权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis

系统性幼年特发性关节炎中的 IRF5 和巨噬细胞激活综合征

基本信息

批准号：
10199939
负责人：
Betsy J Barnes
金额：
$ 57.14万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-24 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199939
关键词：
ATAC-seq Acute Adrenal Cortex Hormones Anemia Arthritis Autoimmune Diseases Autoimmunity Blood Platelets Blood specimen Bone Marrow CD14 gene Cells Cessation of life Childhood Chronic Complication Data Development Disease Erythrocytes Ferritin Gene Expression Genes Haplotypes Human Human Herpesvirus 4 In Vitro Inflammatory Interleukin-1 Interleukin-6 Kinetics Leukocytes Liver Macrophage activation syndrome Methods Modeling Molecular NF-kappa B Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Phagocytes Phagocytosis Population Rheumatism Risk Secondary to Serum Signal Transduction Spleen Syndrome Systemic Lupus Erythematosus TLR7 gene Testing Therapeutic Therapeutic Intervention Thrombocytopenia Transgenic Organisms Variant Virus Diseases cell type cytokine cytopenia experimental study genetic variant in vivo inhibitor/antagonist macrophage monocyte mouse model new therapeutic target novel overexpression pediatric lupus prevent systemic juvenile idiopathic arthritis therapeutic target transcription factor transcriptome transcriptome sequencing

项目摘要

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.

项目总结