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Complement in the Pathogenesis of Autoimmune Arthritis

补体在自身免疫性关节炎发病机制中的作用

基本信息

批准号：
10255878
负责人：
Vernon Michael Holers
金额：
$ 34.21万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2021-02-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255878
关键词：
Address Adopted Affect Animal Model Antibodies Antigens Appearance Arthritis Attention Autoantibodies Autoantigens Autoimmune Diseases Biological Markers Biopsy Blood Blood specimen Cells Clinical Trials Complement Complement Activation Complement Factor H Development Diagnosis Disease Disease model Disease remission Fibroblasts Funding Generations Goals Grant Human Immune Individual Inflammation Inflammatory Inflammatory Arthritis Injury Joints Knowledge Lectin Lung Mannose Binding Lectin Mediator of activation protein Medicine Mucositis Mus Natural History Natural Immunity Outcome Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phase Phenotype Play Population Positioning Attribute Process Proteins Regulation Reporting Rheumatoid Arthritis Role Sampling Serine Protease Synovial Cell Synovial Membrane Synovitis System Systemic Lupus Erythematosus Therapeutic Tissues Translating Translational Research United States National Institutes of Health Work autoimmune arthritis bone erosion cell type citrullinated protein complement pathway complement system disability ficolin human disease human model immunoregulation improved in vivo information model inhibitor/antagonist insight mouse model mucosal site natural antibodies neoantigens next generation novel pathogen patient subsets pre-clinical prognostic programs skills societal costs targeted treatment tissue injury

项目摘要

The complement system is a major pro-inflammatory and immunomodulatory pathway and plays a central role in the mechanisms that drive the pathogenesis of experimental murine models of human rheumatoid arthritis (RA). In these murine models, inappropriate complement activation that is directed to self-tissues drives initial cellular influx into the joint as well as synovial inflammation and bone erosions. However, despite the extensive insights into the murine disease that we have developed with support of this grant, including the activation pathways involved, how control of the system is overcome and how individual effector pathways promote tissue damage, we do not know how the complement system plays a pathogenic role in patients with RA. Recent findings in our studies of the human disease have identified a prolonged preclinical phase in RA characterized by the presence of circulating autoantibodies and mucosal inflammation that appears to drive the initial break in tolerance to citrullinated self-antigens. Following that asymptomatic phase, where complement activation is present in the mucosal site but not systemically, it is likely that complement activation and effector mechanisms are then especially important as the disease transitions to the very early phases of synovitis when circulating autoantibodies directed against citrullinated proteins initially react with antigens which develop and are displayed in the joint. To build our understanding of the human disease and translate information from models of disease to patients themselves, the major focus of this competing renewal proposal is to understand how the complement system is involved in the early synovitis in RA. We are especially well positioned to accomplish this important goal, as with other support mechanisms we are able to identify and follow subjects from the preclinical period into the very first appearance of synovitis and the diagnosis of RA. By obtaining synovial biopsies, a skill set also developed in our program in the last 3-4 years through other funding, and informative blood samples from patients in this important transition period, we will work to characterize the role of complement activation as well as its regulatory and effector mechanisms in the initial development of inflammatory arthritis and synovitis in patients. In addition, as there are distinct sub-types of RA, designated pathotypes, which have prognostic importance, we will determine what complement activation processes are associated with individual pathotypes. Finally, we will focus special attention on a major synovial cell type in human RA, which are highly inflammatory fibroblast-like synoviocytes, whose importance is increasingly understood and for which there are reported complement signatures in unbiased omics studies. We will define the mechanisms by which complement interacts with this cell type, both with regard to how complement is activated as well as defining the phenotypic changes in these cells following activation. A major goal in these studies is to use information gained to inform the use of current and next generation complement therapeutics in this important human autoimmune disease.

补体系统是一个主要的促炎和免疫调节途径，并发挥核心作用