The Immune System in Aging

  • Anjali Desai
  • Raymond L. YungEmail author


The human immune system is a highly evolved system that plays a central role in health and disease. Unders-tanding the aging-associated immune changes is critical to explaining both the disease susceptibility and the different clinical course of rheumatic diseases in the elderly. This is particularly important as the rheumatology discipline is firmly rooted in the era of biologic therapy that is entirely dependent on advances in our knowledge of the immune and inflammatory basis of autoimmune diseases. In this chapter, we briefly review the basic components of the immune system, the recent advances in our understanding of immune senescence, the concept of “inflamm-aging,” and how these age-related changes may be important in determining the health/disease status of the rheumatology patients.


Immune senescence Inflammation Aging 


  1. 1.
    Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmstrom V. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther. 2004;6(4):R335–46.PubMedCrossRefGoogle Scholar
  2. 2.
    Crispin JC, Martínez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun. 2003;21(3):273.PubMedCrossRefGoogle Scholar
  3. 3.
    Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199(7):971–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Honorati MC, Meliconi R, Pulsatelli L, Cane S, Fizziero L, Facchini A. High in vivo expression of interleukin-17 receptor in synovial endothelial cells and chondrocytes from arthritis patients. Rheuma-tology (Oxford). 2001;40:522–7.CrossRefGoogle Scholar
  5. 5.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103:1345–52.PubMedCrossRefGoogle Scholar
  6. 6.
    Huang M, Liao JJ, Bonasera S, Longo DL, Goetzl EJ. Nuclear factor-kB-dependent reversal of aging-induced alterations in T cell cytokines. FASEB J. 2008;22(7):2142–50.PubMedCrossRefGoogle Scholar
  7. 7.
    Bleesing JJ, Brown M, Novicio C, et al. A composite picture of TcR alpha/beta(+) CD4(−) CD8(−) T cells (alpha/beta-DNTCs) in humans with autoimmune lymphoproliferative syndrome. Clin Immunol. 2002;104:21–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Cohen PL, Caricchio R, Abraham V, et al. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med. 2002;196:135–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Aprahamian T, Takemura Y, Goukassian D, Walsh K. Ageing is associated with diminished apoptotic cell clearance in vivo. Clin Exp Immunol. 2008;152(3):448–55.PubMedCrossRefGoogle Scholar
  10. 10.
    Schindowski K, Leutner S, Muller WE, Eckert A. Age related changes of apoptotic cell death in human lymphocytes. Neurobiol Aging. 2000;21:661–70.PubMedCrossRefGoogle Scholar
  11. 11.
    Wallace DL, Zhang Y, Ghattas H, Worth A, Irvine A, Bennett AR, et al. Direct measurement of T cell subset kinetics in vivo in elderly men and women. J Immunol. 2004;173(3):1787–94.PubMedGoogle Scholar
  12. 12.
    Kohler S, Wagner U, Pierer M, Kimmig S, Oppmann B, Mowes B, et al. Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol. 2005;35(6):1987–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, et al. The influence of age on T cell generation and TCR diversity. J Immunol. 2005;174(11):7446–52.PubMedGoogle Scholar
  14. 14.
    Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint J-P, Labalette M. Accumulation of memory T cells from childhood to old age: Central and effector memory cells in CD4+ versus effector memory and terminally differentiated memory cells in CD8+ compartment. Mech Ageing Dev. 2006;127(3):274.PubMedCrossRefGoogle Scholar
  15. 15.
    Hakim FT, Gress RE. Immunosenescence: deficits in adaptive immunity in the elderly. Tissue Antigens. 2007;70(3):179–89.PubMedCrossRefGoogle Scholar
  16. 16.
    Whisler RL, Beiqing L, Chen M. Age-related decreases in IL-2 production by human T cells are associated with impaired activation of nuclear transcriptional factors AP-1 and NF-AT. Cell Immunol. 1996;169(2):185.PubMedCrossRefGoogle Scholar
  17. 17.
    Haynes L, Linton P-J, Eaton SM, Tonkonogy SL, Swain SL. Interleukin 2, but not other common gamma chain–binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice. J Exp Med. 1999;190(7):1013–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Nagel JE, Chopra R, Chrest FJ, McCoy MT, Schneider EL, Holbrook NJ, et al. Decreased proliferation, interleukin 2 synthesis, and interleukin 2 receptor expression are accompanied by decreased mRNA expression in phytohemagglutinin-stimulated cells from elderly donors. J Clin Invest. 1988;81(4):1096–102.PubMedCrossRefGoogle Scholar
  19. 19.
    Chiu Y-C, Yang R-S, Hsieh K-H, Fong Y-C, Way T-D, Lee T-S, et al. Stromal cell-derived factor-1 induces matrix metalloprotease-13 expression in human chondrocytes. Mol Pharmacol. 2007;72(3):695–703.PubMedCrossRefGoogle Scholar
  20. 20.
    Nanki T, Hayashida K, El-Gabalawy HS, Suson S, Shi K, Girschick HJ, et al. Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol. 2000;165(11):6590–8.PubMedGoogle Scholar
  21. 21.
    Mo R, Chen J, Han Y, Bueno-Cannizares C, Misek DE, Lescure PA, et al. T cell chemokine receptor expression in aging. J Immunol. 2003;170(2):895–904.PubMedGoogle Scholar
  22. 22.
    Dejaco C, Duftner C, Schirmer M. Are regulatory T-cells linked with aging? Exp Gerontol. 2006;41(4):339.PubMedCrossRefGoogle Scholar
  23. 23.
    Gregg R, Smith CM, Clark FJ, Dunnion D, Khan N, Chakraverty R, et al. The number of human peripheral blood CD4+CD25high regulatory T cells increases with age. Clin Exp Immunol. 2005;140(3):540–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Csiszar A, Ungvari Z, Edwards JG, Kaley G. Aging induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J. 2003;17:1183–5.PubMedGoogle Scholar
  25. 25.
    Hussein MR, Fathi N, El-Din AM, Hassan HI, Abdullah F, Al-Hakeem E, et al. Alterations of the CD4(+), CD8 (+) T cell subsets, interleukins-1beta, IL-10, IL-17, tumor necrosis factor-alpha and soluble intercellular adhesion molecule-1 in rheumatoid arthritis and osteoarthritis: preliminary observations. Pathol Oncol Res. 2008;14(3):321–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Ginaldi L, De Martinis M, D’Ostilio A, Marini L, Loreto MF, Corsi MP, et al. The immune system in the elderly: I specific humoral immunity. Immunol Res. 1999;20(2):101–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Ginaldi L, De Martinis M, D’Ostilio A, Marini L, Loreto MF, Martorelli V, et al. The immune system in the elderly: II specific cellular immunity. Immunol Res. 1999;20(2):109–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Shearer GM. Th1/Th2 changes in aging. Mech Ageing Dev. 1997;94(1–3):1–5.PubMedGoogle Scholar
  29. 29.
    Ide K, Hayakawa H, Yagi T, Sato A, Koide Y, Yoshida A, et al. Decreased expression of Th2 type cytokine mRNA contributes to the lack of allergic bronchial inflammation in aged rats. J Immunol. 1999;163(1):396–402.PubMedGoogle Scholar
  30. 30.
    Li SP, Miller RA. Age-associated decline in IL-4 production by murine T lymphocytes in extended culture. Cell Immunol. 1993;151(1):187–95.PubMedCrossRefGoogle Scholar
  31. 31.
    Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, Usui T, Kita T. Altered Th1/Th2 commitment in human CD4+ T cells with ageing. Clin Exp Immunol. 2000;120(2):267–73.PubMedCrossRefGoogle Scholar
  32. 32.
    Uciechowski P, Kahmann L, Plümäkers B, Malavolta M, Mocchegiani E, Dedoussis G, et al. TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation. Exp Gerontol. 2008;43(5):493.PubMedCrossRefGoogle Scholar
  33. 33.
    Iancu EM, Speiser DE, Rufer N. Assessing ageing of individual T lymphocytes: mission impossible? Mech Ageing Dev. 2008;129(1–2):67–78.PubMedCrossRefGoogle Scholar
  34. 34.
    Weng NP, Granger L, Hodes RJ. Telomere lengthening and telomerase activation during human B cell differentiation. Proc Natl Acad Sci USA. 1997;94(20):10827–32.PubMedCrossRefGoogle Scholar
  35. 35.
    Weng NP, Hathcock KS, Hodes RJ. Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential. Immunity. 1998;9(2):151–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Salmon M, Akbar AN. Telomere erosion: a new link between HLA DR4 and rheumatoid arthritis? Trends Immunol. 2004;25(7):339–41.PubMedCrossRefGoogle Scholar
  37. 37.
    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(4):990–1000.PubMedCrossRefGoogle Scholar
  38. 38.
    Colonna-Romano G, Bulati M, Aquino A, Scialabba G, Candore G, Lio D, et al. B cells in the aged: CD27, CD5, and CD40 expression. Mech Ageing Dev. 2003;124(4):389.PubMedCrossRefGoogle Scholar
  39. 39.
    Shi Y, Yamazaki T, Okubo Y, Uehara Y, Sugane K, Agematsu K. Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J Immunol. 2005;175(5):3262–7.PubMedGoogle Scholar
  40. 40.
    Chong Y, Ikematsu H, Yamaji K, Nishimura M, Nabeshima S, Kashiwagi S, et al. CD27(+) (memory) B cell decrease and apoptosis-resistant CD27(−) (naive) B cell increase in aged humans: implications for age-related peripheral B cell developmental disturbances. Int Immunol. 2005;17(4):383–90.PubMedCrossRefGoogle Scholar
  41. 41.
    Agrawal A, Agrawal S, Cao JN, Su H, Osann K, Gupta S. Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J Immunol. 2007;178(11):6912–22.PubMedGoogle Scholar
  42. 42.
    Lung TL, Saurwein-Teissl M, Parson W, Schonitzer D, Grubeck-Loebenstein B. Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine. 2000;18(16):1606–12.PubMedCrossRefGoogle Scholar
  43. 43.
    Shodell M, Siegal FP. Circulating, interferon-producing plasmacytoid dendritic cells decline during human ageing. Scand J Immunol. 2002;56(5):518–21.PubMedCrossRefGoogle Scholar
  44. 44.
    Grolleau-Julius A, Harning E, Abernathy L, Yung RL. Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res. 2008;68(15):6341–9.PubMedCrossRefGoogle Scholar
  45. 45.
  46. 46.
    Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. The aging of hematopoietic stem cells. Nat Med. 1996;2(9):1011–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA. Aging hematopoietic stem cells decline in func-tion and exhibit epigenetic dysregulation. PLoS Biol. 2007;5(8):e201.PubMedCrossRefGoogle Scholar
  48. 48.
    Li L, Hsu HC, Grizzle WE, Stockard CR, Ho KJ, Lott P, et al. Cellular mechanism of thymic involution. Scand J Immunol. 2003;57(5):410–22.PubMedCrossRefGoogle Scholar
  49. 49.
    Franceschi C. Inflammaging as a major characteristic of old people: can it be prevented or cured? Nutr Rev. 2007;65(12 Pt 2):S173–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, et al. Increased cytokine production in mononu-clear cells of healthy elderly people. Eur J Immunol. 1993;23(9):2375–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24(8):1159–69.PubMedCrossRefGoogle Scholar
  52. 52.
    Aspinall R, Del Giudice G, Effros R, Grubeck-Loebenstein B, Sambhara S. Challenges for vaccination in the elderly. Immun Ageing. 2007;4(1):9.PubMedCrossRefGoogle Scholar
  53. 53.
    Huckriede A, Bungener L, Stegmann T, Daemen T, Medema J, Palache AM, et al. The virosome concept for influenza vaccines. Vaccine. 2005;23(Supplement 1):S26.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of MichiganAnn ArborUSA

Personalised recommendations