Taylor Devon K, Ito Emi, Thorn Mitchell, Sundar Krishnan, Tedder Thomas, Spatz Linda A
Department of Biochemistry, The Graduate Program in Biochemistry, The City College of New York, The Graduate Center, CUNY, New York, NY 10016, USA.
Mol Immunol. 2006 Apr;43(11):1776-90. doi: 10.1016/j.molimm.2005.11.003. Epub 2006 Jan 20.
Mice transgenic for the R4A-Cmu heavy chain of an anti-dsDNA antibody, maintain tolerance by anergy and deletion. In C57BL/6 mice overexpressing CD19, a molecule, which lowers the threshold for B cell activation, elevated levels of serum autoantibodies have been observed. In the present study, we wished to determine whether CD19 overexpression could alter the induction of tolerance in R4A-Cmu mice and lead to the secretion of transgenic anti-dsDNA antibodies. We, therefore, bred R4A-Cmu transgenic mice-to-mice transgenic for human CD19 (hCD19) and generated R4A-Cmu mice heterozygous and homozygous for hCD19. We, now report the spontaneous secretion of transgenic IgM anti-dsDNA antibody in the sera of R4A-Cmu mice overexpressing CD19, indicative of a loss of B cell tolerance. We observe that transgenic B cells secreting anti-dsDNA antibody in these mice are T independent and display a marginal zone like phenotype althought they do not reside in the MZ. In addition, they appear to be derived from the conventional B2 subset rather than the B1 subset. Interestingly, a subset of the anti-dsDNA B cells in these mice still display the phenotype and functional characteristics of anergic B cells. These B cells cannot be activated to secrete antibody following BCR crosslinking, however, they are hyper-responsive to activation by innate signaling mechanisms. This suggests that CD19 overexpression may promote anergic B cells to escape tolerance by converging with BCR independent pathways, thereby rendering these B cells hyper-responsive to innate signaling.
抗双链DNA抗体R4A-Cμ重链的转基因小鼠通过无反应性和细胞缺失维持耐受性。在过表达CD19（一种降低B细胞活化阈值的分子）的C57BL/6小鼠中，已观察到血清自身抗体水平升高。在本研究中，我们希望确定CD19过表达是否会改变R4A-Cμ小鼠的耐受性诱导，并导致转基因抗双链DNA抗体的分泌。因此，我们将R4A-Cμ转基因小鼠与人类CD19（hCD19）转基因小鼠杂交，培育出hCD19杂合和纯合的R4A-Cμ小鼠。我们现在报告，在过表达CD19的R4A-Cμ小鼠血清中自发分泌转基因IgM抗双链DNA抗体，这表明B细胞耐受性丧失。我们观察到，在这些小鼠中分泌抗双链DNA抗体的转基因B细胞不依赖T细胞，尽管它们并不位于边缘区（MZ），但表现出类似边缘区的表型。此外，它们似乎来源于传统的B2亚群而非B1亚群。有趣的是，这些小鼠中一部分抗双链DNA B细胞仍表现出无反应性B细胞的表型和功能特征。这些B细胞在BCR交联后不能被激活分泌抗体，然而，它们对先天信号机制的激活反应过度。这表明CD19过表达可能通过与不依赖BCR的途径汇聚，促进无反应性B细胞逃避耐受性，从而使这些B细胞对先天信号反应过度。
