IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis

项目摘要 巨噬细胞活化综合征（MAS）是风湿性疾病的急性并发症。MAS是 最常见于全身性幼年特发性关节炎（sJIA）和儿童狼疮患者， MAS可以在病毒感染后发展，例如EBV。MAS涉及激活的 骨髓、脾脏和肝脏中的巨噬细胞吞噬红细胞（RBC）， 白细胞MAS与炎性细胞因子增加、血细胞减少如贫血和 血小板减少症和高血清铁蛋白。在没有治疗的情况下，MAS可能是致命的， 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， 对开发新的治疗干预方法具有重要意义。鉴定新 通路有助于MAS，我们专注于识别病理性巨噬细胞在小鼠模型 的MAS。由于RBC、血小板和白细胞的吞噬作用可以是急性炎症的主要贡献者， 在MAS中观察到的血细胞减少，我们推断特化的吞噬细胞可能参与疾病的发病机制。 我们发现，通过内体TLR 7和TLR 9的慢性信号传导直接诱导了一种新的 巨噬细胞群称为炎性噬血细胞（iHPC），其从Ly 6Chi分化而来 单核细胞TLR 7的转基因过表达不仅导致iHPC的发生，而且还导致了iHPC的发生。 致命的MAS样疾病，可以通过iHPC消耗来挽救。继发于sJIA和病毒感染的MAS 与编码IRF 5的基因变异有关，IRF 5是TLR下游激活的转录因子 单核细胞和巨噬细胞中的信号传导。我们的初步数据显示IRF 5也参与TLR 7- 在体外和体内诱导iHPC分化，并且IRF 5在我们的小鼠中的iHPC中被过度激活 TLR 7诱导的MAS模型。本申请的前提是，IRF 5信号转导在内体蛋白下游， TLR 7和TLR 9是iHPC分化和MAS的关键组分。在本提案中，我们将1）测试 假设IRF 5是TLR 7驱动的MAS小鼠模型中iHPC分化和疾病所必需的，2） 确定IRF 5参与iHPC分化的机制，以及3）检验以下假设： IRF 5在来自患有MAS的sJIA患者的iHPC和/或单核细胞中被组成性激活。成功完成 这些研究将确定IRF 5是否是sJIA和其他疾病中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.