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J. Exp. Med.,
Volume 188, Number 1, July 1, 1998 169-180
By
From the * Max-Planck-Institut für Neurobiologie, D-82152 Martinsried, Germany; the We studied the cellular basis of self tolerance of B cells specific for brain autoantigens using
transgenic mice engineered to produce high titers of autoantibodies against the myelin oligodendrocyte glycoprotein (MOG), a surface component of central nervous system myelin. We
generated "knock-in" mice by replacing the germline JH locus with the rearranged immunoglobulin (Ig) H chain variable (V) gene of a pathogenic MOG-specific monoclonal antibody.
In the transgenic mice, conventional B cells reach normal numbers in bone marrow and periphery and express exclusively transgenic H chains, resulting in high titers of MOG-specific
serum Igs. Additionally, about one third of transgenic B cells bind MOG, thus demonstrating
the absence of active tolerization. Furthermore, peritoneal B-1 lymphocytes are strongly depleted. Upon immunization with MOG, the mature transgenic B cell population undergoes
normal differentiation to plasma cells secreting MOG-specific IgG antibodies, during which
both Ig isotype switching and somatic mutation occur. In naive transgenic mice, the presence
of this substantial autoreactive B cell population is benign, and the mice fail to develop either spontaneous neurological disease or pathological evidence of demyelination. However, the
presence of the transgene both accelerates and exacerbates experimental autoimmune encephalitis, irrespective of the identity of the initial autoimmune insult.
Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany; and the § Institute of
Neurology, University of Vienna, A-1090 Vienna, Austria
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