B-Cell Generation Activation, and Differentiation CHAPTER 11 253 k 属 -)25-50% of mature B cells expres (c)H-2 dk transgenics Light-chain editing mature b cells with new light chains no longer bind Kk GURE11-5 Experimental evidence for negative selection(clonal mature so that 25%-50% of the splenic B cells expressed the trans. deletion) of self-reactive B cells during maturation in the bone mar- gene-encoded anti-K as membrane lg. More detailed analysis of the row. The presence or absence of mature peripheral B cells expressing H-2dktransgenics revealed a few peripheral B cells that expressed the a transgene- encoded igM against the H-2 class I molecule K was transgene-encoded u chain but a different light chain( c). Apparently determined in H-2 mice(a)and H-2 mice(b). In the H-2a trans- a few immature b cells underwent light-chain editing, so they no genic, the immature B cells recognized the self-antigen K and were longer bound the K molecule and consequently escaped negative se. deleted by negative selection. In the H-2transgenics, the immature lection. Adapted from D A Nemazee and K Burki, 1989, Nature 337. B cells did not bind to a self-antigen and consequently went on to 562: S.L. Tiegs et al., 1993, JEM 177: 1009. (e.g, the K molecule in H-2transgenics) present on stro- does not always result in their immediate deletion(Figure mal cells, leading to crosslinking of the antibodies and subse- 11-5c). Instead, maturation of the self-reactive cell is arrested quent death of the immature B cells while the B cell"edits"the light-chain gene of its receptor In this case, the H-2 transgenics produced a few mature Self-Reactive B Cells May Be Rescued B cells that expressed mlgm containing the u chain encoded by Editing of Light-Chain Genes in the transgene, but different, endogenous light chains. One explanation for these results is that when some immature Later work using the transgenic system described by Nemazee B cells bind a self-antigen, maturation is arrested; the cells nd Burki showed that negative selection of immature B cells up-regulate RAG-1 and RAG-2 expression and begin further(e.g., the Kk molecule in H-2d/k transgenics) present on stro￾mal cells, leading to crosslinking of the antibodies and subse￾quent death of the immature B cells. Self-Reactive B Cells May Be Rescued by Editing of Light-Chain Genes Later work using the transgenic system described by Nemazee and Burki showed that negative selection of immature B cells does not always result in their immediate deletion (Figure 11-5c). Instead, maturation of the self-reactive cell is arrested while the B cell “edits” the light-chain gene of its receptor. In this case, the H-2d/k transgenics produced a few mature B cells that expressed mIgM containing the chain encoded in the transgene, but different, endogenous light chains. One explanation for these results is that when some immature B cells bind a self-antigen, maturation is arrested; the cells up-regulate RAG-1 and RAG-2 expression and begin further B-Cell Generation, Activation, and Differentiation CHAPTER 11 253 Kd (b) H-2d transgenics 25–50% of mature B cells express anti -Kk (c) H-2 d/k transgenics A few mature B cells with new light chains no longer bind Kk Light-chain editing Immature B cells Bone-marrow stromal cell Anti-Kk Kk (a) H-2d/k transgenics No mature B cells express anti-Kk Kd FIGURE 11-5 Experimental evidence for negative selection (clonal deletion) of self-reactive B cells during maturation in the bone mar￾row. The presence or absence of mature peripheral B cells expressing a transgene-encoded IgM against the H-2 class I molecule Kk was determined in H-2d/k mice (a) and H-2d mice (b). In the H-2d/k trans￾genics, the immature B cells recognized the self-antigen Kk and were deleted by negative selection. In the H-2d transgenics, the immature B cells did not bind to a self-antigen and consequently went on to mature, so that 25%–50% of the splenic B cells expressed the trans￾gene-encoded anti-Kk as membrane Ig. More detailed analysis of the H-2d/k transgenics revealed a few peripheral B cells that expressed the transgene-encoded chain but a different light chain (c). Apparently, a few immature B cells underwent light-chain editing, so they no longer bound the Kk molecule and consequently escaped negative se￾lection. [Adapted from D. A. Nemazee and K. Burki, 1989, Nature 337: 562; S. L. Tiegs et al., 1993, JEM 177:1009.]