FcγRIIB regulation of BCR/TLR-dependent autoreactive B-cell responses
FcγRIIB regulation of BCR/TLR-dependent autoreactive B-cell responses
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DOI：
10.1002/eji.200940184
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发表时间：
2010-10-01
影响因子：
5.4
通讯作者：
Marshak-Rothstein, Ann
中科院分区：
文献类型：
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作者：
Avalos, Ana M.;Uccellini, Melissa B.;Marshak-Rothstein, Ann
免疫复合物(IC)使Fcγ受体II B(Fc Gamma RIIB)与BCR发生交联，可下调抗原特异性B细胞应答。因此，在系统性红斑狼疮患者和狼疮小鼠模型中，FcγRIIB缺陷与B细胞过度活动有关。然而，我们先前已经证明，小鼠IgG2a自身反应的AM14B细胞通过一种依赖于BCR和内体TLR9的机制对染色质相关IC做出强有力的反应，尽管Fc-Gamma RIIB共表达。为了进一步评估Fc Gamma RIIB对自身反应性B细胞调控的潜在贡献，我们现在比较了Fc Gamma RIIB缺乏和Fc Gamma RIIB充足的AM14 B细胞的IC触发反应。我们发现，当含有低亲和力TLR9配体的DNA IC(CG贫乏的dsDNA片段)刺激时，Fc-Gamma RIIB缺陷细胞的反应明显好于Fc-Gamma RIIB充足细胞。AM14B细胞也通过BCR/TLR7共参与反应RNA相关的IC，但这种依赖于BCR/TLR7的反应通常高度依赖于干扰素-α的共刺激。然而，我们现在发现，AM14 FcγRIIB-/-B细胞可以非常有效地被RNA IC激活，而不需要补充干扰素-α启动。这些结果表明，FcγRIIB能有效地调节BCR/TLR9和BCR/TLR7依赖的自身反应性B细胞的激活。
Crosslinking of Fc gamma receptor II B (Fc gamma RIIB) and the BCR by immune complexes (IC) can downregulate antigen-specific B-cell responses. Accordingly, Fc gamma RIIB deficiencies have been associated with B-cell hyperactivity in patients with systemic lupus erythematosus and mouse models of lupus. However, we have previously shown that murine IgG2a-autoreactive AM14 B cells respond robustly to chromatin-associated IC through a mechanism dependent on both the BCR and the endosomal TLR9, despite Fc gamma RIIB coexpression. To further evaluate the potential contribution of Fc gamma RIIB to the regulation of autoreactive B cells, we have now compared the IC-triggered responses of Fc gamma RIIB-deficient and Fc gamma RIIB-sufficient AM14 B cells. We find that Fc gamma RIIB-deficient cells respond significantly better than Fc gamma RIIB-sufficient cells when stimulated with DNA IC that incorporate low-affinity TLR9 ligand (CG-poor dsDNA fragments). AM14 B cells also respond to RNA-associated IC through BCR/TLR7 coengagement, but such BCR/TLR7-dependent responses are normally highly dependent on IFN-alpha costimulation. However, we now show that AM14 Fc gamma RIIB-/- B cells are very effectively activated by RNA IC without supplemental IFN-alpha priming. These results demonstrate that Fc gamma RIIB can effectively modulate both BCR/TLR9 and BCR/TLR7 endosomal-dependent activation of autoreactive B cells.