c-Rel gain in B cells drives germinal center reactions and autoantibody production
c-Rel gain in B cells drives germinal center reactions and autoantibody production
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DOI：
10.1172/jci124382
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发表时间：
2020-06-01
影响因子：
15.9
通讯作者：
Schmidt-Supprian, Marc
中科院分区：
文献类型：
--
作者：
Kober-Hasslacher, Maike;Oh-Strauss, Hyunju;Schmidt-Supprian, Marc
NF-κ B B转录因子c-Rel的单核苷酸多态性和基因座扩增分别与人类自身免疫性疾病和B细胞淋巴瘤相关。然而，增强的c-Rel水平的功能后果仍然是谜。在这里，我们在小鼠B细胞中特异性地过表达c-Rel，并证明c-Rel蛋白水平线性地决定了生发中心B（GCB）细胞和同种型转换的浆细胞的扩增。c-Rel缺陷小鼠的B细胞中的c-Rel表达完全挽救了终末B细胞分化，强调了其关键的B细胞内在作用。出乎意料的是，在GCB细胞中，非转录依赖性调节在B细胞亚群中产生最高的c-Rel蛋白水平。在c-Rel过表达的GCB细胞中，这导致核转位增强，转录程序发生深刻改变，并增加增殖。最后，我们通过显示B细胞中c-Rel过表达引起自身抗体产生和肾免疫复合物沉积，提供了c-Rel增益和自身免疫之间的联系。
Single-nucleotide polymorphisms and locus amplification fink the NF-kappa B transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center B (GCB) cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels among B cell subsets. In c-Rel-overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program, and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.