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Anticerebral antibodies in functional psychoses
322
BIOL PSYCHIATRY 1991;29:322-328
Anticerebral Antibodies in Functional Psychoses Satoru Shima, Kazuhide Yano, Masahiko Sugiura, Yukiko Tokunaga
Anticerebral antibodies to rabbit brain were investigated by the indirect immunofluorescence method in the sera of 44 schizophrenics and 52 depressives diagnosed according to DSM-III-R, and of 54 healthy volunteers. Four types of staining pattern were observed: type A (nerve cells), type B (blood vessels), type C (nuclei), and type D (glial cells); 34.1% of schizophrenics (27.3% after the absorption with rabbit liver acetone powder) showed type A, as compared with 3.8% (1.9% after the absorption) of depressives and with none of the controls.
Introduction Recent advances in the field of psychoimmunology have revealed several kinds of abm~rmalities in functional psychoses. Natural killer-cell activity, which is important in the defense against viruses implicated as potential pathogens of the functional psychoses (Crow 1987), is reported to be low in schizophrenia (DeLisi et al 1983) and in depression (Evans et al 1988). With regard to lymphocyte subpopulations, elevated percentages of B cells and decreased percentages of T cells or suppressor T cells were reported in schizophrenics by some, but not all investigators (Vartanian et al !978; Zarrabi et al 1979; DeLisi et al 1982; Coffee et al 1983). Some studies have demonstrated deficient cellular immunity, such as decreased responses to pokeweed mitogen (PWM), phytohemagglutinin (PHA), or concanavalin A (Con A) in depressed parents (Schleifer et al 1984; Calabrese et al 1986), although others failed to find any such impairment (Schleifer et al 1985; Albrecht et al 1985). Several studies have reported generalized increases of immunoglobulin in schizophrenia (Solomon et al 1969; Amkraut et al 1973; Strahilevitz et al 1976), though others have shown generalized decreases (Bock et al 1970; DeLisi et al 1981). Autoantibodies have also been investigated in the functional psychoses: a number of studies showed increased antinuclear antibody titers in depressives (von Brauchitsch 1972; Johnstone and Whaley 1975; Presley et al 1976; Whalley et al 1981) as well as in schizophrenia (Berglund et al 1970; Alarcon-Segovia et al 1973; Gottfries and Gottfries 1974; Quismorio et al 1975), although drug treatment may be responsible for the excess of antinuclear antibodies. Though Heath and Krupp (1967) demonstrated the presence of an antibody in schizophrenic brain in sera of 12 of 14 schizophrenics using
From the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (SS), Biomedical Laboratories, Kawagoe-shi (KY, MS), and the Department of Pharmacology, School of Medicine, Keio University (YT), Tokyo, Japan. Address reprint requests to Dr. Satoru Shima, Department of Neuropsychialry, School of Medicine, Keio University, 35 Shinanolmachi, Shinjuku-Ku, Tokyo 160, Japan. Received November 1, 1989, revised July 23, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
Anticerebral Antibodies
alOL PsYcmATRV 1991;29:322-328
323
the fluorescent antibody staining method, Whittingham et al (1968) failed to confirm K s observation. By a hemagglutination technique, Pandey et al (1981) demonstrated antibrain antibody in 48.1% of 54 schizophrenic patients, particularly those with a past history or family history of the disorder. Baron et al (1977), using radioimmtmofixation assay, found a higher incidence of antibrain antibodies in schizophrenics as compared with r ~ controls. Employing radioimmunochemical assay, Delisi et al (1985) found that antibrain antibodies are nonspecific and were only present among a small percentage of patients in their study. We have recently developed a new assay to detect anticerebral antibodies by the indirect imnmnofluorescence method and reported that anticerebral antibodies were found in some patients suffering from Alzheimer's disease as well as those with schizophrenia (Sugiura et al 1989). The current study reports the ability of this method to discriminate functional psychoses.
Methods The patient group consisted of 44 schizophrenics (18 men and 26 women, aged 19-67, mean age 36.4 years) and 52 depressives (21 men and 31 women, aged 19-71, mean age 47.0 years) diagnosed according to DSM-III-R criteria (Aalaerican Psychia~c Association 1987). Fifty-four healthy volunteers_ were recruited as control subjects: 38 men and 16 women, aged 21-69, mean age 34.5 years. All the patients and the volunteers gave informed consent. In the present study, completely different samples were investigated than from a previous report (Sugiura et ~ ! 989). Sera were collected from both the patients and the volunteers, and were frozen untU the subsequent assay. Aliquots of the same sera were absorbed with rabbit liver acetone powder (100 mg/ml serum) at 4°C for 16 hr. Rabbit cerebrums were o b ~ n e d from male New Zealand white rabbits. Diluted sera ( × 10--80) of both the patients and the c6n~ols were investigated. Aliquots of serum (25 lzl), with or without absorption with ~bbit liver acetone powder, were added to the cryostat sections on slides and kept for 30 ~ at room temperature in a humidified chamber. They were then washed twice with PBS (pH 7.4). Twenty-five microliters of FITC-labeled antihuman IgG solution ( x 10) was then added to the sections. The slides were kept for 30 rain at room temperature. Washed twice with PBS (pH 7.4), the sections were examined under an incident-fluorescence microscoFe (Olympus BHT-RFK) by one of us (K.Y.) who was blind to the diagnoses.
Results Four types of staining pattern were found: type A which is supposed to represent staining of the nerve cells (Figure la); type B blood vessels (lb); type C nuclei (Ic); type D glial cells (ld). Table 1 shows the frequencies of each type in both patients and controls; nearly a third of the sera of schizophrenic patients showed the type A staining pattern. Although the frequency of the type A slightly decreased after absorption, 27.3% of the sera remained to show this pattern. In the schizophrenic patients, other types were also found in some sera, but they could not be detected after absorption. Though types A,B,C, and D were found in a small percentage of depressed patients, all the staining patterns except for the type A of 1 patient were complelely absorbed by liver acetone powder. Though only type B was detected in 3.7% of controls, no sera showed any staining pattern after absorption. The frequencies of type A patterns were not different between those patients who had received medication (n = 25) and those who had not (n = 19). No significant difference
BIOL PSYCHIATRY 1991;29:322-328
324
Shima et al
(a)
(b) Figure la and Ib
of the mean age of schizophrenics was found betwt~en type A positive and type A negative patterns.
Discussion Several previous studies have indicated abnormalities of the immune system in at least some schizophrenics and depressives. In the present study, an additional finding was obtained, which is consistent with such immunological abnormalities.
Anticerebral Antibodies
slot. PS¥CHIA~V
3~
1991~'9:322-328
(c)
(d) Figure lc and ld
Although the fluorescent antibodies technique is long las~.~ng and seems somewhat primitive, it is powerful and easy to handle. The assay has the advantage of being able to distinguish several patterns and to detect more specific findings in comparison with other assays using homogenates of brain tissues. Our assay with rabbit brain has another advantage: animal brain is more desirable than human brain on ethical grounds and it is obtainable at death without postmortem changes. As often mentioned, most of the previous biological studies before the 1970s lacked diagnostic reliability. In the present study, DSM-III-R was used for diagnosis.
326
BIOL PSYCHIATRY 1991 ;29:32?,-328
Shima et
al
Table 1. Frequencies of Each Staining Pattern in Patients and Controls Schizophrenia(n = 44)
Type A Type B Type C Type D
Preab.
Postab.
34.1% 15.9 2.3 15.9
27.3% 0 0 0
Del~-ssion (n = 52) Preab. 3.8% 3.8 1.9 3.8
Postab. i.9~ 0 0 0
Controls (n = 54) Preab. O~ 3.7 0 0
Postab. 0~ 0 0 0
Preab.: preabsorption; Postab.: postabsorption.
In interpreting the finding that the anticerebral antibodies were detected in nearly a third of schizophrenics, several issues must be considered. First, we believe our methodology is sound: interrater and interassay reliability were both found to be high, whereas sera were assayed blindly. Second, some psychotropic drugs are known to alter the immune system. However, the frequencies of type A pattern were not different between those schizophrenics who had received medication and those who had not. We therefore considered it plausible that medication could play little, if any, role in the present result. Third, it is well known that autoantibodies are sometimes found in the elderly, but there was no significant difference between the mean age of schizophrenics with type A patterns and that of schizophrenics without. Age was not thought to be a confounding factor. Among the anticerebral antibodies, type A, (i.e., a~:~inervecell antibody) seems to be specific, as all other staining patterns were completely abserbed by liver acetone powder. As the presence of type A could discriminate between schizophrenics and controls or depressives, the pattern seems to be a unique and moderately sensitive marker for schizophrenia. However, the underlying pathophysiology that produces the antibodies to rabbit brain is unknown; the phenomenon observed in this study may be considered to occur at some point in the process from pathogenesis to the final common pathway. We have recently reported that anticezebral antibodies were found in some patients with Alzheimer's disease as well as those with schizophrenia (Sugiura et al 1989). Though we cannot give any definite explanation for this, the pathophysiology relevant to anticerebral antibodies may be different in schizophrenia and Alzheimer's disease. Essentially the ages of onset are quite different: Alzheimer's disease is usually involutional, whereas that of schizophrenia is typically at puberty. Though the final pathway of the production of anticerebral antibodies (which may be regarded to reflect 'destruction' of cerebral tissues) seems to be shared by both diseases, the underlying process may be different. Identification of the mechanism involved in this phenomenon might throw new light on the pathophysiology, etiok,gy, or even a more effective treatment strategy for schizophrenia. Other immunological markers along with anticerebral antibodies will reveal these differences. We hope that further research can clarify these important issues. We thank Profs. H. Hosaki, T. NaK~zawa,and Y. Kato, and Drs. S. Takase, T. Kitamura,S. Inada, and S. Kanbafor commenton the manuscript.
References Alarcon-Segovia D, Fishbein E, Cetina JA, et al (1973): Antigenic specificity of chlorpromazineinduced antinuclear antibodies. Clin Exp Immunol 15:543-548. Albrecht J, Helderman JH, Schlesser MA, et al (1985): A controlled study of cellular immune function in affective disorders before and during somatic therapy. Psychiatry Res 15:185-193.
Anticerebral Antibodies
BIOl.. I ~ Y ~ T R Y 1991;~:322-328
327
American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental D~orders, 3rd ed rev. Washington, DC: American Psychiatric Press. Amkraut A, Solomon GF, Allansmith M, et al (1973): Immunoglobulins and improvement in acute schizophrenic reactions. Arch Gen Psychiatry 28:673-677. Baron M, Stern M, Anavi R, et al (1977): Tissue-binding factor in schizophrenic ~ A cF"mic~~ and genetic study. Biol Psychiatry 12:199-219. Berglund S, GottfTies CG, Gotffries 1, et alf 1970): Chlorpromazine-induced antinuclear factors. Acta Med Scand 187:67-74. Bock E, Weeke B, Rafaelsen OJ (1970): Immunoglob,~lins in schizophrenic patients. Lancet 2:523. Calabresc JR, Skwerer RG, Bama B, et al (1986): Depression, immunocompetence and prostaglandins of the E series. Psychiatry Res 17:41-47. Coffee CE, Sullivan JL, Rice JR (1983): T lymphocytes in schizophrenia. Biol Psychiatry 18:113119. Crow TJ (1987): Integrated viral genes as potential pathogens in the functional psychoses. J Psychiatry Res 21:479-485. L~.Lisi LE, Weinberger DR, Potkin S, et al (1981): Quantitative determination of immunoglobulins in CSF and plasma of chronic schizophrenic patients. Br J Psychiatry 139:513-518. DeLisi LE, Goodman S, Neckers LM, et al (1982): An analysis of lymphocyte subpopulations in schizophrenic patients. Biol Psychiatry 17:1003-1009. DeLisi LE, Ortaldo JR, Maluish AE, et al (1983): Deficient natural killer cell (NK) activity and macrophage functioning in schizophrenic patients. J Neural Transm 58:99-106. Delisi LE, Weber RJ, Pert CB (1985): Arc there antibodies against brain in sera from schizophrenic patient? Review and prospectus. Biol Psychiatry 20:110-115. Evans DL, Pedersen CA, Folds JD (1988): Major depression and immunity: Preliminary evidence of decreased natural killer cell populations. Prog Neuropsychopha~ol Biol Psychiatry 12:739748. Gottfl'ies CG, Gottfries I (1974): Antinuclear factors in relation to age, sex, mental disease and treatment with phenothiazines. Acta Psychiatry Scand [Suppl] 255:193-201. Heath RG, Krupp IM (1967): Schizophrenia as an immunologic disorder. Arch Gen Psychiatry 16:1-9. Johnstone EC, Whaley K (1975): Antinuclear antibodies in psychiatric illness: Their relationship to diagnosis and drug treatment. Br Med J ii:724-725. Pandey RS, Gupta AK, Chaturvedi UC (1981): Autoimmune model of schizophrenia with special reference to antibrain antibodies. Biol Psychiatry 16:1123-1136. ~esley . ~ , ,,,-,,,ttoh'~A, ~mi,, ,,,,,,,,~,,,, . . . . . N ~1~1o-7~..,, ,,,. ,~,~,,,,.~,.~A ,,; .... ~'~" antibodies in patients oa li*~hiumca,-bonat¢. Br Med J ii:280--281. Quismorio FP, Bjarnason DF, Kiely WF, et al (1975): Antinuclear antibodies in chronic psychotic patients treated with chlorpromazine. Am J Psychiatry 132:1204-1206. Schleifer SJ, Keller SE, Meyerson AT, et al (1984): Lymphocyte function in major depressive disorder. Arch Gen Psychiatry 41:484-486. Schleifer SJ, Keller SE, Siris SG, et al (1985). Depression and immunity: Lymphocyte functions in ambulatory depressed patients, hospitalized schizophrenic patients, and patients hospitalizezl for herniorrhaphy. Arch Gen Psychiatry 42:129-133. Solomon GF, Allaasmith M, McClellan B, et al (1969): Immunoglobulins in psychiatric patients. Arch Gen Psychiatry 20:272-277. Strahilevitz M, Fleischman JB, Fischer GW, et al (1976): lmmunoglobulin levels in psychiatric patients. Am J Psychiatry 133:772-777. Sugiura M, Yokoi Y, Maruyama S, et al (1989): Detection of anti-cerebral autoantibodies in schizophrenia and Alzheimer's disease. J Clin Lab lmmunol 28:1-3. Vartanian ME, Kolyaskina GI, Lozovsky DV, et al (1978): Aspects of humoral and cellular
328
BiOL PSYCHIATRY
1991:29:322-328
Shima et al
immunity in schizophrenia. In Bergsma D, Goldstein AL (eds), Neurochemical and Immunologwal Components ofSchizophrpnia, Vol. 18. New York: Alan R. Liss, 339-364. yon Brauchitsch H (1972): Antinuclear factor in psychiatric disorders. Am J Psychiatry 128: :5:~21554. Whalley LJ, Roberts DF, Wentzel J, et al (1981): Antinuclear antibodies and histocompatibility antigens in patients on long-term lithium therapy. J Affective Disord 3:123-130. Whittingham S, Mackay IR, Jones IH, et al (1968): Ab~nce of brain antibodies in patients with schizophrenia. Br Med J i:347-348+ Zarrabi MH. Zucker S. Miller F, et al (1979)" Immunotogic and coagulation disorders in chlorpromazine-treated patients. Ann Intern Med 91: i94--199.
BIOL PSYCHIATRY 1991;29:322-328
Anticerebral Antibodies in Functional Psychoses Satoru Shima, Kazuhide Yano, Masahiko Sugiura, Yukiko Tokunaga
Anticerebral antibodies to rabbit brain were investigated by the indirect immunofluorescence method in the sera of 44 schizophrenics and 52 depressives diagnosed according to DSM-III-R, and of 54 healthy volunteers. Four types of staining pattern were observed: type A (nerve cells), type B (blood vessels), type C (nuclei), and type D (glial cells); 34.1% of schizophrenics (27.3% after the absorption with rabbit liver acetone powder) showed type A, as compared with 3.8% (1.9% after the absorption) of depressives and with none of the controls.
Introduction Recent advances in the field of psychoimmunology have revealed several kinds of abm~rmalities in functional psychoses. Natural killer-cell activity, which is important in the defense against viruses implicated as potential pathogens of the functional psychoses (Crow 1987), is reported to be low in schizophrenia (DeLisi et al 1983) and in depression (Evans et al 1988). With regard to lymphocyte subpopulations, elevated percentages of B cells and decreased percentages of T cells or suppressor T cells were reported in schizophrenics by some, but not all investigators (Vartanian et al !978; Zarrabi et al 1979; DeLisi et al 1982; Coffee et al 1983). Some studies have demonstrated deficient cellular immunity, such as decreased responses to pokeweed mitogen (PWM), phytohemagglutinin (PHA), or concanavalin A (Con A) in depressed parents (Schleifer et al 1984; Calabrese et al 1986), although others failed to find any such impairment (Schleifer et al 1985; Albrecht et al 1985). Several studies have reported generalized increases of immunoglobulin in schizophrenia (Solomon et al 1969; Amkraut et al 1973; Strahilevitz et al 1976), though others have shown generalized decreases (Bock et al 1970; DeLisi et al 1981). Autoantibodies have also been investigated in the functional psychoses: a number of studies showed increased antinuclear antibody titers in depressives (von Brauchitsch 1972; Johnstone and Whaley 1975; Presley et al 1976; Whalley et al 1981) as well as in schizophrenia (Berglund et al 1970; Alarcon-Segovia et al 1973; Gottfries and Gottfries 1974; Quismorio et al 1975), although drug treatment may be responsible for the excess of antinuclear antibodies. Though Heath and Krupp (1967) demonstrated the presence of an antibody in schizophrenic brain in sera of 12 of 14 schizophrenics using
From the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (SS), Biomedical Laboratories, Kawagoe-shi (KY, MS), and the Department of Pharmacology, School of Medicine, Keio University (YT), Tokyo, Japan. Address reprint requests to Dr. Satoru Shima, Department of Neuropsychialry, School of Medicine, Keio University, 35 Shinanolmachi, Shinjuku-Ku, Tokyo 160, Japan. Received November 1, 1989, revised July 23, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
Anticerebral Antibodies
alOL PsYcmATRV 1991;29:322-328
323
the fluorescent antibody staining method, Whittingham et al (1968) failed to confirm K s observation. By a hemagglutination technique, Pandey et al (1981) demonstrated antibrain antibody in 48.1% of 54 schizophrenic patients, particularly those with a past history or family history of the disorder. Baron et al (1977), using radioimmtmofixation assay, found a higher incidence of antibrain antibodies in schizophrenics as compared with r ~ controls. Employing radioimmunochemical assay, Delisi et al (1985) found that antibrain antibodies are nonspecific and were only present among a small percentage of patients in their study. We have recently developed a new assay to detect anticerebral antibodies by the indirect imnmnofluorescence method and reported that anticerebral antibodies were found in some patients suffering from Alzheimer's disease as well as those with schizophrenia (Sugiura et al 1989). The current study reports the ability of this method to discriminate functional psychoses.
Methods The patient group consisted of 44 schizophrenics (18 men and 26 women, aged 19-67, mean age 36.4 years) and 52 depressives (21 men and 31 women, aged 19-71, mean age 47.0 years) diagnosed according to DSM-III-R criteria (Aalaerican Psychia~c Association 1987). Fifty-four healthy volunteers_ were recruited as control subjects: 38 men and 16 women, aged 21-69, mean age 34.5 years. All the patients and the volunteers gave informed consent. In the present study, completely different samples were investigated than from a previous report (Sugiura et ~ ! 989). Sera were collected from both the patients and the volunteers, and were frozen untU the subsequent assay. Aliquots of the same sera were absorbed with rabbit liver acetone powder (100 mg/ml serum) at 4°C for 16 hr. Rabbit cerebrums were o b ~ n e d from male New Zealand white rabbits. Diluted sera ( × 10--80) of both the patients and the c6n~ols were investigated. Aliquots of serum (25 lzl), with or without absorption with ~bbit liver acetone powder, were added to the cryostat sections on slides and kept for 30 ~ at room temperature in a humidified chamber. They were then washed twice with PBS (pH 7.4). Twenty-five microliters of FITC-labeled antihuman IgG solution ( x 10) was then added to the sections. The slides were kept for 30 rain at room temperature. Washed twice with PBS (pH 7.4), the sections were examined under an incident-fluorescence microscoFe (Olympus BHT-RFK) by one of us (K.Y.) who was blind to the diagnoses.
Results Four types of staining pattern were found: type A which is supposed to represent staining of the nerve cells (Figure la); type B blood vessels (lb); type C nuclei (Ic); type D glial cells (ld). Table 1 shows the frequencies of each type in both patients and controls; nearly a third of the sera of schizophrenic patients showed the type A staining pattern. Although the frequency of the type A slightly decreased after absorption, 27.3% of the sera remained to show this pattern. In the schizophrenic patients, other types were also found in some sera, but they could not be detected after absorption. Though types A,B,C, and D were found in a small percentage of depressed patients, all the staining patterns except for the type A of 1 patient were complelely absorbed by liver acetone powder. Though only type B was detected in 3.7% of controls, no sera showed any staining pattern after absorption. The frequencies of type A patterns were not different between those patients who had received medication (n = 25) and those who had not (n = 19). No significant difference
BIOL PSYCHIATRY 1991;29:322-328
324
Shima et al
(a)
(b) Figure la and Ib
of the mean age of schizophrenics was found betwt~en type A positive and type A negative patterns.
Discussion Several previous studies have indicated abnormalities of the immune system in at least some schizophrenics and depressives. In the present study, an additional finding was obtained, which is consistent with such immunological abnormalities.
Anticerebral Antibodies
slot. PS¥CHIA~V
3~
1991~'9:322-328
(c)
(d) Figure lc and ld
Although the fluorescent antibodies technique is long las~.~ng and seems somewhat primitive, it is powerful and easy to handle. The assay has the advantage of being able to distinguish several patterns and to detect more specific findings in comparison with other assays using homogenates of brain tissues. Our assay with rabbit brain has another advantage: animal brain is more desirable than human brain on ethical grounds and it is obtainable at death without postmortem changes. As often mentioned, most of the previous biological studies before the 1970s lacked diagnostic reliability. In the present study, DSM-III-R was used for diagnosis.
326
BIOL PSYCHIATRY 1991 ;29:32?,-328
Shima et
al
Table 1. Frequencies of Each Staining Pattern in Patients and Controls Schizophrenia(n = 44)
Type A Type B Type C Type D
Preab.
Postab.
34.1% 15.9 2.3 15.9
27.3% 0 0 0
Del~-ssion (n = 52) Preab. 3.8% 3.8 1.9 3.8
Postab. i.9~ 0 0 0
Controls (n = 54) Preab. O~ 3.7 0 0
Postab. 0~ 0 0 0
Preab.: preabsorption; Postab.: postabsorption.
In interpreting the finding that the anticerebral antibodies were detected in nearly a third of schizophrenics, several issues must be considered. First, we believe our methodology is sound: interrater and interassay reliability were both found to be high, whereas sera were assayed blindly. Second, some psychotropic drugs are known to alter the immune system. However, the frequencies of type A pattern were not different between those schizophrenics who had received medication and those who had not. We therefore considered it plausible that medication could play little, if any, role in the present result. Third, it is well known that autoantibodies are sometimes found in the elderly, but there was no significant difference between the mean age of schizophrenics with type A patterns and that of schizophrenics without. Age was not thought to be a confounding factor. Among the anticerebral antibodies, type A, (i.e., a~:~inervecell antibody) seems to be specific, as all other staining patterns were completely abserbed by liver acetone powder. As the presence of type A could discriminate between schizophrenics and controls or depressives, the pattern seems to be a unique and moderately sensitive marker for schizophrenia. However, the underlying pathophysiology that produces the antibodies to rabbit brain is unknown; the phenomenon observed in this study may be considered to occur at some point in the process from pathogenesis to the final common pathway. We have recently reported that anticezebral antibodies were found in some patients with Alzheimer's disease as well as those with schizophrenia (Sugiura et al 1989). Though we cannot give any definite explanation for this, the pathophysiology relevant to anticerebral antibodies may be different in schizophrenia and Alzheimer's disease. Essentially the ages of onset are quite different: Alzheimer's disease is usually involutional, whereas that of schizophrenia is typically at puberty. Though the final pathway of the production of anticerebral antibodies (which may be regarded to reflect 'destruction' of cerebral tissues) seems to be shared by both diseases, the underlying process may be different. Identification of the mechanism involved in this phenomenon might throw new light on the pathophysiology, etiok,gy, or even a more effective treatment strategy for schizophrenia. Other immunological markers along with anticerebral antibodies will reveal these differences. We hope that further research can clarify these important issues. We thank Profs. H. Hosaki, T. NaK~zawa,and Y. Kato, and Drs. S. Takase, T. Kitamura,S. Inada, and S. Kanbafor commenton the manuscript.
References Alarcon-Segovia D, Fishbein E, Cetina JA, et al (1973): Antigenic specificity of chlorpromazineinduced antinuclear antibodies. Clin Exp Immunol 15:543-548. Albrecht J, Helderman JH, Schlesser MA, et al (1985): A controlled study of cellular immune function in affective disorders before and during somatic therapy. Psychiatry Res 15:185-193.
Anticerebral Antibodies
BIOl.. I ~ Y ~ T R Y 1991;~:322-328
327
American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental D~orders, 3rd ed rev. Washington, DC: American Psychiatric Press. Amkraut A, Solomon GF, Allansmith M, et al (1973): Immunoglobulins and improvement in acute schizophrenic reactions. Arch Gen Psychiatry 28:673-677. Baron M, Stern M, Anavi R, et al (1977): Tissue-binding factor in schizophrenic ~ A cF"mic~~ and genetic study. Biol Psychiatry 12:199-219. Berglund S, GottfTies CG, Gotffries 1, et alf 1970): Chlorpromazine-induced antinuclear factors. Acta Med Scand 187:67-74. Bock E, Weeke B, Rafaelsen OJ (1970): Immunoglob,~lins in schizophrenic patients. Lancet 2:523. Calabresc JR, Skwerer RG, Bama B, et al (1986): Depression, immunocompetence and prostaglandins of the E series. Psychiatry Res 17:41-47. Coffee CE, Sullivan JL, Rice JR (1983): T lymphocytes in schizophrenia. Biol Psychiatry 18:113119. Crow TJ (1987): Integrated viral genes as potential pathogens in the functional psychoses. J Psychiatry Res 21:479-485. L~.Lisi LE, Weinberger DR, Potkin S, et al (1981): Quantitative determination of immunoglobulins in CSF and plasma of chronic schizophrenic patients. Br J Psychiatry 139:513-518. DeLisi LE, Goodman S, Neckers LM, et al (1982): An analysis of lymphocyte subpopulations in schizophrenic patients. Biol Psychiatry 17:1003-1009. DeLisi LE, Ortaldo JR, Maluish AE, et al (1983): Deficient natural killer cell (NK) activity and macrophage functioning in schizophrenic patients. J Neural Transm 58:99-106. Delisi LE, Weber RJ, Pert CB (1985): Arc there antibodies against brain in sera from schizophrenic patient? Review and prospectus. Biol Psychiatry 20:110-115. Evans DL, Pedersen CA, Folds JD (1988): Major depression and immunity: Preliminary evidence of decreased natural killer cell populations. Prog Neuropsychopha~ol Biol Psychiatry 12:739748. Gottfl'ies CG, Gottfries I (1974): Antinuclear factors in relation to age, sex, mental disease and treatment with phenothiazines. Acta Psychiatry Scand [Suppl] 255:193-201. Heath RG, Krupp IM (1967): Schizophrenia as an immunologic disorder. Arch Gen Psychiatry 16:1-9. Johnstone EC, Whaley K (1975): Antinuclear antibodies in psychiatric illness: Their relationship to diagnosis and drug treatment. Br Med J ii:724-725. Pandey RS, Gupta AK, Chaturvedi UC (1981): Autoimmune model of schizophrenia with special reference to antibrain antibodies. Biol Psychiatry 16:1123-1136. ~esley . ~ , ,,,-,,,ttoh'~A, ~mi,, ,,,,,,,,~,,,, . . . . . N ~1~1o-7~..,, ,,,. ,~,~,,,,.~,.~A ,,; .... ~'~" antibodies in patients oa li*~hiumca,-bonat¢. Br Med J ii:280--281. Quismorio FP, Bjarnason DF, Kiely WF, et al (1975): Antinuclear antibodies in chronic psychotic patients treated with chlorpromazine. Am J Psychiatry 132:1204-1206. Schleifer SJ, Keller SE, Meyerson AT, et al (1984): Lymphocyte function in major depressive disorder. Arch Gen Psychiatry 41:484-486. Schleifer SJ, Keller SE, Siris SG, et al (1985). Depression and immunity: Lymphocyte functions in ambulatory depressed patients, hospitalized schizophrenic patients, and patients hospitalizezl for herniorrhaphy. Arch Gen Psychiatry 42:129-133. Solomon GF, Allaasmith M, McClellan B, et al (1969): Immunoglobulins in psychiatric patients. Arch Gen Psychiatry 20:272-277. Strahilevitz M, Fleischman JB, Fischer GW, et al (1976): lmmunoglobulin levels in psychiatric patients. Am J Psychiatry 133:772-777. Sugiura M, Yokoi Y, Maruyama S, et al (1989): Detection of anti-cerebral autoantibodies in schizophrenia and Alzheimer's disease. J Clin Lab lmmunol 28:1-3. Vartanian ME, Kolyaskina GI, Lozovsky DV, et al (1978): Aspects of humoral and cellular
328
BiOL PSYCHIATRY
1991:29:322-328
Shima et al
immunity in schizophrenia. In Bergsma D, Goldstein AL (eds), Neurochemical and Immunologwal Components ofSchizophrpnia, Vol. 18. New York: Alan R. Liss, 339-364. yon Brauchitsch H (1972): Antinuclear factor in psychiatric disorders. Am J Psychiatry 128: :5:~21554. Whalley LJ, Roberts DF, Wentzel J, et al (1981): Antinuclear antibodies and histocompatibility antigens in patients on long-term lithium therapy. J Affective Disord 3:123-130. Whittingham S, Mackay IR, Jones IH, et al (1968): Ab~nce of brain antibodies in patients with schizophrenia. Br Med J i:347-348+ Zarrabi MH. Zucker S. Miller F, et al (1979)" Immunotogic and coagulation disorders in chlorpromazine-treated patients. Ann Intern Med 91: i94--199.