Immunosenescence, autoimmunity, and rheumatoid arthritis

Abstract

Current disease models of autoimmune syndromes, such as rheumatoid arthritis, propose that chronic inflammation is caused by 'forbidden T-cell clones' that recognize disease-inducing antigens and drive tissue-injurious immune reactions. Reappraisal of disease incidence data, however, emphasizes that rheumatoid arthritis is a syndrome of the elderly that occurs with highest likelihood in individuals in whom the processes of T-cell generation and T-cell repertoire formation are compromised. Thymic T-cell production declines rapidly with advancing age. Multiple mechanisms, including antigen-driven clonal expansion and homeostasis-driven autoproliferation of post-thymic T cells, impose replicative stress on T cells and induce the biological program of cellular senescence. T-cell immunosenescence is associated with profound changes in T-cell functional profile and leads to accumulation of CD4+ T cells that have lost CD28 but have gained killer immunoglobulin-like receptors and cytolytic capability and produce large amounts of interferon-gamma. In patients with rheumatoid arthritis, T-cell immunosenescence occurs prematurely, probably due to a deficiency in the ability to generate sufficient numbers of novel T cells. We propose that autoimmunity in rheumatoid arthritis is a consequence of immunodegeneration that is associated with age-inappropriate remodeling of the T-cell pool.