B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers.
B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers.
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DOI：
10.4049/jimmunol.1401720
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发表时间：
2014-11-01
期刊：
影响因子：
--
通讯作者：
Rahman ZS
中科院分区：
文献类型：
--
作者：
Soni C;Wong EB;Domeier PP;Khan TN;Satoh T;Akira S;Rahman ZS
自发生发中心（Spt-GC） B细胞和滤泡辅助性T细胞（Tfh）产生高亲和力自身抗体，参与系统性红斑狼疮（SLE）的发展。Toll样受体（TLRs）在SLE发病机制中起关键作用。虽然之前的研究主要集中在TLR-MyD88信号在B细胞免疫激活、自身抗体库和全身性炎症中的内在作用，但对tlr控制Spt-GCs形成的机制的深入研究仍不清楚。利用MyD88、TLR2、3、4、7或9缺失的非自身免疫性C57BL/6 （B6）小鼠，我们发现B细胞固有的TLR7信号是Spt-GC形成的先决条件，没有自身免疫性易感基因和TLRs过表达的混杂影响。TLR7缺乏也导致自身免疫B6。Sle1b小鼠无法形成Spt-GCs，导致自身抗体显著降低。相反,B6。是的，b6 . sleb。yaa小鼠表达额外的TLR7和B6拷贝。用TLR7激动剂治疗的Sle1b小鼠增加了Spt-GCs和Tfh。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。相反，TLR9抑制Spt-GC的发展。我们的研究结果表明，在非自身免疫性和自身免疫性疾病中，TLR7是Spt-GC形成的绝对需要，TLR9具有负调控功能。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，在自身免疫易感基因存在的情况下，TLR7依赖的Spt-GCs产生致病性自身抗体。因此，B细胞中TLR7的单一拷贝是破坏gc耐受检查点的最低要求。
Spontaneous germinal center (Spt-GC) B cells and follicular helper T cells (Tfh) generate high affinity autoantibodies involved in the development of systemic lupus erythematosus (SLE). Toll like receptors (TLRs) play a pivotal role in SLE pathogenesis. While previous studies have focused on the B cell intrinsic role of TLR-MyD88 signaling on immune activation, autoantibody repertoire and systemic inflammation, a thorough investigation of the mechanisms by which TLRs control the formation of Spt-GCs remains unclear. Using non-autoimmune C57BL/6 (B6) mice deficient in MyD88, TLR2, 3, 4, 7 or 9, 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 Tfh. 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 of TLR7 and a negative regulatory function for TLR9 in Spt-GC formation under non-autoimmune and autoimmune conditions. Our data suggest that, under non-autoimmune conditions, Spt-GCs initiated by TLR7 produce protective antibodies. 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.
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影响因子：
32.4
作者：
Herlands, Robin A.;Christensen, Sean R.;Sweet, Rebecca A.;Hershberg, Uri;Shlomchik, Mark J.
通讯作者：
Shlomchik, Mark J.
影响因子：
32.4
作者：
Hou B;Saudan P;Ott G;Wheeler ML;Ji M;Kuzmich L;Lee LM;Coffman RL;Bachmann MF;DeFranco AL
通讯作者：
DeFranco AL
DOI：
10.4049/jimmunol.1202195
发表时间：
2012-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hwang SH;Lee H;Yamamoto M;Jones LA;Dayalan J;Hopkins R;Zhou XJ;Yarovinsky F;Connolly JE;Curotto de Lafaille MA;Wakeland EK;Fairhurst AM
通讯作者：
Fairhurst AM
DOI：
10.4049/jimmunol.1400098
发表时间：
2014-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jackson SW;Scharping NE;Kolhatkar NS;Khim S;Schwartz MA;Li QZ;Hudkins KL;Alpers CE;Liggitt D;Rawlings DJ
通讯作者：
Rawlings DJ
影响因子：
32.4
作者：
Hou, Baidong;Reizis, Boris;DeFranco, Anthony L.
通讯作者：
DeFranco, Anthony L.