- Email: [email protected]
CEREBRAL ATROPHY AN IMMUNOLOGICAL DISORDER?
219
virus from unengorged bat bedbugs (Stricticimexparvus and C. insuetus) and from suckling bats (Tadarida plicata) collected in caves in central Thailand. These investigators concluded that, although they did not directly demonstrate transmission of Kaeng Khoi virus from the bedbugs to bats by bite, the evidence was sufficient to implicate the bedbug as a possible vector of the virus. Investigators in the Vector-Borne Diseases Division of the Center for Disease Control (Fort Collins, Colorado) have shown that Oeciacus vicarius, which infests the nests of swallows, is the biological vector and reservoir of Fort Morgan virus, a member of the Western equine encephalitis group, and is a reservoir of Bijou bridge virus in the Venezuelan equine encephalitis group. Fort Morgan virus was recovered from wild-caught swallowbugs and from the sera of nestling swallows and sparrows inhabiting the infested nests. Neutralising antibody, but not virus, was detected in the blood of adult birds. In contrast, infectious virus was repeatedly isolated from swallowbugs collected during the winter, at a time when both nestling birds and mosquitoes were absent from the study site. Swallowbugs fed experimentally on viræmic nestling sparrows became infected and were able to transmit the virus to other nestling sparrows. Bijou bridge virus was recovered from wild caught swallowbugs and from birds that were also infected with Fort Morgan virus. Bijou bridge virus was also transmitted in the laboratory to swallowbugs and from the swallowbugs to nestling birds. 20 The bat-bedbug and swallowbug studies provide evidence that Cimicidæ may be reservoirs and vectors of viruses in nature. Our studies of C. hemipterus suggest that this arthropod may be a vector of H.B.v. Clearly, H.B.v. antigens can persist in this organism for long periods, but whether it can transmit H.B.v. to man or laboratory animals remains to be determined. We thank Mamadou Sarr of S.L.A.P. in Thies, Senegal, and Beatrice Tremolet and Caroline Jamet for assistance in the collections; Dr Jean Coz of O.R.S.T.O.M. at the Pasteur Institute in Dakar, Dr Yves Robin, Pasteur Institute, Dakar, and Dr de Lautrec, department of hygiene, Faculte de Medicine, for providing lavoratory space and technical assistance. This work was supported by U.S. Public Health Service grants CA-06551, RR-05539, and CA-06927 from the National Institutes of Health and by an appropriation from the Commonwealth
of Pennsylvania. Requests for reprints should be addressed to W.T.L., Institute for Cancer Research, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111. U.S.A. REFERENCES 1.
Blumberg, B. S., Sutnick, A. I., London, W. T., Millman, I. New Engl. J. Med. 1970, 283, 349. 2. Prince, A. M. Am. J. trop. Med. Hyg. 1970, 19, 872. 3. Szmuness, W., Prince, A. M., Diebolt, G., Leblanc, L., Baylet, R., Masseyeff, R., Linhard, J. Am. J. Epidem. 1973, 98, 104. 4. Blumberg, B. S., Hesser, J. E., Economidou, I., Hadziyannis, S., Gioustozi, A., Heliakis, P., Livades, D. Devel. Biol. Standard. 1975, 30, 270. 5. Prince, A. M., Metselaar, D., Kafuko, G. W., Mukwaya, L. G., Ling, C. M., Overby, L. R. Lancet, 1972, ii, 247. 6. Dick, S. J., Tamburro, C. H., Leevy, C. M. J. Am. med. Ass. 1974, 12, 1627. 7. Blumberg, B. S., Wills, W., London, W. T., Millman, I. Res. Commun. chem. Path. Pharmac. 1973, 6, 719. 8. Wills, W., Saimot, G., Brochard, C., Blumberg, B. S., London, W. T., Dechene, R., Millman, I. Am. J. trop. Med. Hyg. 1976, 25, 186. 9. Brotman, B., Prince, A. M., Godfrey, H. R. Lancet, 1973, i, 1305. 10. Newkirk, M. M., Downe, A. E. R., Simon, J. B. Gastroenterology, 1975, 69, 982. 11. Scheidegger, J. J. Int. Archs Allergy, 1955, 7, 103. 12. Werner, B. G., O’Connell, A. P., Summers, J. Proc.
15. Grady, G. F. Lancet, 1976, ii, 492.
AN IMMUNOLOGICAL DISORDER?
BRANISLAV D.
SLOBODAN JAKULIĆ JANKOVIĆ JOZEF HORVAT
Immunology Research Centre and Dr Laza K. Lazarević Psychiatric Clinic, Belgrade, Yugoslavia Patients with cerebral atrophy of unknown origin, patients with nuclear forms of schizophrenia or neurosis, and normal subjects were skin-tested with human brain and liver proteins. The frequency of positive delayed skin-sensitivity reactions to brain proteins was significantly higher in the cerebral-atrophy group than in other groups, thus suggesting a correlation between cerebral atrophy and cellmediated immunity. Introduction
Summary
CEREBRAL atrophy of unknown origin is a psychiatric enigma.1.2 This report describes our investigations of a possible relationship between cerebral atrophy and delayed skin hypersensitivity to human brain proteins.
Materials and Methods Water-soluble fractions3 were isolated from fresh human brain and liver. In Ouchterlony’s double diffusion, humanbrain-protein (H.B.P.) fraction developed 5 precipitin lines, and human-liver-protein (H.L.P.) fraction developed 2 lines when brought into contact with rabbit anti-H.B.P. serum. To test the encephalitogenicity of H.B.P., guineapigs and rats were immunised with 5 mg, 10 mg, and 20 mg of H.B.P. in Freund’s complete adjuvant4 (32-44 animals in each group) and skintested 7, 14, 21, and 28 days later with old tuberculin 1/10 and 60 µg H.B.P., and 60 µg H.L.P. Reactions4 were read at 24 hours. The animals were killed, and the cerebrum, cerebellum, and several levels of spinal cord were processed for histology. Nervous-tissue sections from rabbits immunised with H.B.P. were also examined. Other groups of animals were immunised with H.L.P. A total of 594 subjects, 187 of them (75 women, 112 men) with cerebral atrophy, were injected intradermally with 100 µg of H.B.P. and H.L.P. into the left forearm, and reactions were read 24 hours later. For pneumoencephalography,S 30 ml of air was injected into the lumbar subarachnoid space. Radiologically, cortical atrophy was indicated by widening of sulci, and white-matter atrophy by enlarged ventricled.6.7 Intellectual deterioration was the predominant symptom. Neurological examinations revealed a variety of disinhibition signs. The patients’ history and clinical examination excluded the following causes of cerebral atrophy: intoxication, hypoxia, nutritional and hormonal deficiencies, neoplasms, epilepsy, cerebral arteriosclerosis, senility, Pick’s disease, Huntington’s chorea, hereditary disorders, Alzheimer’s disease, parkinsonism, obstructions of brain ducti and foramina, hydrocephalus in childhood, aneurysms, abscesses, congenital cerebral maldevelopment, abnormal intracranial pressure, drug abuse, and noncerebral organic illnesses. About 30% of patients had had a head injury 1-5 years before the onset of the disease, and about 25% regularly consumed alcohol without showing signs of intoxication. Patients were treated with neuroleptic drugs Szmunes, W., Mach, M. I., Prince, A. M., Hoofnagle, J. H., Cherubin, C. E., Harley, E. J., Block, G. H. Ann. intern. Med. 1975, 83, 489. 17. Blumberg, B. S. Bull. Acad. Med. Toronto, 1972, 45, 45. 18. Stevens, C. E., Beasley, R. P. Tsui, J., Lee, W. New Engl. J. Med. 1975, 292, 16.
natn.
Acad. Sci. U.S.A.
1977, 74, 2149. Usinger, R. L. Monograph of Cimicidæ; p. 326. Entomological Society America, College Park, Maryland, 1976. 14. Magnius, L. O., Espmark, J. A. J. Immun. 1972, 109, 1017. 13.
CEREBRAL ATROPHY
of
771. 19.
Williams, J. E., Imlarp, S., Top, F. H., Cavanaugh, D. C., Russell, P. K.
Bull. Wld Hlth Org. 1976, 53, 365. 20. Monath, T. Personal communication.
220 TABLE I-DELAYED SKIN HYPERSENSITIVITY TO HUMAN BRAIN PROTEIN IN CEREBRAL ATROPHY
*
An arithmetic
+= 1;
score
reflecting an overall
response
was
calculated for each group,
depending on the degree of induration defined as follows: 0=0;
+ +-2;, +++=3; and ++++=4. the
t 18 patients were excluded because radiological diagnosis was equivocal. 6,7 t Figures in parenthesis are patients with no history of head injury or trauma. TABLE II—AGE AND DURATION OF ILLNESS IN 187 PATIENTS reaction was positive in all patients but negative in norWITH CEREBRAL ATROPHY mal subjects. There was no correlation between delayed skin hypersensitivity to H.B.P. and age or duration of illness in patients with cerebral atrophy (table n). In the 8 months after skin-testing, there was no evidence in any patient that the procedure had aggravated the disease. About a fifth of patients with cerebral atrophy developed local reactions to H.L.P., and 18% had anti-brain antibodies in their sera. The reaction of 35% of patients with nuclear schizophrenia to H.B.P. suggests that cell-mediated immunity, as well as the proposed activity of a unique anti-brain antibody,8 may be involved in the development of
schizophrenia. Discussion
(chlorpromazine, thioproperazine, methotrimeprazine, trimipramine, or fluphenazine). None of these drugs is known to induce delayed hypersensitivity to human brain proteins. Two control groups were set up-patients with nuclear forms of schizophrenia (I.C.D. code 295.0-295.3), patients with neurosis (I.C.D. code 300.0-300.4), and normal subjects. All patients in this study are still alive. Results
These results suggest a relationship between cerebral and cellular immunity. However, although the skin reaction described may well represent delayed hypersensitivity to brain proteins, it does not prove that those antigens cause the brain damage.9 Whether or not cerebral atrophy is a direct consequence of an autoimmune process remains to be seen. Immunochemical characterisation of the causal antigen and immunohistopathological evaluation of the cerebral atrophy are still
atrophy
Guineapigs and rats immunised with H.B.P. produced lacking. Another possibility raised by these results is that positive delayed skin reactions to H.B.P., H.L.P., and tuberculin, the strongest reactions being to H.B.P. and senile and presenile psychoses2 caused by or associated tuberculin. However, neurological and histopathological with brain damage and dementias of unknown origin examinations did not reveal allergic encephalomyelitis in may have a common immune denominator. these animals or in the rabbits in which anti-H.B.P. antibodies had been raised. The risk of using H.B.P. for skintesting a human being was therefore thought to be very small. Animals immunised with H.L.P. developed delayed skin hypersensitivity to H.L.P. but no histological lesions in the liver. The frequency of delayed skin hypersensitivity reactions to H.B.P. (table i) was significantly higher in patients with cerebral atrophy (69%) than in control groups (35% and 2.5%). The exclusion of proven cases of head trauma increased the proportion of positive skin reactions (768%). To evaluate the reproducibility of the skin-test, 47 patients with cerebral atrophy and positive skin reactions and 14 normal subjects with negative skin reactions were reinjected with H.B.P. into the right forearm 3-14 months after the first skin test. Again, the skin
We thank the medical personnel of the Dr Laza K. Lazarevic Psychiatric Clinic and the Immunology Research Centre who volunteered to take part in this study. This work was supported by the Republic of Serbia Research Fund, Belgrade.
Requests for reprints should be addressed to B. D. J., Immunology Research Centre, Vojvode Stepe 458, Belgrade, Yugoslavia. REFERENCES 1. Gregory, I. Fundamentals of Psychiatry; p. 653. Philadelphia, 1968. 2. Kolb, L. C. Modern Clinical Psychiatry; p. 299. Philadelphia, 1973. 3. Warecka, K., Moeller, H. J., Vogel, H. M., I. J. Neurochem. 1972,
Tripatzis,
19, 719. 4. Arnason, B. G., Janković, B. D., Waksman, B. H., Wennersten, C. J. exp. Med. 1962, 116, 177. 5. Lindgren, E. Acta radiol. 1949, 31, 161. 6. Robertson, E. G. Pneumoencephalography. Springfield, 1957. 7. Lim, S. T., Potts, G., Deck, M. D. F. Radiology, 1972,104, 585. 8. Heath, R. G., Krupp, I. M. Archs gen. Psychiat. 1967, 16, 1. 9. Paterson, P. Y. Adv. Immun. 1966, 5, 131.
virus from unengorged bat bedbugs (Stricticimexparvus and C. insuetus) and from suckling bats (Tadarida plicata) collected in caves in central Thailand. These investigators concluded that, although they did not directly demonstrate transmission of Kaeng Khoi virus from the bedbugs to bats by bite, the evidence was sufficient to implicate the bedbug as a possible vector of the virus. Investigators in the Vector-Borne Diseases Division of the Center for Disease Control (Fort Collins, Colorado) have shown that Oeciacus vicarius, which infests the nests of swallows, is the biological vector and reservoir of Fort Morgan virus, a member of the Western equine encephalitis group, and is a reservoir of Bijou bridge virus in the Venezuelan equine encephalitis group. Fort Morgan virus was recovered from wild-caught swallowbugs and from the sera of nestling swallows and sparrows inhabiting the infested nests. Neutralising antibody, but not virus, was detected in the blood of adult birds. In contrast, infectious virus was repeatedly isolated from swallowbugs collected during the winter, at a time when both nestling birds and mosquitoes were absent from the study site. Swallowbugs fed experimentally on viræmic nestling sparrows became infected and were able to transmit the virus to other nestling sparrows. Bijou bridge virus was recovered from wild caught swallowbugs and from birds that were also infected with Fort Morgan virus. Bijou bridge virus was also transmitted in the laboratory to swallowbugs and from the swallowbugs to nestling birds. 20 The bat-bedbug and swallowbug studies provide evidence that Cimicidæ may be reservoirs and vectors of viruses in nature. Our studies of C. hemipterus suggest that this arthropod may be a vector of H.B.v. Clearly, H.B.v. antigens can persist in this organism for long periods, but whether it can transmit H.B.v. to man or laboratory animals remains to be determined. We thank Mamadou Sarr of S.L.A.P. in Thies, Senegal, and Beatrice Tremolet and Caroline Jamet for assistance in the collections; Dr Jean Coz of O.R.S.T.O.M. at the Pasteur Institute in Dakar, Dr Yves Robin, Pasteur Institute, Dakar, and Dr de Lautrec, department of hygiene, Faculte de Medicine, for providing lavoratory space and technical assistance. This work was supported by U.S. Public Health Service grants CA-06551, RR-05539, and CA-06927 from the National Institutes of Health and by an appropriation from the Commonwealth
of Pennsylvania. Requests for reprints should be addressed to W.T.L., Institute for Cancer Research, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111. U.S.A. REFERENCES 1.
Blumberg, B. S., Sutnick, A. I., London, W. T., Millman, I. New Engl. J. Med. 1970, 283, 349. 2. Prince, A. M. Am. J. trop. Med. Hyg. 1970, 19, 872. 3. Szmuness, W., Prince, A. M., Diebolt, G., Leblanc, L., Baylet, R., Masseyeff, R., Linhard, J. Am. J. Epidem. 1973, 98, 104. 4. Blumberg, B. S., Hesser, J. E., Economidou, I., Hadziyannis, S., Gioustozi, A., Heliakis, P., Livades, D. Devel. Biol. Standard. 1975, 30, 270. 5. Prince, A. M., Metselaar, D., Kafuko, G. W., Mukwaya, L. G., Ling, C. M., Overby, L. R. Lancet, 1972, ii, 247. 6. Dick, S. J., Tamburro, C. H., Leevy, C. M. J. Am. med. Ass. 1974, 12, 1627. 7. Blumberg, B. S., Wills, W., London, W. T., Millman, I. Res. Commun. chem. Path. Pharmac. 1973, 6, 719. 8. Wills, W., Saimot, G., Brochard, C., Blumberg, B. S., London, W. T., Dechene, R., Millman, I. Am. J. trop. Med. Hyg. 1976, 25, 186. 9. Brotman, B., Prince, A. M., Godfrey, H. R. Lancet, 1973, i, 1305. 10. Newkirk, M. M., Downe, A. E. R., Simon, J. B. Gastroenterology, 1975, 69, 982. 11. Scheidegger, J. J. Int. Archs Allergy, 1955, 7, 103. 12. Werner, B. G., O’Connell, A. P., Summers, J. Proc.
15. Grady, G. F. Lancet, 1976, ii, 492.
AN IMMUNOLOGICAL DISORDER?
BRANISLAV D.
SLOBODAN JAKULIĆ JANKOVIĆ JOZEF HORVAT
Immunology Research Centre and Dr Laza K. Lazarević Psychiatric Clinic, Belgrade, Yugoslavia Patients with cerebral atrophy of unknown origin, patients with nuclear forms of schizophrenia or neurosis, and normal subjects were skin-tested with human brain and liver proteins. The frequency of positive delayed skin-sensitivity reactions to brain proteins was significantly higher in the cerebral-atrophy group than in other groups, thus suggesting a correlation between cerebral atrophy and cellmediated immunity. Introduction
Summary
CEREBRAL atrophy of unknown origin is a psychiatric enigma.1.2 This report describes our investigations of a possible relationship between cerebral atrophy and delayed skin hypersensitivity to human brain proteins.
Materials and Methods Water-soluble fractions3 were isolated from fresh human brain and liver. In Ouchterlony’s double diffusion, humanbrain-protein (H.B.P.) fraction developed 5 precipitin lines, and human-liver-protein (H.L.P.) fraction developed 2 lines when brought into contact with rabbit anti-H.B.P. serum. To test the encephalitogenicity of H.B.P., guineapigs and rats were immunised with 5 mg, 10 mg, and 20 mg of H.B.P. in Freund’s complete adjuvant4 (32-44 animals in each group) and skintested 7, 14, 21, and 28 days later with old tuberculin 1/10 and 60 µg H.B.P., and 60 µg H.L.P. Reactions4 were read at 24 hours. The animals were killed, and the cerebrum, cerebellum, and several levels of spinal cord were processed for histology. Nervous-tissue sections from rabbits immunised with H.B.P. were also examined. Other groups of animals were immunised with H.L.P. A total of 594 subjects, 187 of them (75 women, 112 men) with cerebral atrophy, were injected intradermally with 100 µg of H.B.P. and H.L.P. into the left forearm, and reactions were read 24 hours later. For pneumoencephalography,S 30 ml of air was injected into the lumbar subarachnoid space. Radiologically, cortical atrophy was indicated by widening of sulci, and white-matter atrophy by enlarged ventricled.6.7 Intellectual deterioration was the predominant symptom. Neurological examinations revealed a variety of disinhibition signs. The patients’ history and clinical examination excluded the following causes of cerebral atrophy: intoxication, hypoxia, nutritional and hormonal deficiencies, neoplasms, epilepsy, cerebral arteriosclerosis, senility, Pick’s disease, Huntington’s chorea, hereditary disorders, Alzheimer’s disease, parkinsonism, obstructions of brain ducti and foramina, hydrocephalus in childhood, aneurysms, abscesses, congenital cerebral maldevelopment, abnormal intracranial pressure, drug abuse, and noncerebral organic illnesses. About 30% of patients had had a head injury 1-5 years before the onset of the disease, and about 25% regularly consumed alcohol without showing signs of intoxication. Patients were treated with neuroleptic drugs Szmunes, W., Mach, M. I., Prince, A. M., Hoofnagle, J. H., Cherubin, C. E., Harley, E. J., Block, G. H. Ann. intern. Med. 1975, 83, 489. 17. Blumberg, B. S. Bull. Acad. Med. Toronto, 1972, 45, 45. 18. Stevens, C. E., Beasley, R. P. Tsui, J., Lee, W. New Engl. J. Med. 1975, 292, 16.
natn.
Acad. Sci. U.S.A.
1977, 74, 2149. Usinger, R. L. Monograph of Cimicidæ; p. 326. Entomological Society America, College Park, Maryland, 1976. 14. Magnius, L. O., Espmark, J. A. J. Immun. 1972, 109, 1017. 13.
CEREBRAL ATROPHY
of
771. 19.
Williams, J. E., Imlarp, S., Top, F. H., Cavanaugh, D. C., Russell, P. K.
Bull. Wld Hlth Org. 1976, 53, 365. 20. Monath, T. Personal communication.
220 TABLE I-DELAYED SKIN HYPERSENSITIVITY TO HUMAN BRAIN PROTEIN IN CEREBRAL ATROPHY
*
An arithmetic
+= 1;
score
reflecting an overall
response
was
calculated for each group,
depending on the degree of induration defined as follows: 0=0;
+ +-2;, +++=3; and ++++=4. the
t 18 patients were excluded because radiological diagnosis was equivocal. 6,7 t Figures in parenthesis are patients with no history of head injury or trauma. TABLE II—AGE AND DURATION OF ILLNESS IN 187 PATIENTS reaction was positive in all patients but negative in norWITH CEREBRAL ATROPHY mal subjects. There was no correlation between delayed skin hypersensitivity to H.B.P. and age or duration of illness in patients with cerebral atrophy (table n). In the 8 months after skin-testing, there was no evidence in any patient that the procedure had aggravated the disease. About a fifth of patients with cerebral atrophy developed local reactions to H.L.P., and 18% had anti-brain antibodies in their sera. The reaction of 35% of patients with nuclear schizophrenia to H.B.P. suggests that cell-mediated immunity, as well as the proposed activity of a unique anti-brain antibody,8 may be involved in the development of
schizophrenia. Discussion
(chlorpromazine, thioproperazine, methotrimeprazine, trimipramine, or fluphenazine). None of these drugs is known to induce delayed hypersensitivity to human brain proteins. Two control groups were set up-patients with nuclear forms of schizophrenia (I.C.D. code 295.0-295.3), patients with neurosis (I.C.D. code 300.0-300.4), and normal subjects. All patients in this study are still alive. Results
These results suggest a relationship between cerebral and cellular immunity. However, although the skin reaction described may well represent delayed hypersensitivity to brain proteins, it does not prove that those antigens cause the brain damage.9 Whether or not cerebral atrophy is a direct consequence of an autoimmune process remains to be seen. Immunochemical characterisation of the causal antigen and immunohistopathological evaluation of the cerebral atrophy are still
atrophy
Guineapigs and rats immunised with H.B.P. produced lacking. Another possibility raised by these results is that positive delayed skin reactions to H.B.P., H.L.P., and tuberculin, the strongest reactions being to H.B.P. and senile and presenile psychoses2 caused by or associated tuberculin. However, neurological and histopathological with brain damage and dementias of unknown origin examinations did not reveal allergic encephalomyelitis in may have a common immune denominator. these animals or in the rabbits in which anti-H.B.P. antibodies had been raised. The risk of using H.B.P. for skintesting a human being was therefore thought to be very small. Animals immunised with H.L.P. developed delayed skin hypersensitivity to H.L.P. but no histological lesions in the liver. The frequency of delayed skin hypersensitivity reactions to H.B.P. (table i) was significantly higher in patients with cerebral atrophy (69%) than in control groups (35% and 2.5%). The exclusion of proven cases of head trauma increased the proportion of positive skin reactions (768%). To evaluate the reproducibility of the skin-test, 47 patients with cerebral atrophy and positive skin reactions and 14 normal subjects with negative skin reactions were reinjected with H.B.P. into the right forearm 3-14 months after the first skin test. Again, the skin
We thank the medical personnel of the Dr Laza K. Lazarevic Psychiatric Clinic and the Immunology Research Centre who volunteered to take part in this study. This work was supported by the Republic of Serbia Research Fund, Belgrade.
Requests for reprints should be addressed to B. D. J., Immunology Research Centre, Vojvode Stepe 458, Belgrade, Yugoslavia. REFERENCES 1. Gregory, I. Fundamentals of Psychiatry; p. 653. Philadelphia, 1968. 2. Kolb, L. C. Modern Clinical Psychiatry; p. 299. Philadelphia, 1973. 3. Warecka, K., Moeller, H. J., Vogel, H. M., I. J. Neurochem. 1972,
Tripatzis,
19, 719. 4. Arnason, B. G., Janković, B. D., Waksman, B. H., Wennersten, C. J. exp. Med. 1962, 116, 177. 5. Lindgren, E. Acta radiol. 1949, 31, 161. 6. Robertson, E. G. Pneumoencephalography. Springfield, 1957. 7. Lim, S. T., Potts, G., Deck, M. D. F. Radiology, 1972,104, 585. 8. Heath, R. G., Krupp, I. M. Archs gen. Psychiat. 1967, 16, 1. 9. Paterson, P. Y. Adv. Immun. 1966, 5, 131.