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Anti-synaptic autoimmunity: An emerging clinical entity
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ANTI-SYNAPTIC AUTOIM]VlUNITY: AN EMERGING CLINICAL ENTITY VA Lennon, WS Brimijoin, E l l Lambert*. Mayo Clinic, Rochester, Mlq 55905 and *University of Minnesota, Minneapolis, MN 55455, U.S.A. Three examples of lgG autoaittibody-mediated anti-synaptic a,-'.oimmune disorders have been defined, all involving peripheral cholinergic motor synapses. "l'hese are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LES), and experimental autoimmune preganglionic sympathectomy (EAPS). The latter does not yet have a proven hut, an counterpart, but Shy-Drager syndrome and paranenplastic autonomic neuropathies are potential candidates. In each of the 3 examples, the autoantigen is an exposed functional molecule in synaptic membranes: the postsynaptic nicotinic aeetylcholine receptor (AChR), presynaptic voltage-gated calcium channel (VGCC) and neurotmnsmitter cleavage enzyme, acetylcholinesterase. The pathophysiology in MG and EAPS, but not in LES, involves complement activation. MG affects skeletal neuromuscular transmission exclusively, LES affects both skeletal and autonomic neurotransmission, and EAPS is sele¢;ive for autononuc transmission. The 3 autoimmnne disorders descri~! are prototypes of an entity of anti-synaptic autoimmunity that is emerging in a rapidly expanding field of clinical neumimmunology. Another candidate disorder is the Moerseh-Woltman stiff-man syndrome, a GABA--ergic synaptic disorder for which antibodies reactive with the neumtransmitter synthetic enzyme, glutamic acid decarboxylase, are a valuable marker; antibodies have not yet been proven to be pathogenic in this syndrome. By the year 2000 it can be anticipated that more common neurologic, neuropsychiatrie and gastrointestinal diseases may join this list. These may include idiopathic epilepsy, movement disorders, gut dysmotilities, and certain major psychotic disorders. Supported by NIH grants NS23537 (VAL), NS29646 (WSB) and NS23691 (EHL).
T CELL STIMULATORY AND MYASTHENOGENIC REGIONS IN HUMAN SKELETAL MUSCLE ACETYLCHOLINE RECEPTOR (AChR) a SUBUNIT VA Lennon, DJ McCormick, G E Griesmann, D Walser-Kuntz, M Hayashi, S Talib*, E H L a m b e r t +. Mayo Clinic, Rochester, MN, *University of Minnesota, Minneapolis, MN, and *Applied ImmuncSciences, Menlo park, CA, U.S.A. The nicotinic AChR of human muscle is the target for pathogenic autoantibodies of heterogeneous specjficities in myasthenia gravis. The a subunits account for 40% of the total protein in AChR, and each bears a binding site for neurotransmitter. Potential T cell regulatory segments in the a subtmit were investigated by immunizing female Lewis rats with native human AChR, recombinant a subanit (1-210) or synthetic a peptides. T cell responses were tested in vivo (delayed skin reactivity or T helper-dependent antibody responses), and in vitro (lymph node T cell proliferative responses. Six stimulatory regions were identified: 9-24, 41-56,125-147, 366-389, 389-409 and 418-437. Regions 41-56 and 125-147 were previously identified as T cell stimulatory in Torpedo AChR CZahnet al., 1988; Lennon et al., 1985), and 48-67 and 419-437 are stimulatory for some MG patients' blood T lymphoeytes OProttiet al., 1990). Peptides 125-147 and 389-409 were both myasthenngenic, and both induced AChR-modulating autoantibodies. These antibodies were a specific.by Western blot analysis, and in ELISAs did not bind to any human a peptides of unrelated sequence in a panel representing residues 1-437. One myasthenogenic determinant was mapped to the sequence 129-136. The myasthcnogenicity of 389-409 is evidence that the MA segment of AChR (364-388) crosses the plasma membrane. Our studies indicate that the human AChR is a far more complex autoantigen than anticipated from other experimental autoimmune disease models. Its myasthenogenicity is not attributable to a single immunogenic region at either the B or T cell level. Supported by NII-I grants NSIS057 (VAL), NS24694 (D/M), NS23691(EHL) and NS28608 (ST).
ANTI-SYNAPTIC AUTOIM]VlUNITY: AN EMERGING CLINICAL ENTITY VA Lennon, WS Brimijoin, E l l Lambert*. Mayo Clinic, Rochester, Mlq 55905 and *University of Minnesota, Minneapolis, MN 55455, U.S.A. Three examples of lgG autoaittibody-mediated anti-synaptic a,-'.oimmune disorders have been defined, all involving peripheral cholinergic motor synapses. "l'hese are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LES), and experimental autoimmune preganglionic sympathectomy (EAPS). The latter does not yet have a proven hut, an counterpart, but Shy-Drager syndrome and paranenplastic autonomic neuropathies are potential candidates. In each of the 3 examples, the autoantigen is an exposed functional molecule in synaptic membranes: the postsynaptic nicotinic aeetylcholine receptor (AChR), presynaptic voltage-gated calcium channel (VGCC) and neurotmnsmitter cleavage enzyme, acetylcholinesterase. The pathophysiology in MG and EAPS, but not in LES, involves complement activation. MG affects skeletal neuromuscular transmission exclusively, LES affects both skeletal and autonomic neurotransmission, and EAPS is sele¢;ive for autononuc transmission. The 3 autoimmnne disorders descri~! are prototypes of an entity of anti-synaptic autoimmunity that is emerging in a rapidly expanding field of clinical neumimmunology. Another candidate disorder is the Moerseh-Woltman stiff-man syndrome, a GABA--ergic synaptic disorder for which antibodies reactive with the neumtransmitter synthetic enzyme, glutamic acid decarboxylase, are a valuable marker; antibodies have not yet been proven to be pathogenic in this syndrome. By the year 2000 it can be anticipated that more common neurologic, neuropsychiatrie and gastrointestinal diseases may join this list. These may include idiopathic epilepsy, movement disorders, gut dysmotilities, and certain major psychotic disorders. Supported by NIH grants NS23537 (VAL), NS29646 (WSB) and NS23691 (EHL).
T CELL STIMULATORY AND MYASTHENOGENIC REGIONS IN HUMAN SKELETAL MUSCLE ACETYLCHOLINE RECEPTOR (AChR) a SUBUNIT VA Lennon, DJ McCormick, G E Griesmann, D Walser-Kuntz, M Hayashi, S Talib*, E H L a m b e r t +. Mayo Clinic, Rochester, MN, *University of Minnesota, Minneapolis, MN, and *Applied ImmuncSciences, Menlo park, CA, U.S.A. The nicotinic AChR of human muscle is the target for pathogenic autoantibodies of heterogeneous specjficities in myasthenia gravis. The a subunits account for 40% of the total protein in AChR, and each bears a binding site for neurotransmitter. Potential T cell regulatory segments in the a subtmit were investigated by immunizing female Lewis rats with native human AChR, recombinant a subanit (1-210) or synthetic a peptides. T cell responses were tested in vivo (delayed skin reactivity or T helper-dependent antibody responses), and in vitro (lymph node T cell proliferative responses. Six stimulatory regions were identified: 9-24, 41-56,125-147, 366-389, 389-409 and 418-437. Regions 41-56 and 125-147 were previously identified as T cell stimulatory in Torpedo AChR CZahnet al., 1988; Lennon et al., 1985), and 48-67 and 419-437 are stimulatory for some MG patients' blood T lymphoeytes OProttiet al., 1990). Peptides 125-147 and 389-409 were both myasthenngenic, and both induced AChR-modulating autoantibodies. These antibodies were a specific.by Western blot analysis, and in ELISAs did not bind to any human a peptides of unrelated sequence in a panel representing residues 1-437. One myasthenogenic determinant was mapped to the sequence 129-136. The myasthcnogenicity of 389-409 is evidence that the MA segment of AChR (364-388) crosses the plasma membrane. Our studies indicate that the human AChR is a far more complex autoantigen than anticipated from other experimental autoimmune disease models. Its myasthenogenicity is not attributable to a single immunogenic region at either the B or T cell level. Supported by NII-I grants NSIS057 (VAL), NS24694 (D/M), NS23691(EHL) and NS28608 (ST).