IL-6 contributes to an immune tolerance checkpoint in post germinal center B cells.
IL-6 contributes to an immune tolerance checkpoint in post germinal center B cells.
复制标题
IL-6 有助于生发中心 B 细胞中的免疫耐受检查点。
DOI：
10.1016/j.jaut.2011.09.004
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发表时间：
2012
影响因子：
12.8
通讯作者：
Diamond,Betty
中科院分区：
文献类型：
--
作者：
Yan,Yi;Wang,Ying-Hua;Diamond,Betty
B细胞库的产生涉及产生并随后清除自身反应性B细胞。受体编辑、克隆缺失和无反应性是中枢B细胞耐受的关键机制。生发中心内抗原激活的B细胞的体细胞突变产生第二波自身反应性;但是在B细胞激活的这个阶段起作用的调节机制知之甚少。我们最近确定了一个后生发中心耐受检查点，其中受体编辑被重新诱导以消除体细胞超突变产生的自身反应性。在抗原活化的B细胞中重新诱导重组酶基因RAG 1和RAG 2需要抗原接合B细胞受体和IL-7通过IL-7受体发出信号。我们证明，这一过程需要IL-6上调IL-7受体的表达后生发中心B细胞。通过阻断抗体或单倍不足减少IL-6导致IL-7受体和RAG的表达减少，并且在用DNA的肽模拟物免疫后抗DNA抗体的滴度增加。依赖IL-6启动受体编辑是B细胞内在的。有趣的是，雌二醇降低IL-6的表达，从而增加抗DNA反应。我们的数据揭示了一种新的调控级联反应，以控制后生发中心B细胞自身反应性。
The generation of a B cell repertoire involves producing and subsequently purging autoreactive B cells. Receptor editing, clonal deletion and anergy are key mechanisms of central B cell tolerance. Somatic mutation of antigen-activated B cells within the germinal center produces a second wave of autoreactivity; but the regulatory mechanisms that operate at this phase of B cell activation are poorly understood. We recently identified a post germinal center tolerance checkpoint, where receptor editing is re-induced to extinguish autoreactivity that is generated by somatic hypermutation. Re-induction of the recombinase genes RAG1 and RAG2 in antigen-activated B cells requires antigen to engage the B cell receptor and IL-7 to signal through the IL-7 receptor. We demonstrate that this process requires IL-6 to upregulate IL-7 receptor expression on post germinal center B cells. Diminishing IL-6 by blocking antibody or haplo-insufficiency leads to reduced expression of the IL-7 receptor and RAG and increased titers of anti-DNA antibodies following immunization with a peptide mimetope of DNA. The dependence on IL-6 to initiate receptor editing is B cell intrinsic. Interestingly, estradiol decreases IL-6 expression thereby increasing the anti-DNA response. Our data reveal a novel regulatory cascade to control post germinal center B cell autoreactivity.