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Immunology 7oday, v0!. 3, No. 12, 1982
Antibodies begin to count in the neurology clinic f r o m T o m Barkas Having fostered a journal and its first international congress*, neuroimmunology might be said to have come of age. If non-practitioners are wondering what the term encompasses, the congress discussed cell m a r k e r s a n d receptors, i m m u n e mechanisms in neurological damage, neurovirology, a n d immunological approaches to the investigation and treatment of neurological d i s e a s e s a programme which demonstrates neuroimmunology's origins in the study of nervous system pathology. It has been known since the 1960s that the i m m u n e and neural systems have antigens in common. An example is the O K T 8 h u m a n T-cell antigen which has recently also been found on sheep oligodendrocytes (B. Arnason, Pritzker Med. Sch., Chicago). Furthermore. monoclonal antibodies are now available which react with neurones, astrocytes and thymocytes (C. Goridis, I N S E R M , Marseille) and with glioma cells and l y m p h o i d cells (D. Bigner, Duke University, Durham). H. Bluestein ( U C L A ) showed that sera from patients with systemic lupus erythematosus contained anti-neuronal antibodies, some of which could be absorbed out by lymphocytes. The titre of these antibodies is higher in patients with involvement of the central nervous system, especially in the cerebrospinal fluid itself. At least six different specificities can be defined by binding to neuroblastoma or gliablastoma cell lines. Eaton-Lambert syndrome, motor neurone disease (MND) and GuillainBarra s y n d r o m e are neurological disorders now pushing for classification as %utoimmune'. V. Lennon (Mayo Clinic, Rochester) has found a range of autoantibodies in 73 patients with Eaton-Lambert syndrome, titres to thyrogastric antigens being as high as in thyroiditis or pernicious anaemia. J. Newsom-Davis (Royal Free *The first neuroimmunologycongress was held in Stresa, Italy, on September 27-October 1 1982.
Hospital, London), who has already reported the presence of autoantibody to nerve t e r m i n a l s in this disease, has found that of 11 patients 9 were positive for H L A B8 and 7 for DR3. Immunoglobulin from the sera of patients with M N D binds specifically to rat spinal cord neurones and M N D lymphocytes respond ~ poorly to mitogens (R. H a r r i s o n el al., University of Bath). T h e r e are r e p o r t s t h a t a n t i neuronal antibodies are both present and absent in Guillain-Barr~ syndrome. Reviewing the studies, J. Aarli (University of Bergen) seemed to conclude that they do appear, at least in the acute stage of the disease, and suggested that plasmapheresis should be done only if antibodies were found. A London trial of plasmapheresis has shown no significant benefit at three months (Newsom-Davis). L. H a n s e n el al. (University of Sydney) have electrophysiological and histological evidence that rat sciatic nerves demyelinate in the presence of fresh serum from Guillain-Barrfi patients. Throughout the congress monoclonal antibodies reared their identical heads. V. ter Meulen (University of Wurzburg) demonstrated that for effective immunization against rabies virus, all the viral epitopes must be covered while, in contrast, a single monoclonaI could restore the defective function in vitro of cells from virusinfected SSPE patients. The shadowing of h u m a n glioma cells in nude mice with radiolabelled monoclonals was reported by D. Bigner who emphasized that the antibodies had specific activities almost high enough to make them usable as chemotherapeutic agents. Most monoclonal antibodies to the acetylcholine receptor in the rat (but not the mouse - V. Lennon) and t h e anti-receptor antibodies found in patients with myasthenia gravis bind to a c o m m o n area of the major immunogenic region (MIR) (J. Lindstrom, Salk Institute). The spectrum of myasthenic antibodies (defined by
cross-competition studies with monoclonal antibodies) does not correlate with the severity of the disease perhaps not surprisingly, since competition between two large immunoglobulin molecules for a third, only slightly larger molecule (the receptor) could easily mask m a n y differences. Interestingly, in reconstitution experiments, a monoclonal antibody to the M I R had no effect on receptor activity while an antibody to a distant site inhibited non-competitively. J. Brockes (Cal. Tech.) has raised a monoclonal antibody to the sodium channel protein and has used this as an affinity ligand for further purification of the protein. T h i s antibody has no effect on the binding of specific toxins or the physiological response. N. Geschwind (Harvard University) described the two widely reported studies showing an increased frequency of a u t o i m m u n e disease in left-handed c o m p a r e d with righthanded people. A subsequent study of the frequency of left-handedness in patients with autoimrnune disease or migraine gave less dear-cut results: the frequency was significantly raised in migraine suffers but in myasthenic patients only if the criteria for handedhess were less stringent and not at all in the whole group of autoimmune patients (this group, however, did not contain patients with i m m u n e disorders of the bowel or gut, who were especially p r e v e l a n t in the first studies). Geschwind suggested that the changes are induced by abnormal levels of testosterone, which inhibits both neuronal growth and thymic development. T h e testosterone produced by the tbetal testes may selectively affect the more slowly differentiating left hemisphere, causing a shift to left-handedness, impairing language functions and simultaneously disturbing lymphocyte maturation in the thymus. Why the a u t o i m m u n e diseases of the gut might be especially affected is unclear. Tom Barkas i~ in tt~e Deparlment oj Biochemistry, University of Geneva, Switzerland.
Immunology 7oday, v0!. 3, No. 12, 1982
Antibodies begin to count in the neurology clinic f r o m T o m Barkas Having fostered a journal and its first international congress*, neuroimmunology might be said to have come of age. If non-practitioners are wondering what the term encompasses, the congress discussed cell m a r k e r s a n d receptors, i m m u n e mechanisms in neurological damage, neurovirology, a n d immunological approaches to the investigation and treatment of neurological d i s e a s e s a programme which demonstrates neuroimmunology's origins in the study of nervous system pathology. It has been known since the 1960s that the i m m u n e and neural systems have antigens in common. An example is the O K T 8 h u m a n T-cell antigen which has recently also been found on sheep oligodendrocytes (B. Arnason, Pritzker Med. Sch., Chicago). Furthermore. monoclonal antibodies are now available which react with neurones, astrocytes and thymocytes (C. Goridis, I N S E R M , Marseille) and with glioma cells and l y m p h o i d cells (D. Bigner, Duke University, Durham). H. Bluestein ( U C L A ) showed that sera from patients with systemic lupus erythematosus contained anti-neuronal antibodies, some of which could be absorbed out by lymphocytes. The titre of these antibodies is higher in patients with involvement of the central nervous system, especially in the cerebrospinal fluid itself. At least six different specificities can be defined by binding to neuroblastoma or gliablastoma cell lines. Eaton-Lambert syndrome, motor neurone disease (MND) and GuillainBarra s y n d r o m e are neurological disorders now pushing for classification as %utoimmune'. V. Lennon (Mayo Clinic, Rochester) has found a range of autoantibodies in 73 patients with Eaton-Lambert syndrome, titres to thyrogastric antigens being as high as in thyroiditis or pernicious anaemia. J. Newsom-Davis (Royal Free *The first neuroimmunologycongress was held in Stresa, Italy, on September 27-October 1 1982.
Hospital, London), who has already reported the presence of autoantibody to nerve t e r m i n a l s in this disease, has found that of 11 patients 9 were positive for H L A B8 and 7 for DR3. Immunoglobulin from the sera of patients with M N D binds specifically to rat spinal cord neurones and M N D lymphocytes respond ~ poorly to mitogens (R. H a r r i s o n el al., University of Bath). T h e r e are r e p o r t s t h a t a n t i neuronal antibodies are both present and absent in Guillain-Barr~ syndrome. Reviewing the studies, J. Aarli (University of Bergen) seemed to conclude that they do appear, at least in the acute stage of the disease, and suggested that plasmapheresis should be done only if antibodies were found. A London trial of plasmapheresis has shown no significant benefit at three months (Newsom-Davis). L. H a n s e n el al. (University of Sydney) have electrophysiological and histological evidence that rat sciatic nerves demyelinate in the presence of fresh serum from Guillain-Barrfi patients. Throughout the congress monoclonal antibodies reared their identical heads. V. ter Meulen (University of Wurzburg) demonstrated that for effective immunization against rabies virus, all the viral epitopes must be covered while, in contrast, a single monoclonaI could restore the defective function in vitro of cells from virusinfected SSPE patients. The shadowing of h u m a n glioma cells in nude mice with radiolabelled monoclonals was reported by D. Bigner who emphasized that the antibodies had specific activities almost high enough to make them usable as chemotherapeutic agents. Most monoclonal antibodies to the acetylcholine receptor in the rat (but not the mouse - V. Lennon) and t h e anti-receptor antibodies found in patients with myasthenia gravis bind to a c o m m o n area of the major immunogenic region (MIR) (J. Lindstrom, Salk Institute). The spectrum of myasthenic antibodies (defined by
cross-competition studies with monoclonal antibodies) does not correlate with the severity of the disease perhaps not surprisingly, since competition between two large immunoglobulin molecules for a third, only slightly larger molecule (the receptor) could easily mask m a n y differences. Interestingly, in reconstitution experiments, a monoclonal antibody to the M I R had no effect on receptor activity while an antibody to a distant site inhibited non-competitively. J. Brockes (Cal. Tech.) has raised a monoclonal antibody to the sodium channel protein and has used this as an affinity ligand for further purification of the protein. T h i s antibody has no effect on the binding of specific toxins or the physiological response. N. Geschwind (Harvard University) described the two widely reported studies showing an increased frequency of a u t o i m m u n e disease in left-handed c o m p a r e d with righthanded people. A subsequent study of the frequency of left-handedness in patients with autoimrnune disease or migraine gave less dear-cut results: the frequency was significantly raised in migraine suffers but in myasthenic patients only if the criteria for handedhess were less stringent and not at all in the whole group of autoimmune patients (this group, however, did not contain patients with i m m u n e disorders of the bowel or gut, who were especially p r e v e l a n t in the first studies). Geschwind suggested that the changes are induced by abnormal levels of testosterone, which inhibits both neuronal growth and thymic development. T h e testosterone produced by the tbetal testes may selectively affect the more slowly differentiating left hemisphere, causing a shift to left-handedness, impairing language functions and simultaneously disturbing lymphocyte maturation in the thymus. Why the a u t o i m m u n e diseases of the gut might be especially affected is unclear. Tom Barkas i~ in tt~e Deparlment oj Biochemistry, University of Geneva, Switzerland.
