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Gerontology 2010;56:390–403

Telomeres and Immunological Diseases of Aging

Andrews N.P. · Fujii H. · Goronzy J.J. · Weyand C.M.
Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga., USA
email Corresponding Author

 goto top of outline Key Words

  • Telomeres
  • Aging
  • Immunosenescence

 goto top of outline Abstract

A defining feature of the eukaryotic genome is the presence of linear chromosomes. This arrangement, however, poses several challenges with regard to chromosomal replication and maintenance. To prevent the loss of coding sequences and to suppress gross chromosomal rearrangements, linear chromosomes are capped by repetitive nucleoprotein structures, called telomeres. Each cell division results in a progressive shortening of telomeres that, below a certain threshold, promotes genome instability, senescence, and apoptosis. Telomeric erosion, maintenance, and repair take center stage in determining cell fate. Cells of the immune system are under enormous proliferative demand, stressing telomeric intactness. Lymphocytes are capable of upregulating telomerase, an enzyme that can elongate telomeric sequences and, thus, prolong cellular lifespan. Therefore, telomere dynamics are critical in preserving immune function and have become a focus for studies of immunosenescence and autoimmunity. In this review, we describe the role of telomeric nucleoproteins in shaping telomere architecture and in suppressing DNA damage responses. We summarize new insights into the regulation of telomerase activity, hereditary disorders associated with telomere dysfunction, the role of telomere loss in immune aging, and the impact of telomere dysfunction in chronic inflammatory disease.

Copyright © 2009 S. Karger AG, Basel

 goto top of outline References
  1. Sarkar D, Fisher PB: Molecular mechanisms of aging-associated inflammation. Cancer Lett 2006;236:13–23.
  2. Goronzy JJ, Weyand CM: Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity – catalysts of autoimmunity and chronic inflammation. Arthritis Res Ther 2003;5:225–234.
  3. Shay JW, Wright WE: Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 2005;26:867–874.
  4. Palm W, de Lange T: How shelterin protects mammalian telomeres. Annu Rev Genet 2008;42:301–334.
  5. Bollmann FM: The many faces of telomerase: emerging extratelomeric effects. Bioessays 2008;30:728–732.
  6. Hayflick L, Moorhead PS: The serial cultivation of human diploid cell strains. Exp Cell Res 1961;25:585–621.
  7. Gilson E, Londono-Vallejo A: Telomere length profiles in humans: all ends are not equal. Cell Cycle 2007;6:2486–2494.
  8. Verdun RE, Karlseder J: Replication and protection of telomeres. Nature 2007;447:924–931.
  9. Hemann MT, Strong MA, Hao LY, Greider CW: The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 2001;107:67–77.
  10. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T: Mammalian telomeres end in a large duplex loop. Cell 1999;97:503–514.
  11. Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC: Telomerase maintains telomere structure in normal human cells. Cell 2003;114:241–253.
  12. Anno K, Hayashi A, Takahashi T, Mitsui Y, Ide T, Tahara H: Telomerase activation induces elongation of the telomeric single-stranded overhang, but does not prevent chromosome aberrations in human vascular endothelial cells. Biochem Biophys Res Commun 2007;353:926–932.
  13. Stansel RM, de Lange T, Griffith JD: T-loop assembly in vitro involves binding of TRF2 near the 3′ telomeric overhang. Embo J 2001;20:5532–5540.
  14. de Lange T: Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 2005;19:2100–2110.
  15. Longhese MP: DNA damage response at functional and dysfunctional telomeres. Genes Dev 2008;22:125–140.
  16. Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T: P53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 1999;283:1321–1325.
  17. Denchi EL, de Lange T: Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 2007;448:1068–1071.
  18. Williams ES, Klingler R, Ponnaiya B, Hardt T, Schrock E, Lees-Miller SP, Meek K, Ullrich RL, Bailey SM: Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence. Cancer Res 2009;69:2100–2107.
  19. Akbar AN, Beverley PC, Salmon M: Will telomere erosion lead to a loss of T-cell memory? Nat Rev Immunol 2004;4:737–743.
  20. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW: Specific association of human telomerase activity with immortal cells and cancer. Science 1994;266:2011–2015.
  21. Kyo S, Kanaya T, Takakura M, Tanaka M, Yamashita A, Inoue H, Inoue M: Expression of human telomerase subunits in ovarian malignant, borderline and benign tumors. Int J Cancer 1999;80:804–809.
  22. Horikawa I, Cable PL, Afshari C, Barrett JC: Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res 1999;59:826–830.
  23. Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R: Direct activation of TERT transcription by c-Myc. Nat Genet 1999;21:220–224.
  24. Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, Yutsudo M, Ariga H, Inoue M: Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic Acids Res 2000;28:669–677.
  25. Goueli BS, Janknecht R: Regulation of telomerase reverse transcriptase gene activity by upstream stimulatory factor. Oncogene 2003;22:8042–8047.
  26. Yatabe N, Kyo S, Maida Y, Nishi H, Nakamura M, Kanaya T, Tanaka M, Isaka K, Ogawa S, Inoue M: Hif-1-mediated activation of telomerase in cervical cancer cells. Oncogene 2004;23:3708–3715.
  27. Lv J, Liu H, Wang Q, Tang Z, Hou L, Zhang B: Molecular cloning of a novel human gene encoding histone acetyltransferase-like protein involved in transcriptional activation of hTERT. Biochem Biophys Res Commun 2003;311:506–513.
  28. Nishi H, Nakada T, Kyo S, Inoue M, Shay JW, Isaka K: Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT). Mol Cell Biol 2004;24:6076–6083.
  29. Kanaya T, Kyo S, Hamada K, Takakura M, Kitagawa Y, Harada H, Inoue M: Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription. Clin Cancer Res 2000;6:1239–1247.
  30. Takakura M, Kyo S, Inoue M, Wright WE, Shay JW: Function of AP-1 in transcription of the telomerase reverse transcriptase gene (TERT) in human and mouse cells. Mol Cell Biol 2005;25:8037–8043.
  31. Oh S, Song Y, Yim J, Kim TK: The Wilms’ tumor 1 tumor suppressor gene represses transcription of the human telomerase reverse transcriptase gene. J Biol Chem 1999;274:37473–37478.
  32. Oh S, Song YH, Yim J, Kim TK: Identification of Mad as a repressor of the human telomerase (hTERT) gene. Oncogene 2000;19:1485–1490.
  33. Fujimoto K, Kyo S, Takakura M, Kanaya T, Kitagawa Y, Itoh H, Takahashi M, Inoue M: Identification and characterization of negative regulatory elements of the human telomerase catalytic subunit (hTERT) gene promoter: possible role of MZF-2 in transcriptional repression of hTERT. Nucleic Acids Res 2000;28:2557–2562.
  34. Renaud S, Loukinov D, Bosman FT, Lobanenkov V, Benhattar J: CTCF binds the proximal exonic region of hTERT and inhibits its transcription. Nucleic Acids Res 2005;33:6850–6860.
  35. Li H, Xu D, Li J, Berndt MC, Liu JP: Transforming growth factor beta suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. J Biol Chem 2006;281:25588–25600.
  36. Lou F, Chen X, Jalink M, Zhu Q, Ge N, Zhao S, Fang X, Fan Y, Bjorkholm M, Liu Z, Xu D: The opposing effect of hypoxia-inducible factor-2alpha on expression of telomerase reverse transcriptase. Mol Cancer Res 2007;5:793–800.
  37. Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE: Hif-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 2004;23:1949–1956.
  38. Choi J, Fauce SR, Effros RB: Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun 2008;22:600–605.
  39. Kang SS, Kwon T, Kwon DY, Do SI: Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J Biol Chem 1999;274:13085–13090.
  40. Akiyama M, Hideshima T, Hayashi T, Tai YT, Mitsiades CS, Mitsiades N, Chauhan D, Richardson P, Munshi NC, Anderson KC: Nuclear factor-kappaB p65 mediates tumor necrosis factor alpha-induced nuclear translocation of telomerase reverse transcriptase protein. Cancer Res 2003;63:18–21.
  41. Robertson KD, Jones PA: DNA methylation: past, present and future directions. Carcinogenesis 2000;21:461–467.
  42. Kumakura S, Tsutsui TW, Yagisawa J, Barrett JC, Tsutsui T: Reversible conversion of immortal human cells from telomerase-positive to telomerase-negative cells. Cancer Res 2005;65:2778–2786.
  43. Renaud S, Loukinov D, Abdullaev Z, Guilleret I, Bosman FT, Lobanenkov V, Benhattar J: Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res 2007;35:1245–1256.
  44. Wilson VL, Smith RA, Ma S, Cutler RG: Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 1987;262:9948–9951.
  45. Cong YS, Bacchetti S: Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells. J Biol Chem 2000;275:35665–35668.
  46. Xu D, Popov N, Hou M, Wang Q, Bjorkholm M, Gruber A, Menkel AR, Henriksson M: Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells. Proc Natl Acad Sci USA 2001;98:3826–3831.
  47. Won J, Yim J, Kim TK: Sp1 and Sp3 recruit histone deacetylase to repress transcription of human telomerase reverse transcriptase (hTERT) promoter in normal human somatic cells. J Biol Chem 2002;277:38230–38238.
  48. Vulliamy TJ, Dokal I: Dyskeratosis congenita: the diverse clinical presentation of mutations in the telomerase complex. Biochimie 2008;90:122–130.
  49. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I: The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001;413:432–435.
  50. Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, Masunari Y, Al-Qurashi FH, Aljurf M, Dokal I: Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet 2007;16:1619–1629.
  51. Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, Poustka A, Dokal I: X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998;19:32–38.
  52. Meier UT: The many facets of H/ACA ribonucleoproteins. Chromosoma 2005;114:1–14.
  53. Wong JM, Collins K: Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita. Genes Dev 2006;20:2848–2858.
  54. Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I: Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 2004;36:447–449.
  55. Vulliamy TJ, Marrone A, Knight SW, Walne A, Mason PJ, Dokal I: Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 2006;107:2680–2685.
  56. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS: Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 2005;352:1413–1424.
  57. Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP: TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 2008;82:501–509.
  58. Lavin MF: Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 2008;9:759–769.
  59. Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y: Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 2003;22:5612–5621.
  60. Lee JH, Paull TT: ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 2005;308:551–554.
  61. Digweed M, Sperling K: Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair (Amst) 2004;3:1207–1217.
  62. Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, Raams A, Byrd PJ, Petrini JH, Taylor AM: The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 1999;99:577–587.
  63. Helmink BA, Bredemeyer AL, Lee BS, Huang CY, Sharma GG, Walker LM, Bednarski JJ, Lee WL, Pandita TK, Bassing CH, Sleckman BP: MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks. J Exp Med 2009;206:669–679.
  64. Callen E, Samper E, Ramirez MJ, Creus A, Marcos R, Ortega JJ, Olive T, Badell I, Blasco MA, Surralles J: Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia. Hum Mol Genet 2002;11:439–444.
  65. Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, Shay JW, Ishioka S, Yamakido M: Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 1995;155:3711–3715.
  66. Igarashi H, Sakaguchi N: Telomerase activity is induced in human peripheral B lymphocytes by the stimulation to antigen receptor. Blood 1997;89:1299–1307.
  67. Liu K, Schoonmaker MM, Levine BL, June CH, Hodes RJ, Weng NP: Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. Proc Natl Acad Sci USA 1999;96:5147–5152.
  68. Sheng WY, Chen YR, Wang TC: A major role of PKC theta and NFkappaB in the regulation of hTERT in human T lymphocytes. FEBS Lett 2006;580:6819–6824.
  69. Akiyama M, Yamada O, Hideshima T, Yanagisawa T, Yokoi K, Fujisawa K, Eto Y, Yamada H, Anderson KC: TNFalpha induces rapid activation and nuclear translocation of telomerase in human lymphocytes. Biochem Biophys Res Commun 2004;316:528–532.
  70. Li H, Zhao LL, Funder JW, Liu JP: Protein phosphatase 2A inhibits nuclear telomerase activity in human breast cancer cells. J Biol Chem 1997;272:16729–16732.
  71. Reed JR, Vukmanovic-Stejic M, Fletcher JM, Soares MV, Cook JE, Orteu CH, Jackson SE, Birch KE, Foster GR, Salmon M, Beverley PC, Rustin MH, Akbar AN: Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo. J Exp Med 2004;199:1433–1443.
  72. Surh CD, Sprent J: Homeostasis of naive and memory T cells. Immunity 2008;29:848–862.
  73. Soares MV, Borthwick NJ, Maini MK, Janossy G, Salmon M, Akbar AN: IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire. J Immunol 1998;161:5909–5917.
  74. Wallace DL, Berard M, Soares MV, Oldham J, Cook JE, Akbar AN, Tough DF, Beverley PC: Prolonged exposure of naive CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length. Immunology 2006;119:243–253.
  75. Slagboom PE, Droog S, Boomsma DI: Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet 1994;55:876–882.
  76. Nordfjall K, Larefalk A, Lindgren P, Holmberg D, Roos G: Telomere length and heredity: indications of paternal inheritance. Proc Natl Acad Sci USA 2005;102:16374–16378.
  77. Frenck RW Jr., Blackburn EH, Shannon KM: The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci USA 1998;95:5607–5610.
  78. Rufer N, Brummendorf TH, Kolvraa S, Bischoff C, Christensen K, Wadsworth L, Schulzer M, Lansdorp PM: Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med 1999;190:157–167.
  79. Hodes RJ, Hathcock KS, Weng NP: Telomeres in T and B cells. Nat Rev Immunol 2002;2:699–706.
  80. Aviv A, Chen W, Gardner JP, Kimura M, Brimacombe M, Cao X, Srinivasan SR, Berenson GS: Leukocyte telomere dynamics: longitudinal findings among young adults in the Bogalusa heart study. Am J Epidemiol 2009;169:323–329.
  81. Petersen S, Saretzki G, von Zglinicki T: Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res 1998;239:152–160.
  82. Matsubara Y, Murata M, Yoshida T, Watanabe K, Saito I, Miyaki K, Omae K, Ikeda Y: Telomere length of normal leukocytes is affected by a functional polymorphism of hTERT. Biochem Biophys Res Commun 2006;341:128–131.
  83. Nordfjall K, Osterman P, Melander O, Nilsson P, Roos G: hTERT (-1327)T/C polymorphism is not associated with age-related telomere attrition in peripheral blood. Biochem Biophys Res Commun 2007;358:215–218.
  84. Golbus J, Palella TD, Richardson BC: Quantitative changes in T cell DNA methylation occur during differentiation and ageing. Eur J Immunol 1990;20:1869–1872.
  85. Damjanovic AK, Yang Y, Glaser R, Kiecolt-Glaser JK, Nguyen H, Laskowski B, Zou Y, Beversdorf DQ, Weng NP: Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer’s disease patients. J Immunol 2007;179:4249–4254.
  86. Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H: Trends in oxidative aging theories. Free Radic Biol Med 2007;43:477–503.
  87. Oikawa S, Kawanishi S: Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett 1999;453:365–368.
  88. von Zglinicki T: Oxidative stress shortens telomeres. Trends Biochem Sci 2002;27:339–344.
  89. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, Aviv A, Spector TD: Obesity, cigarette smoking, and telomere length in women. Lancet 2005;366:662–664.
  90. Starr JM, McGurn B, Harris SE, Whalley LJ, Deary IJ, Shiels PG: Association between telomere length and heart disease in a narrow age cohort of older people. Exp Gerontol 2007;42:571–573.
  91. Starr JM, Shiels PG, Harris SE, Pattie A, Pearce MS, Relton CL, Deary IJ: Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey. Mech Ageing Dev 2008;129:745–751.
  92. Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW: DNA repair, genome stability, and aging. Cell 2005;120:497–512.
  93. Andriollo-Sanchez M, Hininger-Favier I, Meunier N, Venneria E, O’Connor JM, Maiani G, Coudray C, Roussel AM: Age-related oxidative stress and antioxidant parameters in middle-aged and older European subjects: the Zenith study. Eur J Clin Nutr 2005;59(Suppl 2):58–62.

    External Resources

  94. Vina J, Borras C, Gambini J, Sastre J, Pallardo FV: Why females live longer than males? Importance of the upregulation of longevity-associated genes by oestrogenic compounds. FEBS Lett 2005;579:2541–2545.
  95. Lee DC, Im JA, Kim JH, Lee HR, Shim JY: Effect of long-term hormone therapy on telomere length in postmenopausal women. Yonsei Med J 2005;46:471–479.
  96. Benetos A, Okuda K, Lajemi M, Kimura M, Thomas F, Skurnick J, Labat C, Bean K, Aviv A: Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity. Hypertension 2001;37:381–385.
  97. Okuda K, Bardeguez A, Gardner JP, Rodriguez P, Ganesh V, Kimura M, Skurnick J, Awad G, Aviv A: Telomere length in the newborn. Pediatr Res 2002;52:377–381.
  98. Engel P, Eck MJ, Terhorst C: The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nat Rev Immunol 2003;3:813–821.
  99. Plunkett FJ, Franzese O, Belaramani LL, Fletcher JM, Gilmour KC, Sharifi R, Khan N, Hislop AD, Cara A, Salmon M, Gaspar HB, Rustin MH, Webster D, Akbar AN: The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome. Mech Ageing Dev 2005;126:855–865.
  100. Effros RB, Allsopp R, Chiu CP, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD, Giorgi JV: Shortened telomeres in the expanded CD28CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 1996;10:F17–F22.
  101. Son NH, Murray S, Yanovski J, Hodes RJ, Weng N: Lineage-specific telomere shortening and unaltered capacity for telomerase expression in human T and B lymphocytes with age. J Immunol 2000;165:1191–1196.
  102. Son NH, Joyce B, Hieatt A, Chrest FJ, Yanovski J, Weng NP: Stable telomere length and telomerase expression from naive to memory B-lymphocyte differentiation. Mech Ageing Dev 2003;124:427–432.
  103. Weng NP: Telomere and adaptive immunity. Mech Ageing Dev 2008;129:60–66.
  104. Gavazzi G, Krause KH: Ageing and infection. Lancet Infect Dis 2002;2:659–666.
  105. Dokal I: Dyskeratosis congenita in all its forms. Br J Haematol 2000;110:768–779.
  106. Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL, Kronenberg M, Cohen D, Schachter F: 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. Exp Gerontol 1994;29:601–609.
  107. Effros RB: Loss of CD28 expression on T lymphocytes: a marker of replicative senescence. Dev Comp Immunol 1997;21:471–478.
  108. Liuzzo G, Goronzy JJ, Yang H, Kopecky SL, Holmes DR, Frye RL, Weyand CM: Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 2000;101:2883–2888.
  109. Martens PB, Goronzy JJ, Schaid D, Weyand CM: Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum 1997;40:1106–1114.
  110. Moosig F, Csernok E, Wang G, Gross WL: 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. Clin Exp Immunol 1998;114:113–118.
  111. Vallejo AN, Weyand CM, Goronzy JJ: T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection. Trends Mol Med 2004;10:119–124.
  112. Namekawa T, Wagner UG, Goronzy JJ, Weyand CM: Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum 1998;41:2108–2116.
  113. Valenzuela HF, Effros RB: Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol 2002;105:117–125.
  114. Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN: The loss of telomerase activity in highly differentiated CD8+CD28CD27 T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol 2007;178:7710–7719.
  115. Rufer N, Migliaccio M, Antonchuk J, Humphries RK, Roosnek E, Lansdorp PM: Transfer of the human telomerase reverse transcriptase (TERT) gene into T lymphocytes results in extension of replicative potential. Blood 2001;98:597–603.
  116. Honda M, Mengesha E, Albano S, Nichols WS, Wallace DJ, Metzger A, Klinenberg JR, Linker-Israeli M: Telomere shortening and decreased replicative potential, contrasted by continued proliferation of telomerase-positive CD8+CD28(lo) T cells in patients with systemic lupus erythematosus. Clin Immunol 2001;99:211–221.
  117. Artlett CM, Black CM, Briggs DC, Stevens CO, Welsh KI: Telomere reduction in scleroderma patients: a possible cause for chromosomal instability. Br J Rheumatol 1996;35:732–737.
  118. Schonland SO, Lopez C, Widmann T, Zimmer J, Bryl E, Goronzy JJ, Weyand CM: Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci USA 2003;100:13471–13476.
  119. Jeanclos E, Krolewski A, Skurnick J, Kimura M, Aviv H, Warram JH, Aviv A: Shortened telomere length in white blood cells of patients with IDDM. Diabetes 1998;47:482–486.
  120. Vogt S, Iking-Konert C, Hug F, Andrassy K, Hansch GM: Shortening of telomeres: Evidence for replicative senescence of T cells derived from patients with Wegener’s granulomatosis. Kidney Int 2003;63:2144–2151.
  121. Wu K, Higashi N, Hansen ER, Lund M, Bang K, Thestrup-Pedersen K: Telomerase activity is increased and telomere length shortened in T cells from blood of patients with atopic dermatitis and psoriasis. J Immunol 2000;165:4742–4747.
  122. Steer SE, Williams FM, Kato B, Gardner JP, Norman PJ, Hall MA, Kimura M, Vaughan R, Aviv A, Spector TD: Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration. Ann Rheum Dis 2007;66:476–480.
  123. Skapenko A, Lipsky PE, Schulze-Koops H: T cell activation as starter and motor of rheumatic inflammation. Curr Top Microbiol Immunol 2006;305:195–211.
  124. Goronzy JJ, Bartz-Bazzanella P, Hu W, Jendro MC, Walser-Kuntz DR, Weyand CM: Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis. J Clin Invest 1994;94:2068–2076.
  125. 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.
  126. 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.
  127. Fujii H, Shao L, Colmegna I, Goronzy JJ, Weyand CM: Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci USA 2009;106:4360–4365.
  128. Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM: T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA 2000;97:9203–9208.
  129. Chung HY, Sung B, Jung KJ, Zou Y, Yu BP: The molecular inflammatory process in aging. Antioxid Redox Signal 2006;8:572–581.
  130. Brod SA: Unregulated inflammation shortens human functional longevity. Inflamm Res 2000;49:561–570.
  131. van der Harst P, van der Steege G, de Boer RA, Voors AA, Hall AS, Mulder MJ, van Gilst WH, van Veldhuisen DJ: Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol 2007;49:1459–1464.
  132. Schreurs MW, Hermsen MA, Geltink RI, Scholten KB, Brink AA, Kueter EW, Tijssen M, Meijer CJ, Ylstra B, Meijer GA, Hooijberg E: Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes. Blood 2005;106:2663–2670.
  133. Roth A, Yssel H, Pene J, Chavez EA, Schertzer M, Lansdorp PM, Spits H, Luiten RM: Telomerase levels control the lifespan of human T lymphocytes. Blood 2003;102:849–857.
  134. Menzel O, Migliaccio M, Goldstein DR, Dahoun S, Delorenzi M, Rufer N: Mechanisms regulating the proliferative potential of human CD8+ T lymphocytes overexpressing telomerase. J Immunol 2006;177:3657–3668.
  135. Fauce SR, Jamieson BD, Chin AC, Mitsuyasu RT, Parish ST, Ng HL, Kitchen CM, Yang OO, Harley CB, Effros RB: Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol 2008;181:7400–7406.
  136. De Meyer T, Rietzschel ER, De Buyzere ML, De Bacquer D, Van Criekinge W, De Backer GG, Gillebert TC, Van Oostveldt P, Bekaert S: Paternal age at birth is an important determinant of offspring telomere length. Hum Mol Genet 2007;16:3097–3102.
  137. Kurosaka D, Yasuda J, Yoshida K, Yokoyama T, Ozawa Y, Obayashi Y, Kingetsu I, Saito S, Yamada A: Telomerase activity and telomere length of peripheral blood mononuclear cells in SLE patients. Lupus 2003;12:591–599.
  138. Wu CH, Hsieh SC, Li KJ, Lu MC, Yu CL: Premature telomere shortening in polymorphonuclear neutrophils from patients with systemic lupus erythematosus is related to the lupus disease activity. Lupus 2007;16:265–272.
  139. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE: Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007;356:1317–1326.
  140. Prelog M, Schwarzenbrunner N, Sailer-Hock M, Kern H, Klein-Franke A, Ausserlechner MJ, Koppelstaetter C, Brunner A, Duftner C, Dejaco C, Strasak AM, Muller T, Zimmerhackl LB, Brunner J: Premature aging of the immune system in children with juvenile idiopathic arthritis. Arthritis Rheum 2008;58:2153–2162.
  141. Bechan GI, Meeker AK, De Marzo AM, Racke F, Jaffe R, Sugar E, Arceci RJ: Telomere length shortening in Langerhans cell histiocytosis. Br J Haematol 2008;140:420–428.
  142. da Costa CE, Egeler RM, Hoogeboom M, Szuhai K, Forsyth RG, Niesters M, de Krijger RR, Tazi A, Hogendoorn PC, Annels NE: Differences in telomerase expression by the CD1a+ cells in Langerhans cell histiocytosis reflect the diverse clinical presentation of the disease. J Pathol 2007;212:188–197.
  143. MacIntyre A, Brouilette SW, Lamb K, Radhakrishnan K, McGlynn L, Chee MM, Parkinson EK, Freeman D, Madhok R, Shiels PG: Association of increased telomere lengths in limited scleroderma, with a lack of age-related telomere erosion. Ann Rheum Dis 2008;67:1780–1782.
  144. Tarhan F, Vural F, Kosova B, Aksu K, Cogulu O, Keser G, Gunduz C, Tombuloglu M, Oder G, Karaca E, Doganavsargil E: Telomerase activity in connective tissue diseases: elevated in rheumatoid arthritis, but markedly decreased in systemic sclerosis. Rheumatol Int 2008;28:579–583.
  145. Colmegna I, Diaz-Borjon A, Fujii H, Schaefer L, Goronzy JJ, Weyand CM: Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum 2008;58:990–1000.
  146. Guan JZ, Maeda T, Sugano M, Oyama J, Higuchi Y, Suzuki T, Makino N: An analysis of telomere length in sarcoidosis. J Gerontol A Biol Sci Med Sci 2007;62:1199–1203.
  147. Beier F, Balabanov S, Amberger CC, Hartmann U, Manger K, Dietz K, Kotter I, Brummendorf TH: Telomere length analysis in monocytes and lymphocytes from patients with systemic lupus erythematosus using multi-color flow-fish. Lupus 2007;16:955–962.
  148. Cong YS, Wright WE, Shay JW: Human telomerase and its regulation. Microbiol Mol Biol Rev 2002;66:407–425, table of contents.

 goto top of outline Author Contacts

Cornelia M. Weyand, MD, PhD
Lowance Center for Human Immunology, Emory University
101 Woodruff Circle
Atlanta, GA 30322 (USA)
Tel. +1 404 727 7310, Fax +1 404 727 7371, E-Mail cweyand@emory.edu

 goto top of outline Article Information

Received: May 29, 2009
Accepted: September 7, 2009
Published online: December 17, 2009
Number of Print Pages : 14
Number of Figures : 3, Number of Tables : 1, Number of References : 148

 goto top of outline Publication Details

Gerontology (International Journal of Experimental, Clinical, Behavioural and Technological Gerontology)

Vol. 56, No. 4, Year 2010 (Cover Date: June 2010)

Journal Editor: Wick G. (Innsbruck)
ISSN: 0304-324X (Print), eISSN: 1423-0003 (Online)

For additional information: http://www.karger.com/GER

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