Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response.
Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response.
复制标题
DOI：
10.1038/gene.2012.10
复制
发表时间：
2012-07
影响因子：
5
通讯作者：
Pitha, P. M.
中科院分区：
文献类型：
--
作者：
Fang, C-M;Roy, S.;Nielsen, E.;Paul, M.;Maul, R.;Paun, A.;Koentgen, F.;Raval, F. M.;Szomolanyi-Tsuda, E.;Pitha, P. M.
IRF-5是一种转录因子，在天然免疫应答中由Toll样受体(TLR7)和TLR9激活。IRF-5不仅能激活I型干扰素，还能激活炎症细胞因子。最重要的是，IRF-5基因的遗传变异表明与狼疮等自身免疫性疾病有很强的关联。在这里，我们报告了IRF5缺陷小鼠对T细胞依赖和非依赖抗原以及对多瘤病毒感染的IgG2a/c反应减弱。这一缺陷是由于B细胞中IRF-5的固有缺失，因为与接受野生型B细胞的小鼠相比，用IRF5IgG2a/c细胞重组的SCID小鼠在病毒感染后−/−2a/c的表达减少。IRF5−/−B细胞在体外可以减少TLR和细胞因子诱导的类向IgG2a/c的转换。在分子机制方面，我们发现IRF-5通过减少Ikaros的表达来调节Ig G2a/c的表达；IRF-5在IRF5−/−B细胞中的重组下调了Ikaros的水平，增加了向Ig G2a/c的转换。我们发现IRF-8而不是IRF-4激活了IKZF1启动子，而IRF-5抑制了IRF-8的转录活性。综上所述，这些结果表明IRF-5-Ikaros轴是IgG2a/c类转换的关键调节器。
IRF-5 is a transcription factor activated by toll like receptor (TLR)7 and TLR9 during innate immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines. Most importantly, a genetic variation in the IRF-5 gene shows a strong association with autoimmune diseases such as Lupus. Here, we report that IRF5-deficient mice have attenuated IgG2a/c responses to T-cell-dependent and -independent antigens and to polyoma virus infection. This defect is due to the intrinsic deletion of IRF-5 in B cells, as SCID mice reconstituted with Irf5−/− B cells show a decrease in IgG2a/c expression after viral infection compared with mice that received wild-type B cells. Irf5−/− B cells in vitro have diminished TLR and cytokine-induced class switching to IgG2a/c. Addressing the molecular mechanism, we show that IRF-5 regulates IgG2a/c expression by decreasing Ikaros expression; reconstitution of IRF-5 in Irf5−/− B cells downregulates Ikaros levels and increases switching to IgG2a/c. The IRF site in ikzf1 promoter binds IRF-5, IRF-4 and IRF-8. We show that IRF-8 but not IRF-4 activates the ikzf1 promoter, and IRF-5 inhibits the transcriptional activity of IRF-8. Collectively, these results identify the IRF-5-Ikaros axis as a critical modulator of IgG2a/c class switching.
登录
查看更多内容
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
30.5
作者：
Cretney, Erika;Xin, Annie;Kallies, Axel
通讯作者：
Kallies, Axel
影响因子：
3.5
作者：
Kozyrev, Sergey V.;Alarcon-Riquelme, Marta E.
通讯作者：
Alarcon-Riquelme, Marta E.
影响因子：
15.9
作者：
Demaria, Olivier;Pagni, Philippe P.;Alexopoulou, Lena
通讯作者：
Alexopoulou, Lena
影响因子：
30.8
作者：
Graham, RR;Kozyrev, SV;Alarcón-Riquelme, ME
通讯作者：
Alarcón-Riquelme, ME