Patients with antibody associated paraneoplastic neurologic syndromes make a profound immune response against their tumor, which cross-reacts with the nervous system and may result in neurological dysfunction. These patients provide the opportunity to study the mechanisms of the anti-tumor immune response and to elucidate the structure and function of human tumor antigens. This application focuses on the paraneoplastic syndrome, Lambert-Eaton myasthenic syndrome (LEMS). LEMS is a disorder of neuromuscular function found in high association with small cell lung cancer. Preliminary studies have resulted in the cloning of two proteins which are highly homologous to the beta subunit of the voltage gated calcium channel. These proteins are likely to represent the target of the immune response in LEMS. Studies are proposed to investigate why patients with antibody associated paraneoplastic diseases mount such a profound immune response against their tumor and how this immune response results in the disruption of neuromuscular and brain dysfunction. Experiments will focus on establishing any structural or functional differences between tumor and normal cell proteins. Cloned antigens will be characterized by DNA sequence analysis. The expression of these antigens in normal and neoplastic tissue will be studied as well as the expression of other tumor proteins that may influence the development of the immune response (i.e., MHC-I). The role of the (3 subunit in calcium channel function and the effect of LEMS IgG on this function will be examined. Of direct clinical relevance will be the development of a specific and sensitive serologic test for LEMS.
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