Complement in Disease - Extracellular Proteins as Complement Regulators

Sammanfattning: Complement activation occurs during inflammatory joint diseases such as rheumatoid arthritis (RA) and is thought to contribute to the chronic inflammation observed within the joints. Previous studies have shown that certain cartilage components of the small leucine-rich repeat protein (SLRP)-family regulate complement activity, thereby possibly contributing to disease progression. The aim of this thesis is to find new interactions between cartilage components and complement, which could provide useful information for the development of novel therapeutic and diagnostic approaches. We found that complement-activating SLRPs also bind the complement inhibitor C4b-binding protein (C4BP) leading to a downregulation of the terminal complement pathway. This may be a mechanism to minimize release of anaphylatoxins and direct the complement response towards clearance of released cartilage constituents. We further found that one member of the SLRP-family, PRELP, inhibits complement directly by binding C9 and inhibiting the formation of the lytic membrane attack complex. PRELP was also found to inhibit the assembly of the alternative pathway C3-convertase and thereby affects two stages of the complement cascade. We found that cartilage oligomeric matrix protein (COMP), which has been shown to be released into the circulation during erosive joint diseases, has a dual role in complement activation; COMP inhibits the classical and lectin pathways whereas it activates the alternative pathway. COMP-induced complement activation can be seen in vivo by the presence of circulating COMP-C3b complexes. Such complexes are present in several rheumatic diseases but absent in healthy controls. COMP-C3b reflects disease activity in RA and levels are decreased upon TNF-α inhibition, which might provide an opportunity to use COMP-C3b as a marker of disease progression in RA. COMP is to our knowledge the first cartilage component whose complement activating properties have been demonstrated in vivo. We further showed that serglycin, a proteoglycan secreted by multiple myeloma cells, inhibits the classical and lectin pathways of complement and that cell surface expression of serglycin leads to protection of these cells from complement attack. This might interfere with immunotherapies that aim at directing complement responses towards multiple myeloma cells. Taken together, several novel interactions between endogenous ligands and complement have been found, which might regulate the progression of different disease processes.