The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes
The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes
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DOI：
10.1038/383542a0
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发表时间：
1996-10-10
期刊：
影响因子：
64.8
通讯作者：
Roeder, RG
中科院分区：
文献类型：
--
作者：
Kim, U;Qin, XF;Roeder, RG
OCA-B最初被鉴定为B细胞限制性共激活因子，其与八聚体结合转录因子（Oct-1和Oct-2）一起发挥作用，在体外介导免疫球蛋白启动子的有效细胞类型特异性转录（1-3）。随后的克隆研究将共激活因子鉴定为单一多肽，命名为OCA-B（参考文献3）、OBF-1（参考文献4）或Bob-1（参考文献5）。OCA-B本身不直接与DNA结合，但与Oct-1或Oct-2相互作用以增强转录激活（1-5）。为了确定OCA-B的生物学作用，我们通过基因靶向产生了OCA-B缺陷小鼠。缺乏OCA-B的小鼠经历正常的抗原非依赖性B细胞分化，包括免疫球蛋白基因和其他早期B细胞限制性基因的适当表达。然而，B细胞的抗原依赖性成熟受到很大影响。对表面IgM交联的增殖反应受损，并且在BCA-B缺陷型B细胞中，包括IgG 1、IgG 2a、IgG 2 B b、IgG 3、伊加和IgE的次级免疫球蛋白同种型的产生严重不足。这种缺陷不是由于同种型转换过程的失败，而是由于正常转换的免疫球蛋白重链基因座的转录水平降低。与同种型产生缺陷的雅阁，在这些突变小鼠中不存在生发中心形成。
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 immunoglobulin promoters in vitro(1-3). Subsequent cloning studies led to identification 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 biological role of OCA-B, we generated OCA-B-deficient mice by gene targeting. Mice lacking OCA-B undergo normal antigen-independent, B-cell differentiation, including appropriate expression of both immunoglobulin genes 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 deficiency in the production of secondary immunoglobulin isotypes including IgG1, 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 rather to reduced levels of transcription from normally switched immunoglobulin heavy-chain loci. In accord dth the defective isotype production, germinal centre formation is absent in these mutant mice.