Paraneoplastic neurologic diseases (PND) represent remote effects of cancer on the nervous system. These disorders are characterized by rapidly progressive deterioration to incapacitation within weeks to months. No effective treatments have been identified. We recently identified three subtypes of antineuronal IgG present in PND patient sera and CSF. IgG has been identified which is reactive with 36-40 kD Purkinje cell cytoplasmic proteins (Type I), 36-42 kD cerebellar granular neuronal proteins (Type II), and neuronal and glial processes and cytoplasm (Type III). Each antibody subtype is associated with particular systemic tumors and specific neurologic disorders. Tumor from PND patients contains specifically bound IgG which, when eluted remains reactive with CNS neurons. Despite these discoveries, the exact sequence of events leading to autoimmune nervous tissue destruction remains unclear. The objectives of this proposal are to explore the autoimmune pathogenesis of PND and examine the relationship of systemic cancer to the development of these disorders. These objectives will be met by the following specific aims: (1) Evaluation of the role of humoral immunity in the pathogenesis of PND. The antineuronal antibodies will be characterized and correlated with tumor histology and the disease, and the role of complement-mediated antibody cytotoxicity in the production of target tissue destruction will be ascertained. (2) Evaluation of the role of cellular immunity in the pathogenesis of PND. Lymphoproliferation, antibody-dependent cytotoxicity, and antigen-directed T cell cytotoxicity will be examined. (3) Purification sequencing, and synthesis of neuronal antigens identified by the Type I, II, and III antibody subtypes. Affinity purification of antigens recognized by antibody subtypes and subsequent sequencing and synthesis of antigenic peptides will be explored. (4) Characterization of Type I, II, and III antigenic epitopes which are co-expressed by tumor and central nervous system tissues. Tumor and nervous system antigens will be compared by immunoblotting and attempts to identify antigenic sequence homology.
