IRF7-mediated development of autoreactive B cells and SLE

项目概要 自身免疫性疾病系统性狼疮中自身反应性 B 细胞发育的驱动机制 红斑狼疮 (SLE) 尚不完全了解。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， 影响数百万美国人和全世界人民的使人衰弱的自身免疫性疾病。开发一个 完全了解此类机制将有助于开发更适合的靶向疗法 目前可用的 SLE 治疗方案会全面抑制免疫系统，并导致复发 感染并增加与疾病相关的发病率和死亡率。 GWAS 研究已确定风险变异 干扰素调节因子 7 (IRF7) 基因，这会增加患 SLE 的风险。 IRF7是关键 调节核酸感应 toll- 下游 I 型干扰素 (T1-IFN) 反应的转录因子 样受体（TLR）可促进小鼠和人类的系统性红斑狼疮。我们的初步数据凸显了以下方面的重要性： 在充分表征的 FcgRIIB-/- SLE 模型中，IRF7 在自身反应性 B 细胞发育和 SLE 表现中的作用。 FcgRIIB-/- 模型已发表的初步数据表明 IRF7 发挥着关键作用，而 自身免疫反应和 SLE 发展中的 T1-IFN 信号传导。这些数据表明 T1-IFN 依赖性和 - IRF7 在自身反应性 B 细胞和 SLE 发展中的独立作用，并指出 IRF7 作为潜在的 尽管最近针对 T1-IFN 的临床试验，SLE 的治疗靶点比单独使用 T1-IFN 阻断疗法更好 受体阻断疗法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 IRF7 在 SLE 发展中的作用，尽管其在 pDC 产生 T1-IFN 中的作用已得到充分证实。重要的是，B IRF7 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 SLE 中的细胞 (AFC) 和滤泡生发中心 (GC) 通路尚不清楚。此外，T1-IFN 独立的 IRF7 在 SLE 中的作用仍不清楚。我们假设 IRF7 调节 B 细胞内在和外在，而 T1-IFN- 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 SLE。我们的初步数据支持这一假设 显示 1) IRF7 在 AFC（浆母细胞/浆细胞）、GC B 细胞和骨髓细胞中显着上调 细胞 2) SLE 患者的活化 B 细胞中 IRF7 表达增加 3) 自身免疫能力急剧下降 易患 SLE 的 FcgRIIB-/- 缺陷小鼠的 AFC 和 GC 反应、自身抗体和免疫复合物沉积 IRF7 4) IRF7 参与 SLE 易感 B 细胞中 B 细胞代谢活性的改变，以及已发表的数据 揭示 5) IRF7 在小鼠和人类 SLE 中的作用。目前的提案将有助于确定 B 细胞固有的 -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 是否可以成为比单独 T1-IFN 或 T1-IFN 受体阻断更好的 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.