PARANEOPLASTIC AUTOIMMUNITY--CALCIUM CHANNELS

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The Lambert-Eaton myasthenic syndrome (LES) is an IgG-mediated paraneoplastic autoimmune disorder of peripheral cholinergic synaptic transmission that causes muscle weakness and autonomic dysfunction, and is highly associated with small cell lung carcinoma (SCLC). Autoimmunity in LES appears to be the byproduct of a polyclonal IgG anti-tumor response directed against neuronal-type voltage-gated Ca2+ channels (VGCC) expressed in SCLC. The anti-VGCC antibodies produced in patients with LES have diverse specificities. Some are reactive with (omega-CgTx)-binding molecules (presumptive VGCC) expressed in human brain neurons and SCLC. IgGs of this specificity are also found in some patients who have SCLC without LES. The long-term objectives of this research are to improve the diagnosis and treatment of both LES and SCLC. Tools for the proposed studies include: frozen characterized sera from 200 LES patients: cryopreserved lymphocytes from 48 LES patients and numerous control patients; fresh specimens of human brain; omega-CgTx-GVIA (a high affinity ligand for some of the neuronal VGCC antigens that are immunoprecipitable by LES IgG); defined SCLC lines binding components of SCLC and neuronal membranes; CDNA probes and oligonucleotide primers and probes encoding a prototypic rat neuronal omega-CgTx-binding (N-type) VGCC; CDNA libraries (lambda gt11) made from RNAs of an omega-CgTx-binding SCLC lineand from human brain neurons. The Specific Aims are 1) to characterize and sequence the VGCC-like antigen of SCLC to which LES IgG binds, and the neuronal VGCC antigens that are targets for pathogenic IgG; ii) to use purified, recombinant and synthetic peptide VGCC antigens, and monoclonal antibodies (Mabs), to define immunologically the VGCC molecules (and epitopes) relevant to the pathogenesis of LES; iii) to develop new animal models to investigate the pathophysiological basis of neuromuscular and autonomic synaptic defects of LES.