Wang H, Shlomchik M J
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8035, USA.
J Exp Med. 1999 Sep 6;190(5):639-49. doi: 10.1084/jem.190.5.639.
In systemic autoimmune disease, self-tolerance fails, leading to autoantibody production. A central issue in immunology is to understand the origins of activated self-reactive B cells. We have used immunoglobulin (Ig) transgenic mice to investigate the regulation of autoreactive B cells with specificity for self-IgG2a (the rheumatoid factor [RF] specificity) to understand how normal mice regulate RF autoantibodies and how this fails in autoimmune mice. We previously showed that normal mice do not tolerize the AM14 RF clone, nor do they appear to activate it. Here we show that in Fas-deficient autoimmune mice, the picture is quite different. RF B cells are activated to divide and secrete, but only when the autoantigen is present. Thus, B cells that are ignored rather than anergized in normal mice can be stimulated to produce autoantibody in Fas-deficient mice. This demonstrates a novel developmental step at which intact Fas-Fas ligand signaling is required to regulate B cells in order to prevent autoimmunity. These data also establish the relevance of ignorant self-specific B cells to autoantibody production in disease and prove that in the case of the RF specificity, the nominal autoantigen IgG2a is the driving autoantigen in vivo.
在系统性自身免疫疾病中，自身耐受性遭到破坏，导致自身抗体产生。免疫学中的一个核心问题是了解活化的自身反应性B细胞的起源。我们利用免疫球蛋白（Ig）转基因小鼠来研究对自身IgG2a具有特异性的自身反应性B细胞（类风湿因子[RF]特异性）的调控，以了解正常小鼠如何调节RF自身抗体以及在自身免疫小鼠中这一过程是如何失败的。我们之前表明，正常小鼠不会使AM14 RF克隆失活，也似乎不会激活它。在此我们表明，在Fas缺陷的自身免疫小鼠中，情况截然不同。RF B细胞被激活而分裂并分泌，但仅在自身抗原存在时才会如此。因此，在正常小鼠中被忽视而非失能的B细胞，在Fas缺陷小鼠中可被刺激产生自身抗体。这证明了一个新的发育阶段，即完整的Fas - Fas配体信号传导是调节B细胞以预防自身免疫所必需的。这些数据还确立了无知的自身特异性B细胞与疾病中自身抗体产生的相关性，并证明就RF特异性而言，名义上的自身抗原IgG2a是体内驱动自身免疫的自身抗原。
