Friday, April 19, 2024
4/19/2024
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 and how that influences clinical outcomes. 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 regulated by inflammatory cytokines as well as activated, and then defining the subsequent phenotypic changes. 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
