AUTOIMMUNITY TO CALCIUM CHANNELS IN LAMBERT EATON SYNDRO

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

The autoimmune response in the Lambert-Eaton myasthenic syndrome (LES), is thought to be triggered by the presence of a tumor, particularly small-cell lung cancer (SCLC). Presynaptic calcium channels at the neuromuscular junction (NMJ) are the target of the antibodies in I[unreadable]S patients, thus it is reasonable to assume that the putative autoantigens in SCLC cells possess the same molecular characteristics as the P/O-type Ca2+ channels found at the human NMJ. The current proposal is aimed at verifying a central hypothesis: SCLc cells express omega-agatoxin WA-sensitive P/Q-type voltage-dependent Ca2+ channels (VDCCs), which act as the primary immunogen in this disease; these channels initiate and maintain LBS patient's autoimmune response and the autoantibodies so produced then destructively cross-react with the target antigens at the NMJ. The long term objective of this proposal is two-fold: 1) to identify the primary and secondary autoantigens that initiate and maintain the production of pathogenic antibodies in L[unreadable]S; and 2) to determine their pathogenic role in clinical manifestation of the peripheral motor and autonomic nervous system dysfunctions characterizing this disease. This study will pursue four Specific Aims: [1] To determine the specificity of L[unreadable]S autoantibodies for subtypes of VDCCs; [2] To determine the cross-reactivity of LBS IgG using cloned alpha1 Ca2+ channel subunit currents expressed in stably transfected human embryonic kidney (HBK293) cell lines and Xenopus oocytes; [3] To develop and characterize an experimental autoimmune animal model of the Lambert-Baton syndrome (EALES); and [4] To determine P/Q-type Ca2+ channel vs. synaptotagmin dysfunction at the NMJs of mice with passively transferred LES.