| Complement is a key component of the innate immune system and is intimately involved in many immunological processes that underlie autoimmune diseases like rheumatoid arthritis (RA). The pathways leading to complement activation have been studied in great detail. However, far less insight is available on the regulation of complement activation by endogenous fluid phase inhibitors.The aim of this study is to delineate the role of these endogenous fluid-phase complement inhibitors in the prevention of harmful immune responses and autoimmunityTo this end, I will focus on the role of C4BP and factor H, the two most prominent fluid phase complement inhibitors, in the prevention of harmful immune responses that are evoked by extracellular DNA. Although for a long time considered to be non-immunogenic, it is now becoming increasingly clear that DNA, either as free entity or as DNA-protein complex, released from dying cells, is immunogenic and capable of breaking immune tolerance to auto-antigens. Because fluid-phase complement inhibitors bind to DNA, my working hypothesis is that they form an essential protective threshold against excessive complement activation. Therefore, it is proposed to investigate the role of fluid-phase complement inhibitors in these processes by:1 Defining how binding of complement components influences the immune activating potential of DNA and DNA-protein complexes in vitro and in vivo 2 Determining how factor H and C4BP influence adaptive immune responses to DNA-protein complexes 3 Defining how fluid-phase complement inhibitors influence the role of DNA and complement in arthritis, as a model for organ-specific inflammation, by using factor H and C4BP deficient mice |
