Stem cell aging and autoimmunity in rheumatoid arthritis

We propose a novel disease model for rheumatoid arthritis (RA), an autoimmune syndrome that is assumed to be caused by the recognition of arthritogenic antigens in the synovium. Support for antigen selection and recognition as crucial events in rheumatoid synovitis has come from the strong association of the disease with HLA-DRB1 genes. However, recent results demonstrate a novel function for the RA-associated HLA-DR4 haplotype, regulating the biology of hematopoietic stem cells (HSCs). Healthy HLA-DR4⁺ individuals have premature aging of HSCs, a defect they acquire during the second decade of life, and accumulate pre-aged T cells. In patients with RA, premature HSC aging is combined with additional restrictions in thymic T-cell output, leading to senescence in the T-cell pool. Senescent T cells are functionally altered, express novel immunoregulatory receptors, are prone to autoimmunity and might directly drive synovitis. Premature aging of stem cells might have implications for other cell lineages, providing the basis for immune-mediated tissue damage and the breakdown of self-tolerance.