activationof the monocyte/macrophage system leading to an overproduction of IL-6 by theinnate immune system.

IL-6 IN THE CENTRAL NERVOUS SYSTEM

IL-6 is a pleiotropic cytokine that is released from various cell types in the blood(macrophages, monocytes, T and B cells). One function of IL-6 is to activate B cellsto synthesize antibodies.

21

However, as with several other cytokines, IL-6 is not onlysynthesized and released in immune cells of the peripheral blood; it is also producedby activated astrocytes and microglia cells in the central nervous system (CNS). Sev-eral findings suggest that IL-6 may mediate the exacerbation of autoimmune disor-ders in the CNS;

22

for example, IL-6 supports the differentiation of B cells, local IgGsynthesis in the CNS, and blood-brain barrier disturbance.

23,24

In the hypothalamus,

T

ABLE

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

Components Innate Adaptive

Cellular Monocytes

macrophages

granulocytes

γ

/

δ

-cells

T and B cells

Humoral Complement, APP,

mannose–binding lectin

(MBL)

Antibodies

459MÜLLER

et al.


IL-6 can induce the release of growth hormone–releasing hormone and TSH, and itstimulates

in vitro

the secretion of prolactin and growth hormone from pituitarycells.

25

A strong relationship between IL-6 and neurotransmitter production has beenreported by various studies. IL-6 can stimulate neurons

in vitro

to secrete dopamineand probably other catecholamines as well.

26

The peripheral application of IL-6 inanimal experiments enhanced the dopaminergic and serotonergic turnover in the hip-pocampus and frontal cortex, without affecting noradrenaline.

27

Conversly, norad-renaline can stimulate astrocytes to release IL-6.

22

Both observations point to adirect influence of activating cytokines, especially IL-6, on the catecholaminergicneurotransmitter system.

IL-6 AND SCHIZOPHRENIA

Several reports have shown increased IL-6 levels in schizophrenia.

13,28–30

Sever-al authors have described a relationship between increased IL-6 levels and clinicalfeatures of schizophrenia: high IL-6 levels were related to the duration of thedisorder

28

and to treatment resistance.

30

These findings suggest that IL-6 serum lev-els may be especially high in patients with an unfavorable course of the disease.However, methodological concerns must be considered.

However, investigations of sIL-6R (soluble IL-6 receptor) levels in the CSFshowed that high levels of sIL-6R can be found in schizophrenic patients, especiallythose with a more marked paranoid-hallucinatory syndrome.

31

These investigationsalso point to a more altered IL-6 system in patients with an unfavorable course of thedisease: longer duration of illness, greater treatment resistance, or more markedparanoid-hallucinatory symptomatology.

Another study found reduced levels of sgp130 in the CSF of schizophrenicpatients compared to depressed patients and psychiatrically healthy controls.

32

Thisresult supports the view of a disturbance in the IL-6 system in schizophrenia,because gp130 is part of the IL-6 system. The soluble protein spg130 acts as anantagonist to the gp130 receptor and mediates the inhibition of the IL-6 system.

33

Functionally, decreased sgp130 levels in the CSF point to a decrease in the inhibitionof the IL-6 system and an increase in its activation.

ANTIPSYCHOTIC THERAPY AND THE IL-6 SYSTEM

There are several observations that antipsychotic therapy with neuroleptics isaccompanied by a functional decrease of the IL-6 system. A significant decrease ofIL-6 during therapy with neuroleptics was described by Maes and coworkers.

13

Twostudies found a significant decrease of sIL-6R levels during antipsychotic therapywith neuroleptics.

13,16

Studies from human CNS cell cultures also showed an inhib-itory effect of various neuroleptics on the production of IL-6 after stimulation withlipopolysacharides, more marked with phenothiazines than with butyrophenones(unpublished results). Similar observations have been described by other authors,too.

30


T HELPER–2 CELL ACTIVATION IN SCHIZOPHRENIA

IL-6 is a product not only of macrophage/monocyte activation, but also ofthe activation of the TH-2 system. Therefore it cannot be known whether a function-al increase of the IL-6 system is a product of TH-2 activation or of the monocyte/macrophage line. However, other results point to activation of the TH-2 system inschizophrenia.

IL-10 is a cytokine that is produced by TH-2 cells. An increase of IL-10 in schizo-phrenic patients compared to healthy controls has been reported.

6

Another studyobserved a strong relationship between IL-10 levels and schizophrenic negativesymptoms in the cerebrospinal fluid of 62 unmedicated schizophrenics.

34

In schizo-phrenics treated with haloperidol, a significant relationship between CSF IL-10 lev-els and the severity of schizophrenic psychosis, measured by the Bunney-Hamburgpsychosis rating scale,

35

was found.

34

These findings suggest that IL-10 levels in theCSF are related to the severity of the psychosis, especially to the negative symptoms.

Another characteristic cytokine that is produced by TH-2 cells is IL-4. Anincrease of IL-4 levels in the CSF of juvenile schizophrenic patients has recentlybeen reported.

36

The production of IgE is also a sign of the activation of the TH-2immune response. Increased levels of IgE in schizophrenic patients compared tocontrols have been observed.

37

The latter findings suggest that the probable increaseof the TH-2 system in schizophrenia not only is a phenomenon of the peripheralimmune system, it also seems to play a role in the CNS immune system.

Earlier descriptions of elevated CD3

+

and CD4

+

cells in unmedicated schizo-phrenics are consistent with the hypothesis of a shift to the TH-2 system with dimin-ished TH-1 immune response in schizophrenia.

15,38

As shown in F

IGURE

1, there is a functional balance between the TH-1 and TH-2systems. It would be expected that overactivation of the TH-2 system would be asso-

FIGURE 1. Model of the immune response in schizophrenia: increase of the unspecific“innate” immune response, impaired cellular TH-1 activation, and shift to a TH-2 response.

461MÜLLER

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ciated with underactivation of the TH-1 system. Many different findings overdecades of years point to decreased activation of the TH-1 system in schizophrenia.

THE T HELPER–1 SYSTEM AND SCHIZOPHRENIA

The key characteristics of the TH-1 system are the production of interferon-

γ

andIL-2. One of the often-replicated findings in schizophrenia is the decreased

in vitro

production of IL-2.

6,39–42

This phenomenon has often been interpreted as theconsequence of an exhaustion of the lymphocytes after overproduction of IL-2, butit may reflect as well the reduced capacity of lymphocytes to produce IL-2. Theobservation of decreased production of IL-2 fits well with another finding: decreasedproduction of interferon-

γ

.

10,43

Both findings indicate decreased production of TH-1–related cytokines and underactivation of the TH-1 system in schizophrenia. Lackof activation of the TH-1–related cellular immune system has also been postulatedby other researchers.

38

Our findings of decreased production of lymphocytes afterstimulation with different specific antigens may also reflect reduced capacity for aTH-1–mediated immune response in schizophrenia. Especially after stimulationwith tuberculin, which provokes a TH-1–mediated immune answer, the reaction wasblunted.

15

sICAM-1: MARKER FOR TH-1 ACTIVATION

Recently, decreased levels of soluble intercellular adhesion molecule–1(sICAM-1) in the serum of schizophrenic patients have been described (Wie-selmann, personal communication; Ref. 44). ICAM-1 is a molecule that mediatesthe adhesion of lymphocytes to other lymphocytes, to endothelial cells, and to paren-chymal cells; but it also mediates the signal for the activation of the cellular immunesystem. ICAM-1 is part of the TH-1 immune response.

45,46

Therefore, decreasedlevels of the soluble form of ICAM-1, which is shedded from lymphocytes, seem torepresent the state of activation of the TH-1 system. However, reduced sICAM-1 lev-els have recently been found in not only the serum, but also the CSF of schizophrenicpatients (Schwarz

et al.

, manuscript in preparation). The latter finding suggests thatthe decreased activation of the TH-1 system may not be restricted to the peripheralimmune system, because CSF parameters reflect more directly the immune patholo-gy of the CNS.

One of the classic epidemiological findings in schizophrenia research is the neg-ative association between schizophrenia and rheumatoid arthritis.

47

This negativeassociation can be interpreted as two sides of the TH-1/TH-2-balance—representedby increased sICAM-1 levels in rheumatoid arthritis and decreased sICAM-1 levelsin schizophrenia. Because sICAM-1 is also a key molecule that mediates the inflam-matory reaction in rheumatoid arthritis, increased sICAM-1 levels are regularlyfound in rheumatoid arthritis.

48

Rheumatoid arthritis is a disorder that is primarilymediated by the cellular TH-1–related immune system.


BLUNTED REACTION OF THE CUTANEOUS CELLULAR IMMUNE RESPONSE IN SCHIZOPHRENIA

Also, the blunted cutaneus reaction to antigens of the Multitest Mérieux that canbe observed in schizophrenic patients (Müller

et al

., manuscript in preparation)points to a blunted response of cell-mediated immunity in schizophrenia. A very ear-ly description of this phenomenon, from long before the era of neuroleptics, is thatby Molholm of the hyposensitivity of schizophrenic patients, compared to a controlgroup, to intracutaneously injected guinea pig serum.

49

Not only was such a bluntedreaction of a cell-mediated (TH-1) immune response observed in the cutaneus reac-tion to antigens, but also decreased antibody production after vaccination with sal-monella was found in unmedicated schizophrenic patients.

11

Descriptions ofimmune reactions before the era of neuroleptics exclude the possibilty that theobserved phenomena may be artefacts of the effects of neuroleptics. Antipsychotictherapy is associated with various effects on the immune system, but these effectsmay counterregulate the immune effects of the disease. Neuroleptics mainly activatethe TH-1 system.

THE TH-1 SYSTEM AND ANTIPSYCHOTIC THERAPY

Recent findings indicate that neuroleptics may have TH-1–stimulating effects.

Invitro

studies show that the decreased interferon-g production becomes normalizedafter therapy with neuroleptics.10 The increase of soluble IL-2 receptors has beendescribed by several groups.

16,18,50

Since sIL-2R are shedded from activated T cells,the increase may reflect an increase of activated IL-2–bearing T cells.

The increase of CD4

+

CD45RO

+

cells during therapy with neuroleptics wasobserved by two groups.

6,51

CD4

+

CD45RO

+

cells are one of the primary sources ofinterferon-g production. The increase of this subpopulation during therapy may con-tribute to an increase in interferon-

γ

production. The reduced sICAM-1 levels in theserum of schizophrenics do not normalize during short-term neuroleptic therapy, buta statistically nonsignificant tendency to increase sICAM-1 could be observed.

44

Onthe other hand, the leucocyte function antigen–1 (LFA-1) molecule on CD4

+

cellsshows increased expression during antipsychotic therapy.

17

LFA-1 is the counter-molecule to ICAM-1. Moreover, the blunted reaction to vaccination with salmonellawas not observed in patients who were treated with neuroleptics.

11

These studiesindicate that the TH-1–mediated immune response increases during antipsychotictherapy. The B cell–mediated immune response also increases during antipsychotictreatment.

B CELLS AND ANTIPSYCHOTIC TREATMENT

Activated B cells are antibody-producing cells. Several observations in the liter-ature point out that B cells are activated during antipsychotic treatment and antibodyproduction may increase. Already during the 1970s

in vitro

studies showed anincrease of antibody production after stimulation with phenothiazines.

52,53

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Many studies described increased antibody production in schizophrenic patients,and those observations led to discussion of a possible autoimmune origin of schizo-phrenia.

54

Nevertheless, the role of antipsychotic treatment was not considered inseveral of these studies. Although findings have repeatedly shown that about 20–35

%

of schizophrenic patients show features of an autoimmune process, the role ofactual or former therapy with neuroleptics may not have been adequately taken intoconsideration.

An increase of IgG—antibodies are mainly IgG-antibodies—in the CSF has beendescribed, especially in patients with predominantly negative symptoms.

7

Increasedantibodies against heat shock protein 60 in schizophrenia is an interesting recentfinding, because it may reflect a mechanism of loss of neuronal protection.

55–57

However, antibodies against heat shock protein 60 are found especially in patientsduring neuroleptic therapy.

An increased number of patients with activated B cells (CD5

+

CD19

+

cells) com-pared to healthy controls has been described in neuroleptic-treated schizophrenicpatients. Our own study shows an increase in the number of activated B cells duringantipsychotic therapy.

51

It seems that not only the TH-1 cell system is activated dur-ing neuroleptic therapy, but also the antibody production by activated B cells.

During antipsychotic therapy, both arms of the specific adaptive immune systemseem to become activated: the specific cellular immunity of the TH-1 system andalso the B cell system with its humoral arm, which produces antibody. Activation ofthe unspecific innate immune system can be found mainly in unmedicated schizo-phrenic patients, which suggests that it may reflect the disease process rather thanthe antipsychotic treatment.

OUTLOOK

A number of immunological methods and various clinical features of schizo-phrenic patients—acuity or chronicity, subtype, course, state of medication—have tobe taken into account in the discussion of the heterogenous results of immunologicalstudies. Moreover, it must be borne in mind that schizophrenia is not a disease entitybut a syndrome. Therefore, results have to be interpreted cautiously.

However, alterations of the immune system in schizophrenia have been observedfor a long time. In the context of both modern, sophisticated immunological methodsand the growing body of knowledge of the multiple functions of immune cells,cytokines, soluble factors, and so on, more precise suggestions and explanationsregarding the interrelationships between the immune functions are possible. Espe-cially the functional differentiation between the innate and the adaptive immune sys-tems and the conceptualization of T helper-1 and T helper-2 cells allow one tounderstand more precisely the functional deficits in schizophrenia. This will lead toa more consistent theory of the immune disturbances in schizophrenia and the roleof antipsychotic therapy, and will have implications for an immune therapy inschizophrenia.


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the immune system and schizophrenia: an integrative view

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