IRF7-mediated development of autoreactive B cells and SLE

项目摘要 自身免疫性疾病系统性狼疮中自身反应性B细胞的形成机制 红斑性狼疮（SLE）是不完全了解。拉赫曼实验室的总体目标是描绘 促进自身反应性B细胞发育、自身抗体产生和SLE的机制， 使人衰弱的自身免疫性疾病，影响数百万美国人和世界各地的人们。开发一 对这些机制的完整理解将有助于开发靶向治疗， 目前可用的SLE治疗方案，全面抑制免疫系统，并导致复发性 感染和增加疾病相关的发病率和死亡率。GWAS研究已经确定了风险变体 干扰素调节因子7（IRF 7）基因，这增加了发展SLE的风险。IRF 7是关键 一种调节I型干扰素（T1-IFN）应答的转录因子，位于核酸传感toll的下游， 在小鼠和人类中促进SLE的TLR。我们的初步数据突出了 IRF 7在自身反应性B细胞发育和充分表征的FcgRIIB-/- SLE模型中的SLE表现中的作用 来自FcgRIIB-/-模型的已发表和初步数据表明IRF 7的关键作用和IRF 7的适度作用。 T1-IFN信号在自身免疫反应和SLE发展中的作用这些数据表明T1-IFN依赖性和 IRF 7在自身反应性B细胞和SLE发展中的独立作用，并指出IRF 7作为一种潜在的 尽管最近的临床试验表明T1-IFN-γ是SLE的一个更好的治疗靶点， 受体阻断治疗显示出有希望的结果。然而，我们对细胞类型特异性作用知之甚少， IRF 7在SLE发展中的作用，尽管其在pDC产生T1-IFN中的作用已被充分确定。重要的是，B IRF 7通过滤泡外抗体形成在自身反应性B细胞发育中的细胞内在和外在作用 细胞（AFC）和滤泡生发中心（GC）途径在SLE中的作用尚不清楚。此外，T1-IFN-非依赖性IRF 7 在SLE中的作用尚不清楚。我们假设IRF 7调节B细胞的内源性和外源性，而T1-IFN-γ调节B细胞的内源性和外源性。 AFC和GC途径中自身反应性B细胞发育的依赖性和非依赖性机制， 导致致病性自身抗体产生和SLE。我们的初步数据支持这一假设 显示1）IRF 7在AFC（浆母细胞/浆细胞）、GC B细胞和骨髓细胞中的显著上调 2）SLE患者活化的B细胞中IRF 7表达增加3）自身免疫性T细胞减少， SLE易感性FcgRIIB-/-缺陷小鼠中的AFC和GC应答、自身抗体和免疫复合物沉积 4）IRF 7参与SLE易感B细胞中改变的B细胞代谢活性，以及已发表的数据 揭示5）IRF 7在小鼠和人SLE中的作用。目前的建议将有助于确定B细胞的内在 和-IRF 7促进自身反应性B细胞和SLE发展的外在作用和机制，和 IRF 7是否可能是比单独的T1-IFN或T1-IFN受体阻断剂更好的SLE治疗选择。

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.