Role of reactive oxygen species in rheumatoid arthritis synovial T lymphocytes

Abstract

In rheumatoid arthritis, an inflammatory infiltrate accumulates and persists in the synovial membrane. Synovial T cells display a number of particular characteristics. While displaying markers of recent activation, synovial T lymphocytes respond poorly to mitogenic stimuli and their cytokine production appears to be suppressed both in situ and in vitro. One of the critical hallmarks from synovial T cells is that they suffer from oxidative stress. Oxidative stress in synovial fluid T lymphocytes inhibits T cell receptor (TCR)-dependent phosphorylation of pivotal signaling molecules, required for efficient T cell proliferation, and contributes to severe hyporesponsiveness of these cells. Chronic exposure of T lymphocytes to free radicals produced by activated phagocytic cells at the site of inflammation has been proposed to be the major cause of deregulated redox homeostasis in RA. In this thesis we further investigate the source of free radicals. We demonstrate that the oxidative stress found in synovial T cells is not the result from exogenous sources but originates from (an) intracellular activated oxidase(s). We demonstrate that the oxidase generating ROS in SF T cells is controlled by the small GTPases Ras and Rap1. We show that in synovial T cells Ras can be activated by a variety of cytokines. Rap1 inhibition is induced by direct cell-cell contact of T lymphocytes with antigen presenting cells (APC), and can be prevented by blocking the co-stimulatory T cell receptor CD28 with CTLA-4. Howevever, we did therapy with a nutrient supplement containing high dose anti-oxidants and poly-unsaturated fatty acids did not lead to clinical improvement of RA disease activity, nor therapy with high dose intravenously administered N-acetyl cysteine.