Our goal is to understand the causes of autoimmune neurological disorders, particularly multiple sclerosis. The cause of MS is unknown, but strong evidence implicates a dysfunction of the immune system. Clinically, patients present with disturbances of sensorimotor and other central nervous system functions, and histologically the disease is characterized by demyelinated areas of brain and spinal cord, with infiltrations of immune cells. The most effective therapies target lymphocytes, by depletion, prevention of proliferation, or prevention of trafficking into the CNS. The most precisely targeted effective therapies are B cell depleting agents, and the most significant lab finding are oligoclonal expanded immunoglobulins in the cerebrospinal fluid, suggesting that B cells are an important component of MS. We are studying the role of this cell type in two complementary approaches. Observationally we are isolating and characterizing autoreactive B cells from patients; and experimentally we are trying to understand how autoreactive B cells can escape from tolerance. Our working hypothesis is that if autoreactive B cells capture their cognate self antigen from a virus-infected cell that also co-expresses viral antigens, these viral antigens can be co-captured by the B cell and presented to T cells, thus qualifying the B cell for fraudulent T cell help and circumventing the normal tolerance mechanism. Isolation and characterization of autoreactive B cells from patientsAutoantibodies involved in neurological diseases often bind to membrane proteins such as ion channels, neurotransmitter receptors and myelin proteins, and often recognize conformational epitopes, rather than simple amino acid sequences. This makes them difficult subjects for traditional antibody techniques such as western blotting and immunoprecipitation, which often involve denaturation steps. We have developed a novel technique for isolating B cells recognizing membrane protein antigens in their native conformation. We plan to characterize B cells identified using this process from the blood and CSF of patients with neurological symptoms. B cell escape from tolerance by viral antigen co-capture.Secretion of autoreactive antibodies is normally avoided directly by the elimination of self-reactive B cells, and indirectly by the elimination of self-reactive T cells, thus depriving self-reactive B cells of the T cell help needed for development into antibody-secreting plasma cells. It is not known why this mechanism fails in autoimmune diseases, but we hypothesize that the second mechanism could be overcome by self-reactive B cells that co-capture both self and viral antigens from the membranes of virus-infected cells and present them to virus-specific T cells. We have observed this phenomenon in vitro using mouse cells, and now plan to examine the plausibility of the process in human cells and in animal models.