Seagal Jane, Edry Efrat, Keren Zohar, Leider Nira, Benny Ofra, Machluf Marcelle, Melamed Doron
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
J Exp Med. 2003 Nov 17;198(10):1609-19. doi: 10.1084/jem.20030357.
In B lymphocytes, immunoglobulin (Ig)M receptors drive development and construction of naive repertoire, whereas IgG receptors promote formation of the memory B cell compartment. This isotype switching process requires appropriate B cell activation and T cell help. In the absence of T cell help, activated B cells undergo Fas-mediated apoptosis, a peripheral mechanism contributing to the establishment of self-tolerance. Using Igmicro-deficient microMT mouse model, where B cell development is blocked at pro-B stage, here we show an alternative developmental pathway used by isotype-switched B cell precursors. We find that isotype switching occurs normally in B cell precursors and is T independent. Ongoing isotype switching was found in both normal and microMT B cell development as reflected by detection of IgG1 germline and postswitch transcripts as well as activation-induced cytidine deaminase expression, resulting in the generation of IgG-expressing cells. These isotype-switched B cells are negatively selected by Fas pathway, as blocking the Fas/FasL interaction rescues the development of isotype-switched B cells in vivo and in vitro. Similar to memory B cells, isotype-switched B cells have a marginal zone phenotype. We suggest a novel developmental pathway used by isotype-switched B cell precursors that effectively circumvents peripheral tolerance requirements. This developmental pathway, however, is strictly controlled by Fas/FasL interaction to prevent B cell autoimmunity.
在B淋巴细胞中，免疫球蛋白（Ig）M受体驱动初始库的发育和构建，而IgG受体促进记忆B细胞区室的形成。这种同种型转换过程需要适当的B细胞活化和T细胞辅助。在缺乏T细胞辅助的情况下，活化的B细胞会经历Fas介导的凋亡，这是一种有助于建立自身耐受性的外周机制。利用Igμ缺陷的μMT小鼠模型（其中B细胞发育在pro-B阶段受阻），我们在此展示了同种型转换的B细胞前体所采用的另一种发育途径。我们发现同种型转换在B细胞前体中正常发生且不依赖T细胞。在正常和μMT B细胞发育过程中均发现了持续的同种型转换，这可通过检测IgG1种系和转换后转录本以及活化诱导的胞苷脱氨酶表达来反映，从而导致产生表达IgG的细胞。这些同种型转换的B细胞通过Fas途径被阴性选择，因为阻断Fas/FasL相互作用可在体内和体外挽救同种型转换的B细胞的发育。与记忆B细胞相似，同种型转换的B细胞具有边缘区表型。我们提出了同种型转换的B细胞前体所采用的一种新的发育途径，该途径有效地规避了外周耐受性要求。然而，这种发育途径受到Fas/FasL相互作用的严格控制，以防止B细胞自身免疫。
