The complement system is a major component of innate immunity and plays a central role in the pro-inflammatory mechanisms that drive the pathogenesis of human rheumatoid arthritis (RA). In this process, inappropriate complement activation that is directed to self-tissues drives cellular influx, synovial inflammation and bone erosions. Recent findings suggest that this pathogenic process is likely to be especially important in the early phases of disease when circulating autoantibodies initially react with antigens which develop and are displayed in the joint. We have used an animal model of RA designated collagen antibody-induced arthritis (CAIA) to understand the molecular basis for these injurious roles of complement. One major focus of the proposed studies will be on how complement is activated within the joint by injured tissues through the engagement of the lectin pathway, which we recently unexpectedly found to play a major role in CAIA. Once activated, the lectin pathway leads to pathogenic engagement of the alternative pathway amplification loop. We will also determine whether factor H (FH), a soluble protein that we have shown plays an essential role in controlling complement activation on the acellular cartilage and stressed fibroblast-like synovial (FLS) cells, is itself the target of de-regulatory proteins from the facor H related (FHR) protein family which modulate its function. Finally, we have made the surprising finding that distal complement effector pathways initiated by anaphylatoxin C5a and C3a receptor engagement amplifies anti-collagen antibody deposition and proximal complement C3 activation, resulting in greatly increased joint damage. We intend to characterize the molecular mechanisms by which this distal amplification process occurs and determine what effector cells and danger signals mediate this effect. As a major focus of this effort, we have identified and wil explore a new injury mechanism through the engagement of hard-wired pathogenic natural antibodies that recognize injury- associated neoepitopes as danger signals and further increase complement activation. Through these efforts we hope to identify novel means by which we can beneficially modulate complement in a therapeutically efficacious manner.
Complement activation is believed to play a major role in the development of inflammatory arthritis, including rheumatoid arthritis (RA) in humans. Studies in animal models identify specific processes that appear to allow complement to be activated and result in tissue destruction. However, important gaps remain in our knowledge of these effects. A better understanding of the regulation of complement in arthritis will provide not only important basic science insights but also potentially help to identify new targets and therapeutic approaches.
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