Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages
- Stefan O. Schönland†,
- Consuelo Lopez†,‡,
- Thomas Widmann†,‡,
- Julia Zimmer†,
- Ewa Bryl†,
- Jörg J. Goronzy†,§, and
- Cornelia M. Weyand†,§,¶
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Edited by Philippa Marrack, National Jewish Medical and Research Center, Denver, CO, and approved September 8, 2003 (received for review June 10, 2003)
Abstract
In rheumatoid arthritis, peripheral blood T cells have age-inappropriate telomeric erosion. We examined whether HLA-DRB1*04 alleles, the major susceptibility genes for this disease, confer risk for T cell senescence. In healthy individuals, HLA-DRB1*04 alleles were associated with excessive loss of telomeres in CD4+ T cells. Accelerated telomeric erosion occurred during the first two decades of life and was followed by reduced homeostatic T cell proliferation during adulthood. Premature telomeric loss also affected granulocytes, suggesting that the hematopoietic stem cell is the primary target. Telomeric repair mechanisms were intact in HLA-DRB1*04 + donors. We propose that HLA-DRB1*04 alleles or genes in linkage disequilibrium regulate stem cell replication and contribute to the accumulation of senescent and autoreactive T cells in rheumatoid arthritis.
Footnotes
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↵ ¶ To whom correspondence should be addressed at: Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: weyand.cornelia{at}mayo.edu.
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↵ ‡ C.L. and T.W. contributed equally to this work.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: HSC, hematopoietic stem cell; RA, rheumatoid arthritis; TCR, T cell antigen receptor; TREC, TCR excision circle; TRF, telomeric restriction fragment.
- Copyright © 2003, The National Academy of Sciences
