International Journal of Neuroscience
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Differential Appearance of Autoantibodies to Human Brain S100 Protein, Neuron Specific Enolase and Myelin Basic Protein in Psychiatric Patients Branislav D. Janković & Dragan Djordjijević To cite this article: Branislav D. Janković & Dragan Djordjijević (1991) Differential Appearance of Autoantibodies to Human Brain S100 Protein, Neuron Specific Enolase and Myelin Basic Protein in Psychiatric Patients, International Journal of Neuroscience, 60:1, 119-127, DOI: 10.3109/00207459109082042 To link to this article: http://dx.doi.org/10.3109/00207459109082042
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Intern. . I . Neuroscience, 1991.
Vol. 60,
Q 1991 Gordon and Breach. Scicna Publishen SA. Printed in the United Kingdom
119-127
Reprints available d i d y from the pu%%her Photocopying permitted by licenrc only
DIFFERENTIAL APPEARANCE OF AUTOANTIBODIES TO HUMAN BRAIN SlOO PROTEIN, NEURON SPECIFIC ENOLASE AND MYELIN BASIC PROTEIN IN PSYCHIATRIC PATIENTS BRANISLAV D. JANKOVIC and DRAGAN DJORDJIJEVIe Immunology Research Center, Vojvode Stepe 458, I1221 Belgrade, Yugoslavia
International Journal of Neuroscience 1991.60:119-127.
(Received June 14. 1990; infinal form October 22. 1990) Sera from psychiatric patients (32 with senile dementia,56 with Alzheimer’s , -d 189 with schizophrenia, 117 with manic-depressive psychoses, 52 with other nonorganic psychoses, 44 with paranoid state, 58
with neurotic depression and 78 with alcoholic syndrome), normal subjects (1 12 blood donors) and 43 hospitalized elderly patients with chroniccardiac failwes without Jcnik syndromewere examined by means of an mzyme-linked immunosorbent assay (ELISA) for the presence of autoantibodies to human brain Sl00 protein, neuron specific enolase (NSE) and myelin basic protein (MBP). These varied antibrain autoantibodiesoccurred at different frequencies.The highest incidence of anti4100 and anti-NSE antibodies was in Alzheimer’s diseasc and senile dementia, tlyn in manic-depressive and other nonorganic psychoses, and the lowest in paranoid state, neurotic depression. schizophrenia and alcoholic syndrome. The frequency ofanti-900 autoantibodies was higher than that ofanti-NSE. Autoantibodies reacting with MBP were rcvcaled in a very small number of psychiatric patients. In healthy individuals and control cardiac patients, the incidence of antibrain autoantibodies was low. These results suggest a differential cornlation between antibrain autoantibodies and psychiatric diseases. Keyworth: antibrain autoanribody;S-IW protein; neuron specific enolase; myelin basic protein; Alzheimer i dementia; immunopsychiatry
Autoimmune mechanisms have been implicated in the pathogenesis of neuropsychiatric diseases (Fessel, 1962). The immense antigenic potentiality of the brain rely upon a wide range of macromolecules and their interplay inside and outside the neuron-glia complexes. In general, these antigens, under the influenceof endogenousand exogenous factors, change their structure and become autoantigens (or modified antigens) which then trigger autoimmune processes leading to autoimmune diseases (JankoviC, 1985b). One of the outstanding features of autoimmune response is the increased incidence and production of autoantibodies whicb by virtue of their specificity bind Address reprint requests to Branislav D. Jankovik, Immunology Research Center, Vojvode Stepc 458, 11221 Belgrade. Yugoslavia. Abbreviations: ELISA. enzyme-linked immunosorbent assay; NSE, neuron Specific e n o h , MBP, myelin basic protein; ICD,international classification of dipeascs; HIV, human immunodeficiency vim; OPD, Gphenylencdiamine dihydrochloride; PBST, phosphate-butTd saline containing Tween 20. We appreciate the generous donation of human brain myelin basic protein by Dr. George A. Hashim, St. Luke/RooseveltHospital, New York, and human brain SloO protein and neuron e f i c enolase by Dr. Joief Horvat, Immunology Research Center, Belgrade. We would like to acknowledg and thank our colleagues of the F’sychiatric Hospital “Lam K. LazamiC,” Belgrade; Department of Neuropsychiatry, Belgrade City Hospital; Department of Neurology, Faculty of Medicine, University of Belgrade; and Psychiatric Hospital, PopovaEa, for +eir continuous support and valuable assiStanain clinical management and records. %s work was supported by the Republic of Serbia Research Fund, Belgrade. 119
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in vivo to neuronal antigens and thus may cause changes at receptor, membrane, intraneuronal and neurosecretion levels. Hence, antibrain autoantibodies are potentially neuromodulating molecules (JankoviC, 1972, 1985a, Rapport, Karpiak & Mohadial, 1979). However, in spite of increasing data, often controversial, the functioning and pathology of antibrain autoantibodies in patients suffering from mental disorders is still poorly understood. This report deals with the incidence and distribution of autoantibodies against well-defined human brain antigens, S100 protein, neuron specific enolase (NSE)and myelin basic protein (MBP) in psychiatric patients, nonpsychiatric patients and normal subjects.
METHODS
International Journal of Neuroscience 1991.60:119-127.
Patients
According to clinical diagnosis, a total of 626 hospitalized psychiatric patients were divided into eight groups: senile dementia (ICD code 290.0), Alzheimer’s disease (ICD code 290. l), schizophrenia (ICD codes 296.0 and 296. I), paranoid state (ICD code 297. I), other nonorganic psychoses (ICD codes 298.0 and 298. I), neurotic depression (ICD code 300.4), and alcoholic syndrome (ICD code 303.0). Patients were without medication for at least 12 days before blood samples were taken. None of the patients suffered from acute or chronic inflammatory disease, and immunological disorders. The control group was composed of 112 healthy blood donors. An additional group of “control patients” suffering from chronic cardiopathy of noninflammatory origin and without senile syndrome volunteered for this study, and served as age-matched control for patients with senile dementia. All subjects used in this study were HIVnegative. Numerical data for each group are shown in Table 1. Brain An tigens
SlOO protein (Moore, 1965), neuron specific enolase (NSE, Marangos, Zis, Clark & Goodwin, 1978) and myelin basic protein (MBP) were isolated from human brain. Chemicals
For detection of antibrain autoantibodies, the following chemicals (Sigma, Heidelberg) were used: Tween 20, bovine serum albumin essentially fatty-acid free and globulin free, o-phenylenediaminedihydrochloride (OPD), and goat antihuman IgG (gammachain specific) peroxydase conjugate. Enzyme-Linked Immunosorbent Assay (ELISA)
Sera from patients and healthy controls were separated, inactivated at 56OC for 30 min, and stored at - 7OoC until use. The wash solution consisted of phosphatebuffered saline (PBST) containing 0.05% of Tween 20, pH 7.2. The flat-bottorned polystyrene microtiter plate (”C, Denmark) was coated with 100pl/well of a 20pg/ml solution of SlOO protein, NSE or MBP in 0.05 M bicarbonate buffer, pH 9.2, And incubated overnight at 4°C. The plate was then washed three times for 3 min in PBST and tapped on absorbent paper. Serum samples from patients and healthy individualswere diluted 1 :200 in PBST, and 100pl of the dilution were added to wells
ANTIBRAIN AUTOANTIEORIES IN PSYCHIATRIC DISEASES
121
TABLE I Sex and age of patients and control subjects
Sex
International Journal of Neuroscience 1991.60:119-127.
Group
n
Female
Male
Senile dementia
32
19
13
Alzheimer's disease
56
26
30
Schizophrenia
I89
69
120
Manic-depressivepsychoses
I I7
41
76
Paranoid state
44
17
27
Other nonorganic psychoses
52
24
28
Neurotic depression
58
33
25
Alcoholic syndrome
78
14
64
Control subjects
112
45
67
Control patients'
43
25
18
Average age (yean) 75.5 (65-86) 47.8 (39-55) 38.8 (24-52) 42.5 (22-53) 47.3 (39-56) 52.7 (47-68) 50.6 (37-66) 44.6 (38-52) 38.2 (28-45) 74.2
(66-84)
In parentheses, range. 'Control patients (suffering from chronic cardiopathy with no senile syndrome) for the senile dementia group.
in triplicate, and incubated at room temperature for 90 min. Thereafter, the plate was washed 5 times for l5min with PBST in Titertek Multiwasher, and 100pl/well of a 1 : 1000 dilution of peroxydaseconjugated antihuman IgG in PBST were added before incubation for 60min at room temperature. After incubation, the plate was washed as described above, and lOOpl/well of freshly prepared substrate solution added (substrate solution: 0.4mg/ml of OPD and 0.01% of H,02in 0.15 M citratephosphate buffer, pH 5.0), and the plate reincubated for 40 min in the dark at room temperature. The enzyme-reaction was stopped by means of 50pl/well of a 4 N HzSOI, and absorbance was read at 492nm using a Titertek Multiscan MCC photometer. A test serum was considered positive when the mean value of the optical density minus one standard deviation was higher than the mean value of the optical density of the negative control serum plus three standard deviations. The reader of ELISA did not have access to clinical diagnosis of patients. Statistical Method
Student's t test was employed. The level of statistical significance was set at p
< .05.
RESULTS
Sera from psychiatric patients, cardiac patients and control individuals were screened for autoantibodies to human brain Sl00 protein, NSE and MBP, and the results are
B. D. JANKOVIC A N D D.DJORDJUEVIC
122
TABLE 11 Autoantibodics to human brain SlOO protein in psychiatric patients
. Anti-S100 autoantibodies Patients
ICD code
n
with antibody
ELISA titee (m- f SD)
Alzheimct's disease senik dementia Manic-dep&ve psychoses Other nonorganic psychoses Alcoholic syndrome Paranoid states Schizophrenia Neurotic depression Hcalthy subjects Control patients'
290.1 290.0 296.0-296.1 298.0-298.1 303.0 297.1 295.0-295.2 300.4
32 56 1 I7 52 78 44 189 58 I12 43
50.0 (16) 39.3 (22) 28.2 (33) 26.9 (14) 15.4 (12) 13.4 (6) 12.7 (24) 10.3 (6) 2.7 (3) 6.9 (1)
20 f 5 21 f 4 17 f 5 19 f 6 17 f 5 14 f 2 17 f 7 15 f 3 6 f I 7*1
International Journal of Neuroscience 1991.60:119-127.
Ye of patients
In parentheses, number of subjects with autoantibodies 'Mean of positive sera. Optical density at wavelength of 492nm x I d bControl patients for the scnik dementia group.
presented in Tables I1 and 111. The data are lined up according to the number of positive sera in different groups of subjects. The highest frequency of autoantibodies to SlOO and NSE was in patients suffering from Alzheimer's disease and senile dementia, and somewhat lower in patients with manicdepressive psychoses. The incidence of anti-S100 and anti-NSE autoantibodies was rather low in patients with paranoid state, neurotic depression, schizophrenia and alcoholic syndrome. ELISA optical density values, designatingantibody titers, of SL 100-positive and NSE-positive sera were similar. Contrary to these findings, in control patients and healthy individuals autoantibodies to SlOO and NSE were detected in a small number of sera, and ELISA titers were much lower in comparison to those found in patients. .
TABLE 111 Autoantibodies to human brain neuron specific cnolase (NSE) in psychiatric patients
Anti-NSEautoantibodies Patients
ICD code
n
% of patients with antibody
ELISA tit& (mf SD)
Alzheimer's disease Senile dementia Other nonorganic psychoses Manic-depressive psychoses Neurotic depression Schizophrenia Paranoid states Alcoholic syndrome Healthy subjects Control patientsb
290. I 290.0 298.0-298.1 296.0-296.1 300.4 295.0-295.2 297.1 303.0
32 56 52 117 58 189 44 78 112 43
3 7 3 12) 25.0(14) 23.I ( 12) 1 5 4 18) 10.3(6) 6.3(12) 4.5(2) 343) 1.8(2) 4.W)
Z f 3 21 f 5 21 f 5 18 f 1 21 f 1 19 f 1 19 f 1 24 f I 6 f 1 6 f 1
In parentheses. number of subjects with autoantibodies. *Mean of positive sera. Optical density at wavelength of 492 nm x Id. bControl patients for the senile dementia group.
ANTIBRAIN AUTOANTIBODIES IN PSYCHIATRIC DISEASES
123
TABLE IV Autoantibodies to human brain SlOO protein, neuron specific enolase (NSE)and myelin basic protein (MBP) in psychiatric paticots (an overview)
YOof sera with antibodies to ~
Group
n
SlOO
NSE
MBP
SlOO and NSE
Psychiatric patients
626
Healthy individuals
112
21.2 (133) 2.7 (3) 6.9 (3)
12.6 (79) 1.8 (2) 4.6 (2)
0.8 (5) 1.8
12.1 (76) 0 (0) 4.6 (2)
Control patients’
43
(2) 2.3 (1)
International Journal of Neuroscience 1991.60:119-127.
In parentheses, number of subjects with autoantibodies ‘Hospitalized elderly patients with chronic cardiopathy without senile syndrome.
In psychiatric patients, as shown in comparative Table IV, the overall incidence of anti-S100 autoantibodies exceeded that of anti-NSE autoantibodies, the antiS100:anti-NSE ratio being 1.8. More than half of seropositive patients contained autoantibodies both to Sl00 and NSE brain antigens. In contrast, anti-MBP autoantibodies were detected in a very small number of sera from psychiatric patients (0.8%), healthy subjects (1.8%), and control patients (2.3%). The incidence of antibrain autoantibodies in relation to the sex indicated that out of 217 autoantibody-positive psychiatric patients, 95 (43.8%) were females and 122 (56.2%) males. DISCUSSION The present results can be interpreted as evidence that antibrain autoantibodies are associated with certain psychiatric disease since the incidence of patients containing autoantibodies is obviously out of physiological range. The demonstration of a unique circulating IgG protein (“taraxein”) in schizophrenic patients and its in vivo antibrain activity (Heath & Krupp, 1967; Heath, Krupp, Byers & Liljkvist, 1967), stimulated the search for autoimmune features of schizophrenia. Several authors described antibrain autoantibodies in 28-95% of schizophrenics (Kolyaskina & Kushner, 1971-71; Baron, Stem, Anavi & Witz, 1977; Pandey, Gupta & Chaturvedi, 1981; Ganguli, Rabin, Kelly, Lyte & Ragu, 1987). In contrast, a number of investigators failed to detect increased production of autoantibodies to brain antigens in schizophrenic patients (Logan & Deodhar, 1970; k h m e , Cotrell, Dohen & Hillegass, 1974; Ehmst, Wiesel, Bjerkenstedt & Tribukait, 1982; Sudin 8r Thelander, 1989). Most probably, differences in methods and antigens used for the demonstration of antibrain autoantibodies accounted for this discrepancy. It should be mentioned here that a cell-mediated autoimmunecomponent, i.e., delayed hypersensitive skin reactions to human brain antigens have been described in schizophrenics and other psychiatric patients (JankoviC, JakuliC & Horvat, 1980; Vartanyan & Kolyaskina, 1987). Possible immune pathways in schizophrenia have been proposed (JankoviC, 1985b) on the basis of humoral and cellular autoimmune mechanisms, changes in dopaminergic system, and clinically identified positive and negative syndromes (Crow,1982). Besides schizophrenia, antibrain autoantibodies were found in a variety of neuropsychiatric disorders, such as multiple sclerosis, Down’s syndrome, Huntington’s
International Journal of Neuroscience 1991.60:119-127.
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B. D. JANKOVIC AND D. DJORDJIJEVIt
disease, idiopathic Parkinson’s disease (JankoviC & KuSiC, 1989), brain tumors, Alzheimer’s disease, senile dementia, brain atrophy, depression, mental retardation, alcoholic syndrome, and so forth, as well as in a number of nonneurological diseases, and normal adults and elderly individuals (JankoviC, 1985a; JankoviC, 1989). The present study shows that the incidence of antibrain autoantibodies is significantly higher in psychiatric patients than in normal subjects. The frequency of these antibodies was rather low even in hospitalized control elderly patients suffering from chronic cardiopathy but without senile syndrome. Of particular importance seems to be the differences among psychiatric diseases with respect to the presence of antibrain autoantibodies. Thus, the highest number of positive sera was observed in patients with Alzheimer’s disease and senile dementia, and the lowest in subjects suffering from alcoholic syndrome, paranoid state, schizophrenia and neurotic depression. In between are individuals with manic-depressive and other, nonorganic psychoses. Such a dichotomy of psychiatric diseases based on antibrain autoantibody presence implicates different involvement of autoantigens in the pathogenesis of certain psychiatric disorders. Thereby, the high incidence of anti-S100 and anti-NSE, and the low frequency of anti-MBP autoantibodies may indicate that SlOO and NSE antigens are much more related to autoimmune mechanisms than MBP antigen. It appears, therefore, that autoimmune processes in certain psychiatric disorders, and particularly in Alzheimer’s disease and senile dementia, are primarily concerned with brain structures in which SlOO and NSE are situated. The implication of brain antigens other than S100, NSE and MBP (Bock, 1982), in the autoimmune pathogenesis of neuropsychiatric diseases remains to be elucidated. Due to the extraordinary capacity of antibody molecules to distinguish clearly among different antigens, antibrain antibodies have been applied in structural and functional dissection of the neuron-glia complex and brain at different levels (JankoviC, 1972, 1985a). In vivo and in vitro studies demonstrated that these antibodies both stimulate and inhibit bioelectrical activity, receptor function, axonal transport, neurosecretion, peptidelprotein synthesis, and other nervous tissue functions. Moreover, these macromolecules are capable of inducing demyelination, epileptic attacks, catatonic state, cerebrovascular accidents, and different pathological phenomena related to the brain. Of particular interest for psychiatry and behavioral sciences is the ability of antibrain autoantibodies to induce behavioral alterations and malfunction of learning and memory (JankoviC, RakiC, Veskov & Horvat, 1968; MihailoviC, Divac, MitroviC, MiloSeviC & JankoviC, 1969; McPherson & Shek, 1970; Karpiak & Rapport, 1975; Kobiler, Fuchs & Samuel, 1976; Rick, G r e p n , Leibowitz & Adinolf, 1980; Burbaeva, Kaminskiy, Klyushnik, Ignatova, Zaiko & Androsova, 1985). Since antibrain antibody originates from nonsynaptic sites and influences the functioning of the neuron, it can be regarded as fitting the term neuromodulator (Florey, 1967; Kandel, Krasne, Sturmwasser & Truman, 1979; Dimuskes, 1980). Although antibrain autoantibodies are potentially pathogenic molecules, their appearance in neuropsychiatric diseases should not be regarded as a failure of the immune system itself. Indeed, it has been shown (Kofler, Dixon & Theofilopulos, 1987) that the elaboration of autoantibodies does not rely on defects in mechanisms generating immunoglobulin repertoire nor on abnormalities within germline genes, but rather on general principles governing antibody response to foreign antigens. In healthy individuals, the appearance of antibrain autoantibodies may result from physiological stimulations of the immune system by circulating neuronal debris. If so, then autoantibodies are helpful in removing physiological amounts of neuronal fragments from the blood. On the other hand, a higher release of brain antigens (or modified antigens) caused by a variety of brain-damaging factors (prions, viruses,
International Journal of Neuroscience 1991.60:119-127.
ANTIBRAIN AUTOANTIBODIES IN PSYCHIATRIC DISEASES
125
bacteria, toxins, drugs, physical injuries, metabolic changes, stress, etc.) provides a stronger stimulus for the immune machinery and, thereby, an increased production of antibrain autoantibodies. In addition, a higher output of brain autoantigens may alter immunological suppressor mechanisms of self-tolerance and facilitate the presentation of self-antigens to T cells (Jankovit, 1985b). This kind of thinking may account for the highest incidence of antibrain autoantibodies in patients with Alzheimer’s disease and senile dementia. Neuropathologically, dementia is characterized by intracellular neurofibrillary tangles and extracellular necrotic plaques (Blessed, Tomlinson & Roth, 1968), and extensive and irreversible neuron degeneration particularly in the memory-associated areas, such as the cortical gray matter and hippocampus (Ball, 1977; Brun & Englund, 1981). These progressive neurodegenerative processes are accompanied by an augmented release of brain antigens which are recognized by the immune system. Pertinent to this is the observation that HLA-DR glycoprotein of the human major histocompatibility complex, which is otherwise associated with immune response, is present in the brain cortex of patients with Alzheimer’s disease, and especially in the area of senile plaque formation (McGeer, Itagaki, Tag0 & McGeer, 1987). We note here the high occurrence of anti-Sl00 and, to a lesser extent, of anti-NSE autoantibodies in patients suffering from dementia. Perhaps, the search for autoantibodies reacting with the tau protein of the neurofibrillary tangle (Tanzi, St. George-Hylop & Gusella, 1989) will provide more specific information on autoimmune properties of the dementia syndrome. The blood-brain barrier forms a major deterrent to the entry of autoantibodies and immunocompetent cells (Johnson, 1982). In order to reach brain parenchyma, attach to neuroglial antigens and alter brain function, circulating antibrain autoantibodies have to cross the barrier. Although the permeability of the barrier for immunoglobulins seems to be higher in certain period of life (Adinolfi, Rick & Leibowitz, 1985) and under some circumstances (Axelsson, Martensson & Alling, 1982; Tanaka, Tsukuda, Koh & Yanagisawa, 1987) the mechanisms governing the penetration of autoantibodies into the brain are still unresolved. Finally, despite suggestive results presented here, answers to the basic questions of why antibrain autoantibodies are much more frequent in one psychiatric disease than in another, how autoantibodies from the circulation reach brain structures, and what kind of neurological mechanisms are triggered by autoantibodies in neuropsychiatric patients, will have to wait for further information. REFERENCES Adinolfi, M., Rick, J. T., & Leibowitz, S. (1985). Studies on the biological effects of antibodies. In M. Adinolfi & A. Bighami (Eds.), Immunological studies of brain cells pnd functions (pp. 141-154). Oxford Blackwell. Axelsson, R., Martensson,E., & Alling, C. (1982). Impairment of the blood-brain barrier as an aetiological factor in paranoid psychosis. British Journal of Psychiatry, 141, 273-281. Ball,M.J. (1977). Neuronal loss,neurofibnllary tan+ and grantdovasculardegenerationin the hippocampus with aging and dementia. Acta Neuropathologica, 37, I 1 1-1 18. Baron, M., Stem,M., A ~ v iR., , & Witz, 1. P. (1977). Tissue-binding factor in schizophrenic sera: a clinical and genetic study. Biological Psychiatry, 12, 199-219. Blessed, G., Tomlinson, B. E., & Roth, M. (1968). The association between quantitative measures of dementia and of smile change in the cerebral gray matter of elderly subjects. British Journal of Psychiatry, 114, 797-8 1 1. Bock, E. (1 982). Nervous-system-specie proteins. Oxford: Blackwell. Boehme, D. H., Cotrell, J. C., Dohen, F. C., & Hillegass, L. M. (1974). Demonstration of nuclear and cytoplasmic fluorescencein brain tissues of schizophrenic and nonschizophrenic patients. Biological Psychiatry, 8, 89-94.
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Rapport, M. M., Karpiak, S. E., & Mohadiak, S. P.(1979). Biological activities of antibodies injected into the brain. Federation Proceedings, 38, 2391-2396. Rick, J. T., Gregson, A. N., Leibowitz, S.,& Adinolfi, M. (1980). Behavioral changes in adult rats following administration of antibodies against brain gangliosides. Developmental Medical Children Neurology, 22, 7 19-724. Sudin, U. & Thelander, S. (1989). Antibody reactivity to brain membrane proteins in serum from schizophrenic patients. Brain Behavior and Immunity, 3, 345-358. Tanaka, Y., Tsukada, N., Koh, C. S., & Yanagisawa, N. (1987). Anti-endothelial cell antibodies and circulating immune complexes in the sera of patients with multiple sclerosis. Journal of Neuroimmunology, 17,49-59. Tanzi, R. E.. St. George-Hylop, P. H., & Gusella, J. F. (1989). Molecular genetic approaches to Alzheimer’s disease. Trends in Neurosciences, 12, 152-158. Vartanyan, M. E. & Kolyaskina, G. I. (1987). A psychiatrists’s view of neuroimmunomodulation. The neuroimmune interaction and mechanisms. Annals of New York Academy of Sciences, 4%. 660-668.
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Differential Appearance of Autoantibodies to Human Brain S100 Protein, Neuron Specific Enolase and Myelin Basic Protein in Psychiatric Patients Branislav D. Janković & Dragan Djordjijević To cite this article: Branislav D. Janković & Dragan Djordjijević (1991) Differential Appearance of Autoantibodies to Human Brain S100 Protein, Neuron Specific Enolase and Myelin Basic Protein in Psychiatric Patients, International Journal of Neuroscience, 60:1, 119-127, DOI: 10.3109/00207459109082042 To link to this article: http://dx.doi.org/10.3109/00207459109082042
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Intern. . I . Neuroscience, 1991.
Vol. 60,
Q 1991 Gordon and Breach. Scicna Publishen SA. Printed in the United Kingdom
119-127
Reprints available d i d y from the pu%%her Photocopying permitted by licenrc only
DIFFERENTIAL APPEARANCE OF AUTOANTIBODIES TO HUMAN BRAIN SlOO PROTEIN, NEURON SPECIFIC ENOLASE AND MYELIN BASIC PROTEIN IN PSYCHIATRIC PATIENTS BRANISLAV D. JANKOVIC and DRAGAN DJORDJIJEVIe Immunology Research Center, Vojvode Stepe 458, I1221 Belgrade, Yugoslavia
International Journal of Neuroscience 1991.60:119-127.
(Received June 14. 1990; infinal form October 22. 1990) Sera from psychiatric patients (32 with senile dementia,56 with Alzheimer’s , -d 189 with schizophrenia, 117 with manic-depressive psychoses, 52 with other nonorganic psychoses, 44 with paranoid state, 58
with neurotic depression and 78 with alcoholic syndrome), normal subjects (1 12 blood donors) and 43 hospitalized elderly patients with chroniccardiac failwes without Jcnik syndromewere examined by means of an mzyme-linked immunosorbent assay (ELISA) for the presence of autoantibodies to human brain Sl00 protein, neuron specific enolase (NSE) and myelin basic protein (MBP). These varied antibrain autoantibodiesoccurred at different frequencies.The highest incidence of anti4100 and anti-NSE antibodies was in Alzheimer’s diseasc and senile dementia, tlyn in manic-depressive and other nonorganic psychoses, and the lowest in paranoid state, neurotic depression. schizophrenia and alcoholic syndrome. The frequency ofanti-900 autoantibodies was higher than that ofanti-NSE. Autoantibodies reacting with MBP were rcvcaled in a very small number of psychiatric patients. In healthy individuals and control cardiac patients, the incidence of antibrain autoantibodies was low. These results suggest a differential cornlation between antibrain autoantibodies and psychiatric diseases. Keyworth: antibrain autoanribody;S-IW protein; neuron specific enolase; myelin basic protein; Alzheimer i dementia; immunopsychiatry
Autoimmune mechanisms have been implicated in the pathogenesis of neuropsychiatric diseases (Fessel, 1962). The immense antigenic potentiality of the brain rely upon a wide range of macromolecules and their interplay inside and outside the neuron-glia complexes. In general, these antigens, under the influenceof endogenousand exogenous factors, change their structure and become autoantigens (or modified antigens) which then trigger autoimmune processes leading to autoimmune diseases (JankoviC, 1985b). One of the outstanding features of autoimmune response is the increased incidence and production of autoantibodies whicb by virtue of their specificity bind Address reprint requests to Branislav D. Jankovik, Immunology Research Center, Vojvode Stepc 458, 11221 Belgrade. Yugoslavia. Abbreviations: ELISA. enzyme-linked immunosorbent assay; NSE, neuron Specific e n o h , MBP, myelin basic protein; ICD,international classification of dipeascs; HIV, human immunodeficiency vim; OPD, Gphenylencdiamine dihydrochloride; PBST, phosphate-butTd saline containing Tween 20. We appreciate the generous donation of human brain myelin basic protein by Dr. George A. Hashim, St. Luke/RooseveltHospital, New York, and human brain SloO protein and neuron e f i c enolase by Dr. Joief Horvat, Immunology Research Center, Belgrade. We would like to acknowledg and thank our colleagues of the F’sychiatric Hospital “Lam K. LazamiC,” Belgrade; Department of Neuropsychiatry, Belgrade City Hospital; Department of Neurology, Faculty of Medicine, University of Belgrade; and Psychiatric Hospital, PopovaEa, for +eir continuous support and valuable assiStanain clinical management and records. %s work was supported by the Republic of Serbia Research Fund, Belgrade. 119
120
B. D. JANKOVIC AND D. DJORDJUEVIC
in vivo to neuronal antigens and thus may cause changes at receptor, membrane, intraneuronal and neurosecretion levels. Hence, antibrain autoantibodies are potentially neuromodulating molecules (JankoviC, 1972, 1985a, Rapport, Karpiak & Mohadial, 1979). However, in spite of increasing data, often controversial, the functioning and pathology of antibrain autoantibodies in patients suffering from mental disorders is still poorly understood. This report deals with the incidence and distribution of autoantibodies against well-defined human brain antigens, S100 protein, neuron specific enolase (NSE)and myelin basic protein (MBP) in psychiatric patients, nonpsychiatric patients and normal subjects.
METHODS
International Journal of Neuroscience 1991.60:119-127.
Patients
According to clinical diagnosis, a total of 626 hospitalized psychiatric patients were divided into eight groups: senile dementia (ICD code 290.0), Alzheimer’s disease (ICD code 290. l), schizophrenia (ICD codes 296.0 and 296. I), paranoid state (ICD code 297. I), other nonorganic psychoses (ICD codes 298.0 and 298. I), neurotic depression (ICD code 300.4), and alcoholic syndrome (ICD code 303.0). Patients were without medication for at least 12 days before blood samples were taken. None of the patients suffered from acute or chronic inflammatory disease, and immunological disorders. The control group was composed of 112 healthy blood donors. An additional group of “control patients” suffering from chronic cardiopathy of noninflammatory origin and without senile syndrome volunteered for this study, and served as age-matched control for patients with senile dementia. All subjects used in this study were HIVnegative. Numerical data for each group are shown in Table 1. Brain An tigens
SlOO protein (Moore, 1965), neuron specific enolase (NSE, Marangos, Zis, Clark & Goodwin, 1978) and myelin basic protein (MBP) were isolated from human brain. Chemicals
For detection of antibrain autoantibodies, the following chemicals (Sigma, Heidelberg) were used: Tween 20, bovine serum albumin essentially fatty-acid free and globulin free, o-phenylenediaminedihydrochloride (OPD), and goat antihuman IgG (gammachain specific) peroxydase conjugate. Enzyme-Linked Immunosorbent Assay (ELISA)
Sera from patients and healthy controls were separated, inactivated at 56OC for 30 min, and stored at - 7OoC until use. The wash solution consisted of phosphatebuffered saline (PBST) containing 0.05% of Tween 20, pH 7.2. The flat-bottorned polystyrene microtiter plate (”C, Denmark) was coated with 100pl/well of a 20pg/ml solution of SlOO protein, NSE or MBP in 0.05 M bicarbonate buffer, pH 9.2, And incubated overnight at 4°C. The plate was then washed three times for 3 min in PBST and tapped on absorbent paper. Serum samples from patients and healthy individualswere diluted 1 :200 in PBST, and 100pl of the dilution were added to wells
ANTIBRAIN AUTOANTIEORIES IN PSYCHIATRIC DISEASES
121
TABLE I Sex and age of patients and control subjects
Sex
International Journal of Neuroscience 1991.60:119-127.
Group
n
Female
Male
Senile dementia
32
19
13
Alzheimer's disease
56
26
30
Schizophrenia
I89
69
120
Manic-depressivepsychoses
I I7
41
76
Paranoid state
44
17
27
Other nonorganic psychoses
52
24
28
Neurotic depression
58
33
25
Alcoholic syndrome
78
14
64
Control subjects
112
45
67
Control patients'
43
25
18
Average age (yean) 75.5 (65-86) 47.8 (39-55) 38.8 (24-52) 42.5 (22-53) 47.3 (39-56) 52.7 (47-68) 50.6 (37-66) 44.6 (38-52) 38.2 (28-45) 74.2
(66-84)
In parentheses, range. 'Control patients (suffering from chronic cardiopathy with no senile syndrome) for the senile dementia group.
in triplicate, and incubated at room temperature for 90 min. Thereafter, the plate was washed 5 times for l5min with PBST in Titertek Multiwasher, and 100pl/well of a 1 : 1000 dilution of peroxydaseconjugated antihuman IgG in PBST were added before incubation for 60min at room temperature. After incubation, the plate was washed as described above, and lOOpl/well of freshly prepared substrate solution added (substrate solution: 0.4mg/ml of OPD and 0.01% of H,02in 0.15 M citratephosphate buffer, pH 5.0), and the plate reincubated for 40 min in the dark at room temperature. The enzyme-reaction was stopped by means of 50pl/well of a 4 N HzSOI, and absorbance was read at 492nm using a Titertek Multiscan MCC photometer. A test serum was considered positive when the mean value of the optical density minus one standard deviation was higher than the mean value of the optical density of the negative control serum plus three standard deviations. The reader of ELISA did not have access to clinical diagnosis of patients. Statistical Method
Student's t test was employed. The level of statistical significance was set at p
< .05.
RESULTS
Sera from psychiatric patients, cardiac patients and control individuals were screened for autoantibodies to human brain Sl00 protein, NSE and MBP, and the results are
B. D. JANKOVIC A N D D.DJORDJUEVIC
122
TABLE 11 Autoantibodics to human brain SlOO protein in psychiatric patients
. Anti-S100 autoantibodies Patients
ICD code
n
with antibody
ELISA titee (m- f SD)
Alzheimct's disease senik dementia Manic-dep&ve psychoses Other nonorganic psychoses Alcoholic syndrome Paranoid states Schizophrenia Neurotic depression Hcalthy subjects Control patients'
290.1 290.0 296.0-296.1 298.0-298.1 303.0 297.1 295.0-295.2 300.4
32 56 1 I7 52 78 44 189 58 I12 43
50.0 (16) 39.3 (22) 28.2 (33) 26.9 (14) 15.4 (12) 13.4 (6) 12.7 (24) 10.3 (6) 2.7 (3) 6.9 (1)
20 f 5 21 f 4 17 f 5 19 f 6 17 f 5 14 f 2 17 f 7 15 f 3 6 f I 7*1
International Journal of Neuroscience 1991.60:119-127.
Ye of patients
In parentheses, number of subjects with autoantibodies 'Mean of positive sera. Optical density at wavelength of 492nm x I d bControl patients for the scnik dementia group.
presented in Tables I1 and 111. The data are lined up according to the number of positive sera in different groups of subjects. The highest frequency of autoantibodies to SlOO and NSE was in patients suffering from Alzheimer's disease and senile dementia, and somewhat lower in patients with manicdepressive psychoses. The incidence of anti-S100 and anti-NSE autoantibodies was rather low in patients with paranoid state, neurotic depression, schizophrenia and alcoholic syndrome. ELISA optical density values, designatingantibody titers, of SL 100-positive and NSE-positive sera were similar. Contrary to these findings, in control patients and healthy individuals autoantibodies to SlOO and NSE were detected in a small number of sera, and ELISA titers were much lower in comparison to those found in patients. .
TABLE 111 Autoantibodies to human brain neuron specific cnolase (NSE) in psychiatric patients
Anti-NSEautoantibodies Patients
ICD code
n
% of patients with antibody
ELISA tit& (mf SD)
Alzheimer's disease Senile dementia Other nonorganic psychoses Manic-depressive psychoses Neurotic depression Schizophrenia Paranoid states Alcoholic syndrome Healthy subjects Control patientsb
290. I 290.0 298.0-298.1 296.0-296.1 300.4 295.0-295.2 297.1 303.0
32 56 52 117 58 189 44 78 112 43
3 7 3 12) 25.0(14) 23.I ( 12) 1 5 4 18) 10.3(6) 6.3(12) 4.5(2) 343) 1.8(2) 4.W)
Z f 3 21 f 5 21 f 5 18 f 1 21 f 1 19 f 1 19 f 1 24 f I 6 f 1 6 f 1
In parentheses. number of subjects with autoantibodies. *Mean of positive sera. Optical density at wavelength of 492 nm x Id. bControl patients for the senile dementia group.
ANTIBRAIN AUTOANTIBODIES IN PSYCHIATRIC DISEASES
123
TABLE IV Autoantibodies to human brain SlOO protein, neuron specific enolase (NSE)and myelin basic protein (MBP) in psychiatric paticots (an overview)
YOof sera with antibodies to ~
Group
n
SlOO
NSE
MBP
SlOO and NSE
Psychiatric patients
626
Healthy individuals
112
21.2 (133) 2.7 (3) 6.9 (3)
12.6 (79) 1.8 (2) 4.6 (2)
0.8 (5) 1.8
12.1 (76) 0 (0) 4.6 (2)
Control patients’
43
(2) 2.3 (1)
International Journal of Neuroscience 1991.60:119-127.
In parentheses, number of subjects with autoantibodies ‘Hospitalized elderly patients with chronic cardiopathy without senile syndrome.
In psychiatric patients, as shown in comparative Table IV, the overall incidence of anti-S100 autoantibodies exceeded that of anti-NSE autoantibodies, the antiS100:anti-NSE ratio being 1.8. More than half of seropositive patients contained autoantibodies both to Sl00 and NSE brain antigens. In contrast, anti-MBP autoantibodies were detected in a very small number of sera from psychiatric patients (0.8%), healthy subjects (1.8%), and control patients (2.3%). The incidence of antibrain autoantibodies in relation to the sex indicated that out of 217 autoantibody-positive psychiatric patients, 95 (43.8%) were females and 122 (56.2%) males. DISCUSSION The present results can be interpreted as evidence that antibrain autoantibodies are associated with certain psychiatric disease since the incidence of patients containing autoantibodies is obviously out of physiological range. The demonstration of a unique circulating IgG protein (“taraxein”) in schizophrenic patients and its in vivo antibrain activity (Heath & Krupp, 1967; Heath, Krupp, Byers & Liljkvist, 1967), stimulated the search for autoimmune features of schizophrenia. Several authors described antibrain autoantibodies in 28-95% of schizophrenics (Kolyaskina & Kushner, 1971-71; Baron, Stem, Anavi & Witz, 1977; Pandey, Gupta & Chaturvedi, 1981; Ganguli, Rabin, Kelly, Lyte & Ragu, 1987). In contrast, a number of investigators failed to detect increased production of autoantibodies to brain antigens in schizophrenic patients (Logan & Deodhar, 1970; k h m e , Cotrell, Dohen & Hillegass, 1974; Ehmst, Wiesel, Bjerkenstedt & Tribukait, 1982; Sudin 8r Thelander, 1989). Most probably, differences in methods and antigens used for the demonstration of antibrain autoantibodies accounted for this discrepancy. It should be mentioned here that a cell-mediated autoimmunecomponent, i.e., delayed hypersensitive skin reactions to human brain antigens have been described in schizophrenics and other psychiatric patients (JankoviC, JakuliC & Horvat, 1980; Vartanyan & Kolyaskina, 1987). Possible immune pathways in schizophrenia have been proposed (JankoviC, 1985b) on the basis of humoral and cellular autoimmune mechanisms, changes in dopaminergic system, and clinically identified positive and negative syndromes (Crow,1982). Besides schizophrenia, antibrain autoantibodies were found in a variety of neuropsychiatric disorders, such as multiple sclerosis, Down’s syndrome, Huntington’s
International Journal of Neuroscience 1991.60:119-127.
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B. D. JANKOVIC AND D. DJORDJIJEVIt
disease, idiopathic Parkinson’s disease (JankoviC & KuSiC, 1989), brain tumors, Alzheimer’s disease, senile dementia, brain atrophy, depression, mental retardation, alcoholic syndrome, and so forth, as well as in a number of nonneurological diseases, and normal adults and elderly individuals (JankoviC, 1985a; JankoviC, 1989). The present study shows that the incidence of antibrain autoantibodies is significantly higher in psychiatric patients than in normal subjects. The frequency of these antibodies was rather low even in hospitalized control elderly patients suffering from chronic cardiopathy but without senile syndrome. Of particular importance seems to be the differences among psychiatric diseases with respect to the presence of antibrain autoantibodies. Thus, the highest number of positive sera was observed in patients with Alzheimer’s disease and senile dementia, and the lowest in subjects suffering from alcoholic syndrome, paranoid state, schizophrenia and neurotic depression. In between are individuals with manic-depressive and other, nonorganic psychoses. Such a dichotomy of psychiatric diseases based on antibrain autoantibody presence implicates different involvement of autoantigens in the pathogenesis of certain psychiatric disorders. Thereby, the high incidence of anti-S100 and anti-NSE, and the low frequency of anti-MBP autoantibodies may indicate that SlOO and NSE antigens are much more related to autoimmune mechanisms than MBP antigen. It appears, therefore, that autoimmune processes in certain psychiatric disorders, and particularly in Alzheimer’s disease and senile dementia, are primarily concerned with brain structures in which SlOO and NSE are situated. The implication of brain antigens other than S100, NSE and MBP (Bock, 1982), in the autoimmune pathogenesis of neuropsychiatric diseases remains to be elucidated. Due to the extraordinary capacity of antibody molecules to distinguish clearly among different antigens, antibrain antibodies have been applied in structural and functional dissection of the neuron-glia complex and brain at different levels (JankoviC, 1972, 1985a). In vivo and in vitro studies demonstrated that these antibodies both stimulate and inhibit bioelectrical activity, receptor function, axonal transport, neurosecretion, peptidelprotein synthesis, and other nervous tissue functions. Moreover, these macromolecules are capable of inducing demyelination, epileptic attacks, catatonic state, cerebrovascular accidents, and different pathological phenomena related to the brain. Of particular interest for psychiatry and behavioral sciences is the ability of antibrain autoantibodies to induce behavioral alterations and malfunction of learning and memory (JankoviC, RakiC, Veskov & Horvat, 1968; MihailoviC, Divac, MitroviC, MiloSeviC & JankoviC, 1969; McPherson & Shek, 1970; Karpiak & Rapport, 1975; Kobiler, Fuchs & Samuel, 1976; Rick, G r e p n , Leibowitz & Adinolf, 1980; Burbaeva, Kaminskiy, Klyushnik, Ignatova, Zaiko & Androsova, 1985). Since antibrain antibody originates from nonsynaptic sites and influences the functioning of the neuron, it can be regarded as fitting the term neuromodulator (Florey, 1967; Kandel, Krasne, Sturmwasser & Truman, 1979; Dimuskes, 1980). Although antibrain autoantibodies are potentially pathogenic molecules, their appearance in neuropsychiatric diseases should not be regarded as a failure of the immune system itself. Indeed, it has been shown (Kofler, Dixon & Theofilopulos, 1987) that the elaboration of autoantibodies does not rely on defects in mechanisms generating immunoglobulin repertoire nor on abnormalities within germline genes, but rather on general principles governing antibody response to foreign antigens. In healthy individuals, the appearance of antibrain autoantibodies may result from physiological stimulations of the immune system by circulating neuronal debris. If so, then autoantibodies are helpful in removing physiological amounts of neuronal fragments from the blood. On the other hand, a higher release of brain antigens (or modified antigens) caused by a variety of brain-damaging factors (prions, viruses,
International Journal of Neuroscience 1991.60:119-127.
ANTIBRAIN AUTOANTIBODIES IN PSYCHIATRIC DISEASES
125
bacteria, toxins, drugs, physical injuries, metabolic changes, stress, etc.) provides a stronger stimulus for the immune machinery and, thereby, an increased production of antibrain autoantibodies. In addition, a higher output of brain autoantigens may alter immunological suppressor mechanisms of self-tolerance and facilitate the presentation of self-antigens to T cells (Jankovit, 1985b). This kind of thinking may account for the highest incidence of antibrain autoantibodies in patients with Alzheimer’s disease and senile dementia. Neuropathologically, dementia is characterized by intracellular neurofibrillary tangles and extracellular necrotic plaques (Blessed, Tomlinson & Roth, 1968), and extensive and irreversible neuron degeneration particularly in the memory-associated areas, such as the cortical gray matter and hippocampus (Ball, 1977; Brun & Englund, 1981). These progressive neurodegenerative processes are accompanied by an augmented release of brain antigens which are recognized by the immune system. Pertinent to this is the observation that HLA-DR glycoprotein of the human major histocompatibility complex, which is otherwise associated with immune response, is present in the brain cortex of patients with Alzheimer’s disease, and especially in the area of senile plaque formation (McGeer, Itagaki, Tag0 & McGeer, 1987). We note here the high occurrence of anti-Sl00 and, to a lesser extent, of anti-NSE autoantibodies in patients suffering from dementia. Perhaps, the search for autoantibodies reacting with the tau protein of the neurofibrillary tangle (Tanzi, St. George-Hylop & Gusella, 1989) will provide more specific information on autoimmune properties of the dementia syndrome. The blood-brain barrier forms a major deterrent to the entry of autoantibodies and immunocompetent cells (Johnson, 1982). In order to reach brain parenchyma, attach to neuroglial antigens and alter brain function, circulating antibrain autoantibodies have to cross the barrier. Although the permeability of the barrier for immunoglobulins seems to be higher in certain period of life (Adinolfi, Rick & Leibowitz, 1985) and under some circumstances (Axelsson, Martensson & Alling, 1982; Tanaka, Tsukuda, Koh & Yanagisawa, 1987) the mechanisms governing the penetration of autoantibodies into the brain are still unresolved. Finally, despite suggestive results presented here, answers to the basic questions of why antibrain autoantibodies are much more frequent in one psychiatric disease than in another, how autoantibodies from the circulation reach brain structures, and what kind of neurological mechanisms are triggered by autoantibodies in neuropsychiatric patients, will have to wait for further information. REFERENCES Adinolfi, M., Rick, J. T., & Leibowitz, S. (1985). Studies on the biological effects of antibodies. In M. Adinolfi & A. Bighami (Eds.), Immunological studies of brain cells pnd functions (pp. 141-154). Oxford Blackwell. Axelsson, R., Martensson,E., & Alling, C. (1982). Impairment of the blood-brain barrier as an aetiological factor in paranoid psychosis. British Journal of Psychiatry, 141, 273-281. Ball,M.J. (1977). Neuronal loss,neurofibnllary tan+ and grantdovasculardegenerationin the hippocampus with aging and dementia. Acta Neuropathologica, 37, I 1 1-1 18. Baron, M., Stem,M., A ~ v iR., , & Witz, 1. P. (1977). Tissue-binding factor in schizophrenic sera: a clinical and genetic study. Biological Psychiatry, 12, 199-219. Blessed, G., Tomlinson, B. E., & Roth, M. (1968). The association between quantitative measures of dementia and of smile change in the cerebral gray matter of elderly subjects. British Journal of Psychiatry, 114, 797-8 1 1. Bock, E. (1 982). Nervous-system-specie proteins. Oxford: Blackwell. Boehme, D. H., Cotrell, J. C., Dohen, F. C., & Hillegass, L. M. (1974). Demonstration of nuclear and cytoplasmic fluorescencein brain tissues of schizophrenic and nonschizophrenic patients. Biological Psychiatry, 8, 89-94.
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Rapport, M. M., Karpiak, S. E., & Mohadiak, S. P.(1979). Biological activities of antibodies injected into the brain. Federation Proceedings, 38, 2391-2396. Rick, J. T., Gregson, A. N., Leibowitz, S.,& Adinolfi, M. (1980). Behavioral changes in adult rats following administration of antibodies against brain gangliosides. Developmental Medical Children Neurology, 22, 7 19-724. Sudin, U. & Thelander, S. (1989). Antibody reactivity to brain membrane proteins in serum from schizophrenic patients. Brain Behavior and Immunity, 3, 345-358. Tanaka, Y., Tsukada, N., Koh, C. S., & Yanagisawa, N. (1987). Anti-endothelial cell antibodies and circulating immune complexes in the sera of patients with multiple sclerosis. Journal of Neuroimmunology, 17,49-59. Tanzi, R. E.. St. George-Hylop, P. H., & Gusella, J. F. (1989). Molecular genetic approaches to Alzheimer’s disease. Trends in Neurosciences, 12, 152-158. Vartanyan, M. E. & Kolyaskina, G. I. (1987). A psychiatrists’s view of neuroimmunomodulation. The neuroimmune interaction and mechanisms. Annals of New York Academy of Sciences, 4%. 660-668.
