Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages.
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.
Department of Medicine and Immunology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Stefan O
SO
Schönland
Consuelo
C
Lopez
Thomas
T
Widmann
Julia
J
Zimmer
Ewa
E
Bryl
Jörg J
JJ
Goronzy
Cornelia M
CM
Weyand
D000367:Age Factors; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D019070:Cell Lineage; D016922:Cellular Senescence; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D005838:Genotype; D006098:Granulocytes / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D007156:Immunologic Memory; D015810:Linkage Disequilibrium; D008214:Lymphocytes / Q000166:cytology*; D008954:Models, Biological; D022423:Myeloid Cells / Q000166:cytology*; D016615:Telomere / Q000648:ultrastructure; D013997:Time Factors
D018106:CD28 Antigens; D017252:CD3 Complex; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D004247:DNA