Role of T Cells Specific for Citrullinated Fibrinogen in Rheumatoid Arthritis



 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an autoimmune disease considered to be primarily mediated by cytokines and antibodies, but there are important gaps in our understanding about the immunological events underlying this disease. The emerging understanding of the key role of cellular and high affinity humoral autoimmune responses to citrullinated autoantigens lends new emphasis to the importance of these immune mechanisms in the pathogenesis of RA. A critical question that we address in this pilot project pertains to th CD4 T cell response to the citrullinated autoantigens that drive the earliest processes of the disease and how these responses are linked to the presence of autoantibodies to these antigens. We have recently investigated citrullinated fibrinogen (CF), an autoantigen to which a substantial class-switched IgG humoral immune response is generated in patients with RA, as an autoantigen for both B cells and CD4 T cells in a mouse model of RA. We have developed mouse models in which monoclonal anti-citrullinated protein antibodies (ACPAs) or T cell lines reactive to citrullinated fibrinogen can be used to exacerbate disease in vivo. Our main objective in this pilot project proposal is to investigate how CD4 T cells specific for CF contribute to the disease process and interact with ACPAs to result in the development of joint-specific damage. Our central hypothesis is that the transition from the preclinical antibody phase of disease to clinical arthritis is a two-hit process following the formation of citrullinated autoantigens in th joint and that both antibodies and T cells reactive to citrullinated proteins contribute to pathogenesis. Our first aim is to investigate the pathogenic potential of CD4 T cells reactive to CF and the mechanisms by which anti-CF CD4 T cells exacerbate disease in a mouse model of RA. To achieve these goals we will examine how CD4 T cell lines specific for CF function in vivo and determine whether the anti-CF line can induce arthritis alone or only in combination with antigen immunization. Under the second aim, we will investigate whether ACPAs can contribute to pathogenesis of RA through synergy with pathogenic CD4 T cells and whether this process requires the development of innate-immune driven local generation of citrullinated target antigens. The significance of our proposed studies lies in the new information they may generate with regard to the basic autoimmune processes by which RA develops. Such information could have important implications for establishing new biomarkers of disease and targets for therapeutic intervention.