B-cell tolerance and autoimmunity.
B-cell tolerance and autoimmunity.
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DOI：
10.12688/f1000research.10583.1
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Tsubata T
中科院分区：
文献类型：
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作者：
Tsubata T
自身反应性B细胞在B细胞发育和分化的不同阶段被耐受，包括未成熟B细胞阶段(中心耐受)和生发中心(GC)B细胞阶段，B细胞耐受涉及多种机制，如缺失、无能和受体编辑。由随机免疫球蛋白可变基因重排产生的自身反应性B细胞在外周受到中枢耐受和无能的耐受，这些过程包括由Bim(Bim)调节的凋亡，Bim是Bcl2家族的促凋亡成员，以及各种磷酸酶(包括Ship-1和SHP-1)对B细胞信号的调节。GC反应过程中体细胞突变产生的自身反应性B细胞也被消除。Fas不直接参与这一过程，但可以阻止GC反应的持续，GC反应允许产生调节不那么严格的B细胞，包括自我反应性B细胞。自身耐受性缺陷可导致狼疮样疾病，产生抗核抗体，这可能是由于存在大量潜在的对核酸有反应的B细胞库，以及在包括B细胞和树突状细胞在内的各种免疫细胞中存在核酸诱导的激活机制。由B细胞产生的抗核抗体和核酸激活的树突状细胞分泌的1型干扰素组成的前馈环在系统性红斑狼疮的发生发展中起着至关重要的作用。
Self-reactive B cells are tolerized at various stages of B-cell development and differentiation, including the immature B-cell stage (central tolerance) and the germinal center (GC) B-cell stage, and B-cell tolerance involves various mechanisms such as deletion, anergy, and receptor editing. Self-reactive B cells generated by random immunoglobulin variable gene rearrangements are tolerized by central tolerance and anergy in the periphery, and these processes involve apoptosis regulated by Bim, a pro-apoptotic member of the Bcl-2 family, and regulation of B-cell signaling by various phosphatases, including SHIP-1 and SHP-1. Self-reactive B cells generated by somatic mutations during GC reaction are also eliminated. Fas is not directly involved in this process but prevents persistence of GC reaction that allows generation of less stringently regulated B cells, including self-reactive B cells. Defects in self-tolerance preferentially cause lupus-like disease with production of anti-nuclear antibodies, probably due to the presence of a large potential B-cell repertoire reactive to nucleic acids and the presence of nucleic acid-induced activation mechanisms in various immune cells, including B cells and dendritic cells. A feed-forward loop composed of anti-nuclear antibodies produced by B cells and type 1 interferons secreted from nucleic acid-activated dendritic cells plays a crucial role in the development of systemic lupus erythematosus.