Soni Chetna, Wong Eric B, Domeier Phillip P, Khan Tahsin N, Satoh Takashi, Akira Shizuo, Rahman Ziaur S M
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033;
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033; Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239; and.
J Immunol. 2014 Nov 1;193(9):4400-14. doi: 10.4049/jimmunol.1401720. Epub 2014 Sep 24.
Spontaneous germinal center (Spt-GC) B cells and follicular helper T cells generate high-affinity autoantibodies that are involved in the development of systemic lupus erythematosus. TLRs play a pivotal role in systemic lupus erythematosus pathogenesis. Although previous studies focused on the B cell-intrinsic role of TLR-MyD88 signaling on immune activation, autoantibody repertoire, and systemic inflammation, the mechanisms by which TLRs control the formation of Spt-GCs remain unclear. Using nonautoimmune C57BL/6 (B6) mice deficient in MyD88, TLR2, TLR3, TLR4, TLR7, or TLR9, we identified B cell-intrinsic TLR7 signaling as a prerequisite to Spt-GC formation without the confounding effects of autoimmune susceptibility genes and the overexpression of TLRs. TLR7 deficiency also rendered autoimmune B6.Sle1b mice unable to form Spt-GCs, leading to markedly decreased autoantibodies. Conversely, B6.yaa and B6.Sle1b.yaa mice expressing an extra copy of TLR7 and B6.Sle1b mice treated with a TLR7 agonist had increased Spt-GCs and follicular helper T cells. Further, TLR7/MyD88 deficiency led to compromised B cell proliferation and survival after B cell stimulation both in vitro and in vivo. In contrast, TLR9 inhibited Spt-GC development. Our findings demonstrate an absolute requirement for TLR7 and a negative regulatory function for TLR9 in Spt-GC formation under nonautoimmune and autoimmune conditions. Our data suggest that, under nonautoimmune conditions, Spt-GCs initiated by TLR7 produce protective Abs. However, in the presence of autoimmune susceptibility genes, TLR7-dependent Spt-GCs produce pathogenic autoantibodies. Thus, a single copy of TLR7 in B cells is the minimal requirement for breaking the GC-tolerance checkpoint.
自发生发中心（Spt-GC）B细胞和滤泡辅助性T细胞产生高亲和力自身抗体，这些抗体参与系统性红斑狼疮的发展。Toll样受体（TLRs）在系统性红斑狼疮发病机制中起关键作用。尽管先前的研究集中于TLR-MyD88信号在免疫激活、自身抗体库和全身炎症方面的B细胞内在作用，但TLRs控制Spt-GCs形成的机制仍不清楚。利用缺乏MyD88、TLR2、TLR3、TLR4、TLR7或TLR9的非自身免疫性C57BL/6（B6）小鼠，我们确定B细胞内在的TLR7信号是Spt-GC形成的先决条件，而没有自身免疫易感性基因和TLRs过表达的混杂影响。TLR7缺陷也使自身免疫性B6.Sle1b小鼠无法形成Spt-GCs，导致自身抗体明显减少。相反，表达额外一份TLR7的B6.yaa和B6.Sle1b.yaa小鼠以及用TLR7激动剂处理的B6.Sle1b小鼠的Spt-GCs和滤泡辅助性T细胞增加。此外，TLR7/MyD88缺陷导致体外和体内B细胞刺激后B细胞增殖和存活受损。相比之下，TLR9抑制Spt-GC发育。我们的研究结果表明，在非自身免疫和自身免疫条件下，Spt-GC形成绝对需要TLR7，而TLR9具有负调节功能。我们的数据表明，在非自身免疫条件下，由TLR7启动的Spt-GCs产生保护性抗体。然而，在存在自身免疫易感性基因的情况下，TLR7依赖性Spt-GCs产生致病性自身抗体。因此，B细胞中一份TLR7是打破生发中心耐受性检查点的最低要求。
