THE B-CELL-SPECIFIC TRANSCRIPTION COACTIVATOR OCA-B OBF-1/BOB-1 IS ESSENTIAL FOR NORMAL PRODUCTION OF IMMUNOGLOBULIN ISOTYPES/

OCA-B was initially identified as a B-cell-restricted coactivator that functions with octamer binding transcription factors (Oct-1 and Oct-2 ) to mediate efficient cell type-specific transcription of immunoglobu lin promoters in vitro(1-3). Subsequent cloning studies led to identif ication of the coactivator as a single polypeptide, designated either as OCA-B (ref. 3), OBF-1 (ref. 4) or Bob-1 (ref. 5). OCA-B itself does not bind to DNA directly, but interacts with either Oct-1 or Oct-2 to potentiate transcriptional activation(1-5). To determine the biologic al role of OCA-B, we generated OCA-B-deficient mice by gene targeting. Mice lacking OCA-B undergo normal antigen-independent, B-cell differe ntiation, including appropriate expression of both immunoglobulin gene s and other early B-cell-restricted genes. However, antigen-dependent maturation of B cells is greatly affected. The proliferative response to surface IgM crosslinking is impaired, and there is a severe deficie ncy in the production of secondary immunoglobulin isotypes including I gG1, IgG2a, IgG2b, IgG3, IgA and IgE in BCA-B-deficient B cells. This defect is not due to a failure of the isotype switching process, but r ather to reduced levels of transcription from normally switched immuno globulin heavy-chain loci. In accord dth the defective isotype product ion, germinal centre formation is absent in these mutant mice.