AUTOIMMUNE PARANEOPLASTIC SYNDROMES

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The Lambert-Eaton myasthenic syndrome (LES) is a disease of neuromuscular transmission in which there is a deficient quantal release of acetylcholine (ACh) in response to a nerve impulse. Its etiology remains unknown. Striking features of this disease include a high incidence of bronchogenic carcinoma (plus or minus 65% of patients), usually of the small cell (oat cell) type (SCC), and a high prevalence of autoantibodies (e.g., to specific thyroid and stomach constituents). Passive transfer of plasma immunoglobulins from patients to mice causes a defect in neuromuscular transmission similar to that of LES. Our hypothesis is that failure of neuromuscular transmission in the LES results from an autoimmune response against cholinergic neurons or related structures, which may be initiated by an antitumor immune response directed against a neuron-related differentation antigen of SCC. We plan to study SCC immunologically to determine whether or not the tumors or their products can express antigens related to cholinergic neurons. Sera from LES patients with and without carcinoma will be tested for reactivity with SCC, cholinergic neurons, and other neural substrates. Cholinergic nerve terminals from the electric organ of Torpedo californica will be investigated as another potential source of antigen relevant to LES. Monoclonal antibodies raised against SCC and cholinergic neuron components will be used both to identify and purify the antigens of relevance. This project's goal is to determine the nature of the primary autoimmune abnormality in LES. A related goal is to establish an animal model for LES that: (1) will facilitate detailed analysis of the mechanisms responsible for the failure of release of ACh quanta in LES; (2) may yield a serologic test for diagnosis of LES and/or small cell carcinoma; and (3) will allow evaluation of new modes of therapy for LES and/or small cell carcinoma. (IB)