Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus
Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus
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DOI：
10.1073/pnas.1005599107
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发表时间：
2010-06-01
影响因子：
11.1
通讯作者：
Honda, Kenya
中科院分区：
文献类型：
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作者：
Savitsky, David A.;Yanai, Hideyuki;Honda, Kenya
干扰素调节因子（IRF）5是Toll样受体信号传导下游激活先天性免疫应答的关键转录因子。基于最近的遗传分析，IRF 5是其潜在参与系统性红斑狼疮（SLE）的焦点，尽管IRF 5如何促成SLE尚不确定。在这项研究中，我们证明了IRF 5在小鼠SLE的发展中通过其在B淋巴细胞中的作用的需要。我们发现，抗核自身抗体和IG肾小球沉积物，SLE的标志，是缺乏在Irf 5（-/-）小鼠挑战开发SLE降植烷注射。特别是，IgG 2a亚型（诱导自身免疫的最主要同种型）自身抗体的产生需要IRF 5。最后，我们提供的证据，这种转录因子在致病性抗体的分泌中的关键作用，通过其直接控制类转换重组的γ 2a基因座。通过证明B细胞的内在作用，这项研究将IRF 5置于可能对理解人类SLE发病机制有影响的背景下。
Interferon regulatory factor (IRF) 5 is a key transcription factor for the activation of innate immune responses downstream of Toll-like receptor signaling. Based on recent genetic analyses, IRF5 is a focus for its potential involvement in systemic lupus erythematosus (SLE), although how IRF5 contributes to SLE is uncertain. In this study, we demonstrate a requirement for IRF5 in the development of murine SLE via its role in B lymphocytes. We show that antinuclear autoantibodies and Ig glomerular deposits, hallmarks of SLE, are absent in Irf5(-/-) mice challenged to develop SLE by pristane injection. In particular, production of autoantibodies of the IgG2a subtype, the most prominent isotype in inducing autoimmunity, requires IRF5. Finally, we provide evidence for the critical role of this transcription factor in the secretion of pathogenic antibodies through its direct control of class switch recombination of the gamma 2a locus. By demonstrating a B-cell-intrinsic role, this study places IRF5 in a context that may have implications for understanding the pathogenesis of human SLE.