Articular cartilage is predominately composed of collagen and proteoglycan (PG) macromolecules. BALB/c mice immunized with human cartilage PG develop progressive polyarthritis. Clinical assessments and histopathologic studies of diarthrodial joints showed that these mice develop disease that is similar to human rheumatoid arthritis. In the progression to arthritis, autoantibodies and T cells develop that cross-react with both degraded and native mouse PG. Development of autoantibodies to PG directly correlates with the onset of disease. The autoreactive B cells, in addition to producing antibodies, are excellent presenters of PG epitopes for T cell recognition. Despite the inability of autoantibodies to transfer disease, autoantibodies synergize, with activated T cells, to promote the development of arthritis. However, the exact role of autoreactive B cells and autoantibodies in this disease remains unclear. Our overall hypothesis is that PG-specific autoantibodies are responsible for initiating the local inflammatory process in the joint through the recruitment of PG-specific lymphocytes, macrophages, and polymorphonuclear leukocytes. We know that circulating PG-specific autoantibodies gain access to the joint and that PGs are normally released from cartilage as a function of cartilage matrix turnover. Binding of the autoantibodies to PGs in the joint may be the first step in the cascade of events that leads to immune complex deposition and the initiation of inflammation. We hypothesize that binding of immune- complexes to Fc-gamma-Rs may act as an important stimulator of macrophages and synovial lining cells. These cells would then produce cytokines and chemokines that promote recruitment of leukocytes and subsequent inflammatory attack to cartilage and bone. Simultaneously these cytokines activate matrix metalloproteinases which further enhance the release of PG fragments into the joint space. In this study we will specifically address the mechanism by which B cells and autoantibodies induce the recruitment of leukocytes to the joint. Using several gene deficient mice, in aim 1 we will define the requirements for B cells and immunoglobulin in the development of PG-induced arthritis and determine whether circulating Ig is required for chemokine expression.
In aim 2 we will assess the involvement of Fc-gamma-Rs in induction of arthritis and whether Fc-gamma-Rs initiate chemokine mRNA expression in the joint.
In aim 3 we will define the requirements for specific chemokines in the systemic and local response to PG that induces arthritis.
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