We propose to establish a computerized database to classify patients with neurological paraneoplastic syndromes (nervous system disorders of unknown cause that occur in patients with identifiable or occult cancer). Two major syndromes are SSN (subacute sensory neuronopathy) associated with small cell lung cancer and a specific antibody to neuronal nuclei and PCD (paraneoplastic cerebellar degeneration) associated with breast and ovarian cancer and anti-Purkinje cell antibody (APCA). We will study the clinical presentation and natural history of the neurological disorder, and the underlying neoplasm, the presence or absence in serum or spinal fluid of autoantibodies against the nervous system (Using immunohistochemistry and immunoblotting) and the presence or absence of immunogenetic markers (i.e. immune complexes, HLA). We hope to identify clinical characteristics that allow one to suspect an occult, potentially curable cancer. We also propose to investigate the source of the autoantibodies and their potential role in the pathogenesis of the neurological disorder. We plan to screen tumor obtained at surgery and established tumor cell lines for the presence or absence of antigens that react with the autoantibodies in serum and spinal fluid (CSF) by immunohistochemistry and immunoblotting. We also intend to utilize purified IgG from patients harboring antibodies to inject into the CSF of animals, first looking for the incorporation of antibody into cells of the central nervous system and, second, in longer term experiments, to determine if the antibody causes cytotoxicity. We plan to study the effect of the IgG from patients on newborn rat dorsal root ganglion cells in tissue culture. The effects of IgG alone, IgG with complement and IgG with appropriate lymphocytes will be determined both with respect to neuronal uptake of the autoantibody and possible cytotoxicity. The serum of patients with SSN will be directly injected into the sciatic nerve of rats to determine if retrograde transport will lead to antibody entering cells of the dorsal root ganglion and if neurological disability is thus produced. Characterization of interactions among tumor, the immune system and the nervous system may advance our understanding of the biology of paraneoplastic syndromes.
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