Liu Yang, Li Lisa, Mohan Chandra
Department of Internal Medicine and Immunology, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
J Immunol. 2008 Jun 1;180(11):7721-7. doi: 10.4049/jimmunol.180.11.7721.
In recently generated B6.56R anti-DNA autoantibody-transgenic mice, it was noted that a substantial fraction of the B cells that had avoided DNA reactivity had done so through the rearrangement and usage of the endogenous, nontargeted H chain (HC) allele. This suggested that rearrangement at the second HC locus might be an important mechanism through which self-reactive B cells might successfully revise their initial Ag specificity. To test the importance of this mechanism in B cell tolerance, we generated B6.56R/56R mice that possessed the 56R anti-DNA H chain transgene inserted into both HC loci. These transgenic homozygotes developed higher titers of anti-DNA Abs, with an expanded population of B220(low)MHC class II(low) B cells, enriched for CD21(low)CD23(low) preplasmablasts. The analysis of hybridomas from these mice revealed that the only avenue by which these B cells could avoid DNA reactivity was through the use of the editor L chains, V(k)20 or V(k)21. Hence, in addition to LC editing, rearrangement and usage of the second HC locus/allele constitutes an important safety valve for B cells the primary BCR of which confers DNA reactivity. In contrast to these tolerance mechanisms, editing the first rearranged HC locus (through HC replacement) and somatic mutations appear to be less frequently used to edit/revise self-reactive B cells.
在最近培育出的携带B6.56R抗DNA自身抗体的转基因小鼠中，人们注意到，相当一部分避免了与DNA发生反应的B细胞是通过内源性、非靶向重链（HC）等位基因的重排和使用来实现的。这表明，第二个HC基因座的重排可能是自身反应性B细胞成功改变其初始抗原特异性的重要机制。为了测试这一机制在B细胞耐受性中的重要性，我们培育了B6.56R/56R小鼠，其两个HC基因座都插入了56R抗DNA重链转基因。这些转基因纯合子产生了更高滴度的抗DNA抗体，B220（低）MHC II类（低）B细胞群体扩大，富含CD21（低）CD23（低）前浆母细胞。对这些小鼠杂交瘤的分析表明，这些B细胞避免与DNA发生反应的唯一途径是使用编辑轻链V（k）20或V（k）21。因此，除了轻链编辑外，第二个HC基因座/等位基因的重排和使用构成了B细胞的一个重要安全阀，其主要BCR赋予DNA反应性。与这些耐受机制相反，编辑第一个重排的HC基因座（通过HC替换）和体细胞突变似乎较少用于编辑/修正自身反应性B细胞。
