T Cell Homeostasis and Repertoire Contraction in Rheumatoid Arthritis

  • J Jörg Goronzy1

    Affiliated with

    Arthritis Res19991(Suppl 1):S05

    DOI: 10.1186/ar19

    Published: 15 November 1999

    Full text

    Rheumatoid arthritis (RA) is not limited to chronic articular inflammation, but patients have alterations in their global immune system in line with the clinical experience of significant systemic disease. Specifically, RA patients frequently have clonal T cell populations in the circulation that characteristically lack the expression of the CD28 molecule. Here, we propose that RA patients have a defect in T cell generation that results in the contraction of the T cell repertoire and eventually in the emergence of CD28null clonal T cells. We have determined the diversity of the peripheral CD4 T cell repertoire by determining the frequencies of arbitrarily selected T cell receptor (TCR) β-chain sequences. Healthy individuals displayed a highly diverse repertoire, with a median frequency of individual TCR β-chain sequences of 1 in 2.4 × 107 CD4 T cells. In RA patients, the median TCR β-chain frequency was 10-fold increased. The loss in TCR diversity was not limited to CD4 memory T cells but also involved naive T cells, suggesting an abnormality in T cell repertoire formation and not a consequence of antigen recognition in the synovium. Also, control patients with chronic inflammatory disease such as hepatitis C expressed a diverse repertoire. In further support for this concept, telomere length studies indicated an increased replicative history of peripheral CD4 T cells in RA patients. Lymphocyte telomeres were age-inappropriately shortened with almost complete telomere erosion at an age of less than 40 years. Again, naive T cells were predominantly affected, and their capacity to undergo clonal burst after stimulation was about 10-fold reduced. These data are consistent with a premature exhaustion of lymphopoiesis in RA that may contribute to the autoimmune response as well as to the immunodeficiency in these patients and has important implications for their clinical management.

    Authors’ Affiliations

    (1)
    Mayo Clinic

    References

    1. Jendro MC, Ganten T, Matteson EL, Weyand CM, Goronzy JJ: Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis. Arthritis Rheum 1995, 38:1242–1251.View ArticlePubMed
    2. Schmidt D, Goronzy JJ, Weyand CM: CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest 1996, 97:2027–2037.View ArticlePubMed
    3. Wagner UG, Koetz K, Weyand CM, Goronzy JJ: Perturbation of the T cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci USA 1998, 95:14447–14452.View ArticlePubMed
    4. Walser-Kuntz DR, Weyand CM, Weaver AJ, O'Fallon WM, Goronzy JJ: Mechanisms underlying the formation of the T cell receptor repertoire in rheumatoid arthritis. Immunity 1995, 2:597–605.View ArticlePubMed
    5. Waase I, Kayser C, Carlson PJ, Goronzy JJ, Weyand CM: Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings. Arthritis Rheum 1996, 39:904–913.View ArticlePubMed
    6. Rittner HL, Zettl A, Jendro MC, Bartz-Bazzanella P, Goronzy JJ, Weyand CM: Multiple mechanisms support oligoclonal T cell expansion in rheumatoid synovitis. Mol Med 1997, 3:452–465.PubMed

    Copyright

    © Current Science Ltd 2000

    Advertisement