Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice
Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice
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DOI：
10.1016/j.immuni.2006.07.014
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发表时间：
2006-09-01
期刊：
影响因子：
32.4
通讯作者：
Imanishi-Kari, Thereza
中科院分区：
文献类型：
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作者：
Berland, Robert;Fernandez, Luis;Imanishi-Kari, Thereza
系统性红斑狼疮（SLE）的特征是产生自身抗体，这些抗体通常针对核酸相关抗原。为了更好地理解如何调节与这些抗原反应的B细胞，我们产生了一个模型系统，其中编码564免疫球蛋白的重链和轻链基因已经靶向非自身免疫性C57 BL/6小鼠品系的重链和轻链基因座。这种抗体识别RNA、单链DNA和核小体。我们发现，表达这种免疫球蛋白的B细胞被激活，在体内产生类别转换的自身抗体，尽管明显正常的诱导无能。这种自身抗体的产生很大程度上依赖于Toll样受体7（TLR 7）。我们进一步表明，这些自身抗体的产生足以导致这些小鼠的肾脏病理。这些结果表明，含有核酸的自身抗原的特定威胁在于它们结合抗原受体和TLR 7的能力。
Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies that are frequently directed against nucleic acid-associated antigens. To better understand how B cells reactive with such antigens are regulated, we generated a model system in which heavy and light chain genes encoding 564 immunoglobulin have been targeted to the heavy and light chain loci of the nonautoimmune C57BL/6 mouse strain. This antibody recognizes RNA, single-stranded DNA, and nucleosomes. We show that B cells expressing this immunoglobulin were activated, producing class-switched autoantibody in vivo despite the apparently normal induction of anergy. This autoantibody production was largely dependent on Toll-like receptor 7 (TLR7). We further show that production of these autoantibodies was sufficient to cause kidney pathology in these mice. These results demonstrate that the particular threat of nucleic acid-containing autoantigens lies in their ability to bind both antigen receptor and TLR7.