Activation of autoreactive B cells by CpG dsDNA
Activation of autoreactive B cells by CpG dsDNA
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DOI：
10.1016/s1074-7613(03)00323-6
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发表时间：
2003-12-01
期刊：
影响因子：
32.4
通讯作者：
Rothstein, AM
中科院分区：
文献类型：
--
作者：
Viglianti, GA;Lau, CM;Rothstein, AM
自身反应性类风湿因子(RF)B细胞对哺乳动物染色质免疫复合体(ICs)的增殖反应是B细胞受体(BCR)和Toll样受体9(TLR9)顺序结合的结果。我们使用由抗半抗原抗体构建的IC和定义的半抗原dsDNA片段来确定介导这一过程的哺乳动物DNA的形式。尽管它们在哺乳动物DNA中的丰度相对较低，但我们发现在这些IC中包含低甲基化的CpG基序是有效激活所必需的。在没有抗体的情况下，相同的片段可以有效地刺激低亲和力的半抗原特异性和DNA反应的3H9B细胞，但不能刺激RF B细胞。这些结果将BCR/TLR9共参与范式扩展到第二类主要的自身反应性B细胞，进一步证实了BCR在染色质配体传递到TLR9中的关键作用，并暗示低甲基化的CpG基序是启动系统性自身免疫病所必需的配体元件。
The proliferative response of autoreactive rheumatoid factor (RF) B cells to mammalian chromatin-containing immune complexes (ICs) results from the sequential engagement of the B cell receptor (BCR) and Toll-like receptor 9 (TLR9). We have used ICs constructed from anti-hapten antibodies and defined haptenated dsDNA fragments to determine the form of mammalian DNA that mediates this process. Despite their relatively low abundance in mammalian DNA, we found that inclusion of hypomethylated CpG motifs in these ICs was necessary for effective activation. In the absence of antibody, the same fragments could efficiently stimulate low-affinity hapten-specific and DNA-reactive 3H9 B cells, but not RF B cells. These results extend the BCR/TLR9 coengagement paradigm to a second major class of autoreactive B cells, further confirm the critical role of the BCR in chromatin ligand delivery to TLR9, and implicate hypomethylated CpG motifs as ligand elements necessary for the initiation of systemic autoimmune disease.