Rheumatoid arthritis (RA) is a heterogeneous, chronic and polyarticular arthritis that affects a significant portion of the world's population. RA is widely believed to be an autoimmune disease, although its etiology and pathogenesis are only partially understood. The goal of this study is to test the hypothesis that activation of Toll-like receptors (TLRs) influence arthritis development by stimulating various players of the innate immune system. This study will focus on the effector phase of autoimmune arthritis using the K/BxN serum transfer model. The activation of TLRs can be achieved either by pathogen-derived ligands (pathogen-associated molecular patterns, or PAMPs) or by ligands endogenous to the host. Therefore, the specific aims of this study include: 1) examining the effect of PAMPs on the development of K/BxN serum-induced arthritis, and 2) determining the role of specific TLRs in the development of serum-induced arthritis in the absence of PAMPs. In the K/BxN arthritis model, mice exhibit a spontaneous arthritic phenotype similar to human RA. Arthritis can be adoptively transferred with serum from arthritic K/BxN mice in a highly reproducible and synchronized manner. This serum transfer model recapitulates the effector phase of arthritis. Therefore, the role of TLRs during the effector phase of arthritis can be efficiently assayed by injection of serum and PAMPs into mice or by transferring serum into mice of various TLR-/- backgrounds. After the effect of various TLRs on arthritis has been determined by these two approaches, the cellular and molecular mediators through which the TLRs exert their influence on arthritis will be elucidated. This study will contribute to our understanding of the etiology and pathogenesis of RA. If a TLR is found to be critical for arthritis development, then administration of TLR blocking reagents may provide novel treatments for RA patients.
