Shortening of telomeres: Evidence for replicative senescence of T cells derived from patients with Wegener's granulomatosis.

BACKGROUND Replicative senescence describes the fact that somatic cells undergo a finite and predictable number of cell divisions before entering an irreversible state of growth arrest. Progressive shortening of the telomeres, a consequence of cell division, is a reliable indicator of replicative senescence. METHOD We analyzed telomere length of DNA derived from T cells of patients suffering from Wegener's granulomatosis by Southern blotting. Moreover, expression of CD28, another marker for replicative senescence, was tested by cytofluorometry. RESULTS In patients with disease for more than 5 years, short telomeres were detected in addition to telomeres of normal length, indicating replicative senescence of discrete T-cell clones. Reduced expression of CD28 was noted, particularly on CD8-positive T cells, derived from patients with disease for more than 5 years and short telomeres. CONCLUSION Our data provide evidence that a portion of T cells had undergone replicative senescence, which in turn indicates clonal expansion of T cells as consequence of activation.

[1]  D A Bloch,et al.  The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. , 2010, Arthritis and rheumatism.

[2]  K. Andrassy,et al.  Polymorphonuclear neutrophils in Wegener's granulomatosis acquire characteristics of antigen presenting cells. , 2001, Kidney international.

[3]  N. Samani,et al.  Telomere shortening in atherosclerosis , 2001, The Lancet.

[4]  J. Klinenberg,et al.  Telomere shortening and decreased replicative potential, contrasted by continued proliferation of telomerase-positive CD8+CD28(lo) T cells in patients with systemic lupus erythematosus. , 2001, Clinical immunology.

[5]  K. Andrassy,et al.  Polymorphonuclear neutrophils as accessory cells for T‐cell activation: major histocompatibility complex class II restricted antigen‐dependent induction of T‐cell proliferation , 2000, Immunology.

[6]  L. Hayflick,et al.  The illusion of cell immortality , 2000, British Journal of Cancer.

[7]  M. Gill,et al.  Accelerated replicative senescence of the peripheral immune system induced by HIV infection , 2000, AIDS.

[8]  R. Falk,et al.  ANCA glomerulonephritis and vasculitis: a Chapel Hill perspective. , 2000, Seminars in nephrology.

[9]  R. Miller.  Telomere diminution as a cause of immune failure in old age: an unfashionable demurral. , 2000, Biochemical Society transactions.

[10]  A. Vallejo,et al.  Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. , 1999, Journal of immunology.

[11]  K. Andrassy,et al.  Expression of major histocompatibility class II antigens on polymorphonuclear neutrophils in patients with Wegener's granulomatosis. , 1999, Kidney international.

[12]  C. Kallenberg,et al.  Differential B- and T-cell activation in Wegener's granulomatosis. , 1999, The Journal of allergy and clinical immunology.

[13]  G. Pawelec,et al.  T cells and aging (update february 1999). , 1999, Frontiers in bioscience : a journal and virtual library.

[14]  J. Grunewald,et al.  Expanded T Cell Populations in Patients with Wegener's Granulomatosis: Characteristics and Correlates with Disease Activity , 1998, Journal of Clinical Immunology.

[15]  Wang,et al.  Costimulatory molecules in Wegener's granulomatosis (WG): lack of expression of CD28 and preferential up‐regulation of its ligands B7‐1 (CD80) and B7‐2 (CD86) on T cells , 1998, Clinical and experimental immunology.

[16]  G. Pawelec,et al.  Human T‐cell clones in long‐term culture as a model of immunosenescence , 1997, Immunological reviews.

[17]  L. Turka,et al.  Differential down-regulation of CD28 by B7-1 and B7-2 engagement. , 1997, Transplantation.

[18]  R. Effros.  Loss of CD28 expression on T lymphocytes: a marker of replicative senescence. , 1997, Developmental and comparative immunology.

[19]  C. Harley,et al.  Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. , 1996, AIDS.

[20]  J. Bluestone,et al.  CD28/B7 system of T cell costimulation. , 1996, Annual review of immunology.

[21]  G. Pawelec,et al.  Long-term culture of monoclonal human T lymphocytes: models for immunosenescence? , 1995, Mechanisms of Ageing and Development.

[22]  C. Kallenberg,et al.  T cell reactivity to proteinase 3 and myeloperoxidase in patients with Wegener's granulomatosis (WG) , 1994, Clinical and experimental immunology.

[23]  R. Effros,et al.  Decline in CD28+ T cells in centenarians and in long-term T cell cultures: A possible cause for both in vivo and in vitro immunosenescence , 1994, Experimental Gerontology.

[24]  R J Falk,et al.  Nomenclature of systemic vasculitides. Proposal of an international consensus conference. , 1994, Arthritis and rheumatism.

[25]  C B Harley,et al.  Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. , 1993, American journal of human genetics.

[26]  C B Harley,et al.  Telomere length predicts replicative capacity of human fibroblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.

[28]  P. Tugwell,et al.  The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. , 1990, Arthritis and rheumatism.

[29]  R. Gleason,et al.  Chronologic and physiologic age affect replicative life-span of fibroblasts from diabetic, prediabetic, and normal donors. , 1978, Science.

[30]  H. Peter,et al.  Activated CD4+ and CD8+ T-cell subsets in Wegener's granulomatosis , 2004, Rheumatology International.

[31]  C. Kallenberg,et al.  Is Wegener's granulomatosis an autoimmune disease? , 2000, Current opinion in rheumatology.