B-LYMPHOCYTES PRODUCING DEMYELINATING AUTOANTIBODIES - DEVELOPMENT AND FUNCTION IN GENE-TARGETED TRANSGENIC MICE

We studied the cellular basis of self tolerance of B cells specific fo r brain autoantigens using transgenic mice engineered to produce high titers of autoantibodies against the myelin oligodendrocyte glycoprote in (MOG), a surface component of central nervous system myelin. We gen erated ''knock-in'' mice by replacing the germline J(H) locus with the rearranged immunoglobulin (Ig) H chain variable (V) gene of a pathoge nic MOG-specific monoclonal antibody. In the transgenic mice, conventi onal B cells reach normal numbers in bone marrow and periphery and exp ress exclusively transgenic H chains, resulting in high titers of MOG- specific serum Igs. Additionally, about one third of transgenic B cell s bind MOG, thus demonstrating dir absence of active tolerization. Fur thermore, peritoneal B-1 lymphocytes are strongly depleted. Upon immun ization with MOG, the mature transgenic B cell population undergoes no rmal differentiation to plasma cells secreting MOG-specific IgG antibo dies, during which both Ig isotype switching and somatic mutation occu r. In naive transgenic mice, the presence of this substantial autoreac tive B cell population is benign, and the mice fall to develop either spontaneous neurological disease or pathological evidence of demyelina tion. However, the presence of the transgene both accelerates and exac erbates experimental autoimmune encephalitis, irrespective of the iden tity of the initial autoimmune insult.