Cellular Interactions in the Pathogenesis of Rheumatoid Arthritis: Cross-Talk Between T Cells and Fibroblast-Like Synoviocytes.

Abstract

Rheumatoid arthritis is a debilitating systemic autoimmune disease with the most prominent clinical pathology appearing as joint disfigurement. Microscopically, an intense inflammatory reaction characterized by numerous joint invading leukocytes and aberrant expression of cytokines promotes cartilage degradation and joint space remodeling by resident fibroblast-like synoviocytes (FLS). In this context, continued research must be done to better understand how the most numerous invading lymphocyte, the T cell, interacts with the FLS. Previous work has shown that bidirectional signaling between these two cell types results in mutual stimulation and activation. However, a complete understanding of the mechanisms and consequences of T cell-FLS interaction has not yet been realized.

To better elucidate this interaction, various in vitro models were employed in this thesis. Classic T cell interactions involve the presentation of antigen; consequently, the capacity of FLS to function as antigen presenting cells (APC) for arthritogenic autoantigens was assessed. Indeed, FLS could function as APC and activate T cells through presentation of autoantigens. Turning towards T cell activation of FLS, cytokine activated T cells were employed which characteristics similar to T cells have found within rheumatoid arthritis synovial tissue. These cytokine activated T cells utilized membrane bound TNFα as a stimulatory molecule to induce secretion of inflammatory cytokines by FLS. Finally, the role of costimulation in the interaction of T cell and FLS was evaluated. FLS were found to express the costimulatory ligand B7-H3, which had differential effects (either activating or inhibitory) on T cells depending on the T cell’s activation state.

Hopefully these results combined will further the goal of a complete understanding of rheumatoid arthritis pathology and contribute towards development of novel treatments for this devastating disease.