Our research is broadly divided into studies concerning 1) the role of autoantibodies in the neurologic manifestations of retrovirus- induced diseases, and 2) regulatory abnormalities of the immune system which lead to the production of pathogenic autoantibodies. 1. Retrovirus-induced neurologic disease. We have developed ELISA and ELISA- spot assays to detect the production of autoantibodies reactive with cells of neuronal, glial and astrocyte origin. Using these new assays, we have identified elevated levels of anti- neuronal antibodies in AIDS patients with neurologic manifestations of HIV infection. Ongoing studies suggest that the concentration of these antibodies, titers of HIV antigen, levels of anti-HIV antibodies, and clinical manifestations of disease, are all reduced following treatment with AZT. Mice inoculated with LP-BM5 type C retroviruses develop a syndrome with marked similarities to human AIDS (know as murine AIDS or MAIDS). We have shown that the humoral manifestations of LP-BM5 infection occur in three non-discrete stages, marked initially by polyclonal B cell activation, then by hypergamma- globulinemia, and finally by generalized immunosuppression. 2. Systemic abnormalities in B cell activation. Approximately 10% of patients with systemic lupus erythematosus develop severe neurologic disorders, including seizures and psychosis. We are analyzing whether the development of these neurologic abnormalities correlates with the appearance of anti-neuronal antibodies in the CSF or serum of patients. Using murine models of SLE, we are investigating the regulatory abnormalities which lead to the production of these autoantibodies. We have found that B cell hyperactivation precedes the onset of clinically detectable disease. We have shown that this hyperactivation process is polyclonal in nature and appears to be lymphokine dependent. We are finding that changes in autoantibody affinity and isotype occur late in the disease process, and may correlate with autoantibody pathogenicity. The factors responsible for these changes (including lymphokines and autoantigens) are under active investigation.
