Passive transfer of Lambert-Eaton myasthenic syndrome with IgG from man to mouse depletes the presynaptic membrane active zones

H. Fukunaga, A. G. Engel, B. Lang, J. Newsom-Davis, A. Vincent

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In the Lambert-aston myasthenic syndrome (LEMS), there is a decreased release of acetylcholine quanta from the nerve terminal by nerve impulse. Recently, an autoimmune origin of LEMS was documented by passive transfer of its electrophysiologic features from man to mouse with IgG. Freeze-fracture electron microscopy of LEMS neuromuscular junctions has revealed a paucity of presynaptic membrane active zones. Thus, the active zones might be the targets of the pathogenic autoantibodies in LEMS. To test this assumption, freeze-fracture electron microscopic studies were done in mice injected with 10 mg of IgG daily from each of three LEMS patients and in control mice treated with normal IgG or no IgG. IgG from patients 1 and 2 impaired neuromuscular transmission in mice, but IgG from patient 3 failed to do so. After 52-69 days of treatment, diaphragm or anterior tibial muscles were removed and coded. Paired muscles from control mice and mice receiving LEMS IgG were studied 'blindly'. Satisfactory freeze-fracture replicas of 185 presynaptic membrane P-faces were analyzed by stereometric methods. In mice treated with LEMS IgG that was pathogenic by electrophysiologic criteria, there was a selective depletion of active zones and active-zone particles but not of other membrane particles and there was a concomitant increase of large membrane particles aggregated into clusters. These findings provide additional evidence that the active zones facilitate quantal transmitter release by nerve impulse, lend further support to the assumption that the active-zone particles are Ca2+ channels, and establish mediation of the membrane lesions in LEMS by IgG.

Original languageEnglish (US)
Pages (from-to)7636-7640
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24 I
StatePublished - 1983

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