IRF7-mediated development of autoreactive B cells and SLE

项目摘要 自身免疫性疾病系统性红斑狼疮中驱动自身反应性B细胞发展的机制 红斑狼疮(SLE)的发病机制尚不完全清楚。拉赫曼实验室的总体目标是描绘出 促进自身反应性B细胞发展、自身抗体产生和系统性红斑狼疮的机制 影响数百万美国人和全世界人民的衰弱的自身免疫性疾病。开发一个 完全了解这种机制将有助于开发靶向疗法，这种疗法将比 目前可用的SLE治疗方案在全球范围内抑制免疫系统，并导致复发 感染和增加与疾病相关的发病率和死亡率。Gwas的研究已经确定了风险变种 在干扰素调节因子7(IRF7)基因中，增加了发生SLE的风险。IRF7是关键 转录因子，调节的I型干扰素(T1-干扰素)反应下游的核酸传感Toll- 促进小鼠和人类系统性红斑狼疮的类受体(TLR)。我们的初步数据强调了 IRF7在自身反应性B细胞的发育和SLE的表现中具有良好的特征性FcgRIIB-/-SLE模型。 已发表的和来自FcgRIIB-/-模型的初步数据表明，IRF7的关键作用和 T1-干扰素信号在自身免疫反应和系统性红斑狼疮发生中的作用。这些数据表明，T1-干扰素依赖于 -IRF7在自身反应性B细胞和SLE发生中的独立作用，并指出IRF7是一种潜在的 与单独使用T1-干扰素阻断疗法相比，SLE的治疗靶点更好，尽管最近对T1-干扰素的临床试验 受体阻断治疗显示了良好的结果。然而，我们对细胞类型特定的作用知之甚少 IRF7在系统性红斑狼疮发生中的作用，尽管它在pDC产生T1-干扰素中的作用已经得到了很好的证实。重要的是，B IRF7通过卵泡外抗体形成在自身反应性B细胞发育中的细胞内和外作用 系统性红斑狼疮的细胞(AFC)和滤泡生发中心(GC)通路尚不清楚。另外，T1-干扰素非依赖性IRF7 在系统性红斑狼疮中的作用尚不清楚。我们假设，IRF7调节B细胞的内源性和外源性，以及T1-干扰素- AFC和GC途径中自身反应性B细胞发育的依赖和独立机制 导致致病性自身抗体的产生和系统性红斑狼疮。这一假设得到了我们初步数据的支持 显示1)IRF7在AFC(浆母细胞/浆细胞)、GC B细胞和髓系细胞中显著上调 细胞2)SLE患者活化的B细胞中IRF7的表达增加3)自身免疫力的急剧下降 系统性红斑狼疮FcgRIIB-/-缺陷小鼠的AFC和GC反应、自身抗体和免疫复合物沉积 在IRF7中，IRF7参与了易患SLE的B细胞中B细胞代谢活动的改变，并发表了数据 揭示了IRF7在小鼠和人类系统性红斑狼疮中的作用。目前的建议将有助于确定B细胞固有的 和-IRF7促进自身反应性B细胞和SLE发展的外在作用和机制，以及 IRF7对SLE的治疗效果是否优于单独阻断T1-干扰素或T1-干扰素受体。

Project Summary Mechanisms that drive the development of autoreactive B cells in an autoimmune disorder systemic lupus erythematosus (SLE) is incompletely understood. Overall goal of the Rahman lab is to delineate the mechanisms that promote the development of autoreactive B cells, autoantibody production and SLE, a debilitating autoimmune disease that affects millions of Americans and people worldwide. Developing a complete understanding of such mechanisms will help develop targeted therapies that would be preferable to currently available SLE treatment options that globally suppress the immune system, and result in recurrent infections and increase disease-associated morbidity and mortality. GWAS studies have identified risk variants in the interferon regulatory factor 7 (IRF7) gene, which increase the risk of developing SLE. IRF7 is the key transcription factor that regulates type I interferon (T1-IFN) response downstream of nucleic acid sensing toll- like receptor (TLR) that promote SLE in mice and humans. Our preliminary data highlight the significance of IRF7 in autoreactive B cell development and SLE manifestations in a well-characterized FcgRIIB-/- SLE model. Published and preliminary data from the FcgRIIB-/- model indicate a critical role for IRF7 and a modest role for T1-IFN signaling in autoimmune responses and SLE development. These data suggest T1-IFN-dependent and -independent roles of IRF7 in autoreactive B cell and SLE development, and point to IRF7 as a potentially better therapeutic target for SLE than T1-IFN blocking therapies alone, although recent clinical trials for T1-IFN receptor blocking therapy showed promising outcome. However, we know little about the cell type-specific role of IRF7 in SLE development, although its role in T1-IFN production by pDCs is well established. Importantly, B cell-intrinsic and -extrinsic roles of IRF7 in autoreactive B cell development via extrafollicular antibody-forming cell (AFC) and follicular germinal center (GC) pathways in SLE are not known. Also, T1-IFN-independent IRF7 role in SLE remains unknown. We hypothesize that IRF7 regulates B cell-intrinsic and -extrinsic, and T1-IFN- dependent and -independent mechanisms in autoreactive B cell development in the AFC and GC pathways, leading to pathogenic autoantibody production and SLE. This hypothesis is supported by our preliminary data showing 1) a significant upregulation of IRF7 in AFCs (plasmablasts/plasma cells), GC B cells and myeloid cells 2) increased IRF7 expression in activated B cells from SLE patients 3) a drastic reduction in autoimmune AFC and GC responses, autoantibodies and immune complex deposition in SLE-prone FcgRIIB-/- mice deficient in IRF7 4) IRF7 involvement in altered B cell metabolic activity in SLE-prone B cells, and published data revealing 5) a role for IRF7 in mouse and human SLE. The current proposal will help determine B cell-intrinsic and -extrinsic roles and mechanisms by which IRF7 promote autoreactive B cell and SLE development, and whether IRF7 could be a better therapeutic option for SLE than T1-IFN or T1-IFN-receptor blocking alone.