The complement system is an important immune effector mechanism in autoimmune arthritis. During the current funding cycle, we have utilized both the collagen-induced arthritis (CIA) and the collagen antibody-induced arthritis (CAIA) models to evaluate the roles of complement in disease pathogenesis. Our studies have defined an important role for complement receptors CR2/CR1 in the development of humoral and cellular autoimmunity to type II collagen. In addition, we have studied in depth the in vivo mechanisms whereby complement is activated in the effector phase of this disease and plays a central role in mediating immune complex injury. Our most unanticipated results have come from studies that have demonstrated an absolute requirement for the alternative pathway and the alternative pathway amplification loop to develop robust inflammatory joint injury during the effector phase of disease. Indeed, using informative gene targeted mice we have found that the presence of the alternative pathway alone is uniquely able to support full arthritis development in the CAIA model. Proposed aims in this competing renewal application will focus substantially upon these particular unanticipated findings and clarify for the first time the relative in vivo role of the soluble complement regulatory protein factor H as compared to membrane regulatory proteins in an immune complex-initiated disease. We will also pursue a new hypothesis that the alternative pathway is primed in vivo for the development of pathologic injury by the activities of the MBL associated serum protease (MASP) protein MASP1 on pro-factor D, as well as define the role of the receptors for the chemotactic peptides C3a and C5a as compared to the membrane attack complex (MAC) in the generation of joint inflammation, and finally explore how complement activation is differentially regulated by the acellular cartilage surface in apposition to the cellular synovium. Our overall goal is to precisely define the in vivo molecular mechanisms by which the alternative pathway is initiated on the cartilage surface and the alternative pathway amplification loop is subsequently engaged in a cascade that results in full complement activation and locally destructive inflammatory joint damage. To accomplish these goals, we will pursue the following specific aims:
Specific Aim #1 : Determine the contribution of MASP-1/3 to priming the alternative pathway for activation as well as the roles of the C3aR, C5aR and MAC in mediating tissue injury during CAIA;
Specific Aim #2. Define the roles of individual soluble and membrane-bound complement regulatory proteins on cartilage and synovium in the control of complement activation and amplification loop engagement;
and Specific Aim #3 : Utilize informative in vitro systems in order to define the contribution of individual soluble and membrane-bound complement regulatory proteins on cartilage and synovium to the generation of pathogenic C3 and C5 activation fragments.
The studies focus on the pathogenesis of joint inflammation and damage in a murine model of rheumatoid arthritis. They are based on the unanticipated finding that one component of a complex multi-protein cascade designated the complement system plays a key role in vivo in the generation of all pro-inflammatory molecules that are derived from this pathway. Studies are designed to develop a more complete understanding of the mechanisms underlying this finding in arthritis models, and to determine how this component of complement integrates with other pro-inflammatory pathways important in disease pathogenesis.
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