IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis

项目摘要 巨噬细胞激活综合征(MAS)是一种与风湿性疾病相关的急性并发症。MAS是 然而，最常见的是系统性幼年特发性关节炎(SJIA)和儿童狼疮患者。 多发性硬化可在病毒感染后发生，如EBV感染。MAS涉及到被激活的 骨髓、脾和肝脏中的巨噬细胞吞噬了红细胞(RBC)和 白细胞。MAS与炎性细胞因子增加、贫血等细胞减少症和 血小板减少和血清铁蛋白升高。在缺乏治疗的情况下，MAS可能是致命的，大多数死亡 SJIA是由于MAS。因此，了解MAS在风湿性和炎症性疾病中的潜在机制 疾病对于开发新的治疗干预方法具有重要意义。辨别小说 在小鼠模型中，我们主要研究病理性巨噬细胞的识别。 MAS的一部分。由于红细胞、血小板和白细胞的吞噬作用可能是急性胰腺炎的主要因素。 MAS中发现的细胞减少，我们推测特化吞噬细胞可能参与疾病的发病机制。 我们发现，通过内体TLR7和TLR9的慢性信号直接诱导了一个新的 巨噬细胞群称为炎性噬血细胞(IHPC)，是从Ly6chi分化而来的 单核细胞。TLR7基因的过表达不仅导致了IHPC的发生，而且还引起了 致命的类MAS疾病，可以通过IHPC耗尽来挽救。继发于sJIA和病毒感染的MAS 与编码IRF5的基因变异有关，IRF5是TLR下游激活的一种转录因子 单核细胞和巨噬细胞中的信号。我们的初步数据显示，IRF5也参与了TLR7- 体外和体内诱导IHPC分化，IRF5在小鼠IHPC中高激活 TLR7诱导的MAS模型。这一应用的前提是IRF5信号在内体下游 TLR7和TLR9是IHPC分化和MAS的重要组成部分。在这份提案中，我们将1)测试 假设IRF5在TLR7驱动的MAS小鼠模型的IHPC分化和疾病中是必需的，2) 确定IRF5参与IHPC分化的机制，并3)检验假设 IRF5在SJIA MAS患者的IHPC和/或单核细胞中被结构性激活。成功完成 将确定IRF5是否是sJIA和其他MAS的可行治疗靶点 自身免疫性疾病。

Project Summary Macrophage Activation Syndrome (MAS) is an acute complication associated with rheumatic diseases. MAS is most commonly seen in patients with systemic juvenile idiopathic arthritis (sJIA) and pediatric lupus, however MAS can develop after viral infections, such as with EBV. MAS involves the accumulation of activated macrophages in the bone marrow, spleen and liver that have phagocytosed red blood cells (RBCs) and leukocytes. MAS is associated with increased inflammatory cytokines, cytopenias such as anemia and thrombocytopenia, and high serum ferritin. In the absence of treatment, MAS can be fatal, and most death in sJIA are due to MAS. Thus, understanding the mechanisms underlying MAS in rheumatic and inflammatory diseases is important for the development of new methods of therapeutic intervention. To identify novel pathways contributing to MAS, we focused on the identification of pathologic macrophages in a mouse model of MAS. As the phagocytosis of RBCs, platelets, and leukocytes can be a major contributor to the acute cytopenia seen in MAS, we reasoned that specialized phagocytes may be involved in disease pathogenesis. We found that chronic signaling via endosomal TLR7 and TLR9 directly induced differentiation of a novel macrophage population termed inflammatory hemophagocytes (iHPC), which differentiated from Ly6Chi monocytes. Transgenic overexpression of TLR7 not only caused the development of iHPC, but also caused a lethal MAS-like disease that could be rescued by iHPC depletion. MAS secondary to sJIA and to viral infection is associated with variants in the gene encoding IRF5, a transcription factor activated downstream of TLR signaling in monocytes and macrophages. Our preliminary data show that IRF5 also participates in TLR7- induced iHPC differentiation both in vitro and in vivo, and that IRF5 is hyper-activated in iHPC in our mouse model of TLR7-induced MAS. The premise of this application is that IRF5 signaling downstream of endosomal TLR7 and TLR9 is a critical component of iHPC differentiation and MAS. In this proposal we will 1) Test the hypothesis that IRF5 is required for iHPC differentiation and disease in a mouse model of TLR7-driven MAS, 2) Determine the mechanisms by which IRF5 participates in iHPC differentiation, and 3) Test the hypothesis that IRF5 is constitutively activated in iHPC and/or monocytes from sJIA patients with MAS. Successful completion of these studies will determine whether IRF5 is a viable therapeutic target for MAS in sJIA and other autoimmune diseases.