B Cell-Intrinsic Role for IRF5 in TLR9/BCR-Induced Human B Cell Activation, Proliferation, and Plasmablast Differentiation.
B Cell-Intrinsic Role for IRF5 in TLR9/BCR-Induced Human B Cell Activation, Proliferation, and Plasmablast Differentiation.
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DOI：
10.3389/fimmu.2017.01938
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发表时间：
2017
影响因子：
7.3
通讯作者：
Barnes BJ
中科院分区：
文献类型：
--
作者：
De S;Zhang B;Shih T;Singh S;Winkler A;Donnelly R;Barnes BJ
在识别抗原后，B细胞经历快速增殖，随后分化为专门的抗体分泌细胞（ASC）。在此转变期间，B细胞依赖于多层转录因子网络来实现B细胞转录景观的显著重塑。在自身免疫性疾病中经常看到ASC水平的增加，并且据信调节转录因子的表达改变在这种不平衡中起作用。转录因子干扰素调节因子5（IRF5）是一种这样的候选者，因为IRF5中的多态性与许多自身免疫性疾病的风险相关并且与IRF5表达升高相关。IRF5遗传风险已在系统性红斑狼疮（SLE）中广泛复制，并且IRF5的缺失部分地通过缺乏致病性自身抗体分泌来改善鼠狼疮模型中的疾病。然而，IRF5是否通过B细胞内在功能促进自身抗体产生仍不清楚。迄今为止，IRF 5在健康人B细胞中的功能尚未被表征。使用人原代幼稚B细胞，我们定义了IRF 5在B细胞活化、增殖和浆母细胞分化中的关键内在作用。靶向的IRF 5敲低导致显著的免疫球蛋白（IG）D保留、减少的增殖、成浆细胞分化和IgG分泌。观察到的降低是由于受损的B细胞活化和克隆扩增。与小鼠研究不同，我们鉴定并确认了新的IRF5靶基因IRF4、ERK 1和MYC，以及介导IRF5 B细胞内在功能的途径。总之，这些结果鉴定IRF 5是人B细胞活化的早期调节剂，并提供了人原代B细胞中的第一个数据集以映射SLE中的IRF 5功能障碍。
Upon recognition of antigen, B cells undergo rapid proliferation followed by differentiation to specialized antibody secreting cells (ASCs). During this transition, B cells are reliant upon a multilayer transcription factor network to achieve a dramatic remodeling of the B cell transcriptional landscape. Increased levels of ASCs are often seen in autoimmune diseases and it is believed that altered expression of regulatory transcription factors play a role in this imbalance. The transcription factor interferon regulatory factor 5 (IRF5) is one such candidate as polymorphisms in IRF5 associate with risk of numerous autoimmune diseases and correlate with elevated IRF5 expression. IRF5 genetic risk has been widely replicated in systemic lupus erythematosus (SLE), and loss of Irf5 ameliorates disease in murine lupus models, in part, through the lack of pathogenic autoantibody secretion. It remains unclear, however, whether IRF5 is contributing to autoantibody production through a B cell-intrinsic function. To date, IRF5 function in healthy human B cells has not been characterized. Using human primary naive B cells, we define a critical intrinsic role for IRF5 in B cell activation, proliferation, and plasmablast differentiation. Targeted IRF5 knockdown resulted in significant immunoglobulin (Ig) D retention, reduced proliferation, plasmablast differentiation, and IgG secretion. The observed decreases were due to impaired B cell activation and clonal expansion. Distinct from murine studies, we identify and confirm new IRF5 target genes, IRF4, ERK1, and MYC, and pathways that mediate IRF5 B cell-intrinsic function. Together, these results identify IRF5 as an early regulator of human B cell activation and provide the first dataset in human primary B cells to map IRF5 dysfunction in SLE.