The Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
J Autoimmun. 2011 Aug;37(1):18-27. doi: 10.1016/j.jaut.2011.03.002. Epub 2011 Apr 1.
How self tolerance is maintained during B cell development in the bone marrow has been a focal area of study in immunology. Receptor editing, anergy and clonal deletion all play important roles in the regulation of autoimmunity in the immature population. The mechanisms of tolerance induction in the periphery, however, are less well characterized. Overexpression of the apoptosis inhibitor Bcl-2 rescues autoreactive B cells from deletion and can contribute to the development of autoimmune disease in certain genetic backgrounds. Using a peptide-induced autoimmunity model, we recently identified a peripheral tolerance checkpoint in antigen-activated B cells that have undergone class switching and somatic hypermutation. At this checkpoint, receptor editing, induced by antigen engagement, dampened the autoantibody response. In this study, we show that receptor editing fails to be induced in antigen-activated DNA-reactive B cells that overexpress Bcl-2 (Bcl-2 Tg). The failure to induce RAG and receptor editing is likely due, at least partially, to the lack of self antigen. First, the levels of circulating DNA and of apoptotic bodies in the spleen of Bcl-2 Tg mice are significantly lower than in control mice. Second, in Bcl-2 Tg mice, RAG can be induced in a population of antigen-activated B cells by providing exogenous soluble antigen. These data suggest that, in addition to its anti-apoptotic activity, Bcl-2 may indirectly inhibit tolerance induction in B cells acquiring anti-nuclear antigen reactivity after peripheral activation by limiting the availability of self antigen.
在骨髓中 B 细胞发育过程中如何维持自身耐受一直是免疫学研究的重点。受体编辑、失能和克隆删除在调节未成熟人群中的自身免疫中都起着重要作用。然而，外周耐受诱导的机制还不太清楚。凋亡抑制剂 Bcl-2 的过度表达可以使自身反应性 B 细胞免于删除，并可能导致某些遗传背景下自身免疫疾病的发展。使用肽诱导的自身免疫模型，我们最近在经历了类别转换和体细胞超突变的抗原激活 B 细胞中发现了一个外周耐受检查点。在这个检查点上，抗原结合诱导的受体编辑减弱了自身抗体反应。在这项研究中，我们表明，在过度表达 Bcl-2（Bcl-2Tg）的抗原激活的 DNA 反应性 B 细胞中，不能诱导受体编辑。不能诱导 RAG 和受体编辑可能至少部分是由于缺乏自身抗原。首先，Bcl-2Tg 小鼠的循环 DNA 水平和脾脏中凋亡小体的水平明显低于对照小鼠。其次，在 Bcl-2Tg 小鼠中，通过提供外源性可溶性抗原，可以在抗原激活的 B 细胞群体中诱导 RAG。这些数据表明，除了其抗凋亡活性外，Bcl-2 可能通过限制自身抗原的可用性，间接抑制外周激活后获得抗核抗原反应的 B 细胞中的耐受诱导，从而抑制 B 细胞中的耐受诱导。
