Immunosenescence, autoimmunity, and rheumatoid arthritis.
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.
Weyand
Cornelia M
CM
Department of Medicine and Immunology, Mayo Clinic, Guggenheim 401, 200 First Street SW, Rochester, MN 55905, USA. weyand.cornelia@mayo.edu
Fulbright
James W
JW
Goronzy
Jörg J
JJ
D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D015703:Antigens, CD / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015551:Autoimmunity / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D003324:Coronary Artery Disease / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000502:physiology*; D018655:Lymphocyte Count; D008875:Middle Aged; D013950:Thymus Gland / Q000502:physiology
D015703:Antigens, CD