Skip to main content
Log in

The immune system in the elderly

III. Innate Immunity

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The capability to cope with infectious agents and cancer cells resides not only in adaptive immune responses against specific antigens, mediated by T and B lymphocytes clonally distributed, but also in natural immune reactions. These innate defence mechanisms include chemotaxis, phagocytosis, natural cytotoxicity, cell interactions, and soluble mediators or cytokines. However, specific and natural immune mechanisms are always closely linked and interconnected, providing the primary defense against pathogens. The Authors discuss the main changes observed with advancing age in granulocytes and natural killer (NK) cell activity, in the expression and function of adhesion molecules, and in the pattern of cytokine production. Since phagocytic function is the primary mechanism through which the immune system eliminates most extracellular pathogenic microrganisms, analysis of this function is of clinical importance. Neutrophils from aged subjects often exhibit a diminished phagocytic capacity, as well as a depressed respiratory burst, notwithstanding an activated state. The activity of NK cells during aging has been studied extensively and different results have been reported. The most consistent data indicate an increase in cells with high NK activity with advancing age. Cells from healthy centenarians can efficiently kill target cells. This finding seems to suggest that innate immunity and in particualr NK cell activity, is not heavily deteriorated with age. Conversely, a low NK activity is a predictor of impending morbidity. Immunosenescence is associated with increased expression of several cell adhesion molecules (CAM) resulting in an augmented capacity to adhere. Finally, also the cytokine network, responsible for differentiation, proliferation, and survival of lymphoid cells, undergoes complex changes with age. The main findings are a Th1 to Th2 cytokine production shift and an increased production of proinflammatory cytokines, which could explain many aspects of age-associated pathological events, such as atherosclerosis and osteoporosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Quaglino D, Ginaldi L, Furia N, De Martinis M: The effect of age on hemopoiesis. Aging Clin. Exp. Res. 1996;8:1–12.

    CAS  Google Scholar 

  2. Makinodan T, Kay MMB: Age influence on the immune system. Adv. Immunol. 1980;29:287–330.

    PubMed  CAS  Google Scholar 

  3. Cooper EL, Rinkevich B, Uhlenbruck G, Valenbois P: Invertebrate immunity: another view point. Scand. J. Immunol. 1992;35:247–266.

    CAS  Google Scholar 

  4. Cooper EL, Zhang Z, Raftos DA, Habicht GS, Beck G, Connors V, Cossarizza A, Franceschi C, Ottaviani E, Scapigliati G, Parrinello N.: When did communication in the immune system begin? Int. J. Immunopathol. Pharmacol. 1994;7:203–217.

    CAS  Google Scholar 

  5. Franceschi C, Cossarizza A, Monti D, Ottaviani E: Cytotoxicity and immunocyte markers in cells from the freshwater snail Planorbarius corneus (L.) (Gastropoda, Pulmonata): implication for the evolution of NK cells. Eur. J. Immunol. 1991;21:489–493.

    Article  PubMed  CAS  Google Scholar 

  6. Ottaviani E, Francini A, Franceschi C: Presence of several cytokine-like molecules in molluscan hemocytes. Biochem. Biophys. Res. Commun. 1993;195:984–988.

    Article  PubMed  CAS  Google Scholar 

  7. Ottaviani E, Franchini A, Caselgrandi E, Cossarizza A, Franceschi C: Relationship between CRF and IL-2: evolutionary evidence. FEBS Lett. 1994;351:19–21.

    Article  PubMed  CAS  Google Scholar 

  8. Franceschi C, Paganelli R, Fagiolo U, Ottaviani E: Cytokines, aging and evolution: the problem of promiscuity. Int. J. Immunopathol. Pharmacol. 1994;7:227–233.

    CAS  Google Scholar 

  9. Esparza B, Sanchez H, Ruiz M, Barranquero M, Sabino E, Merino F: Neutrophil function in elderly persons assessed by flow cytometry. Immunol. Invest. 1996;25:185–190.

    Article  PubMed  CAS  Google Scholar 

  10. Ligthart GJ, Corberand JX, Fournier C, Garanaud P, Hijmans W, Kennes B, Muller-Hermelink HK, Steinmann GG: Admission criteria for immunogerontological studies in man: the SENIEUR protocol. Mech. Aging Dev. 1984;28: 47–55.

    Article  PubMed  CAS  Google Scholar 

  11. Ligthart GJ, Corberand JX, Geertzen HGM, Meinders AE, Knook DL, Hijmans W: Necessity of the assessment of health status in human immunogerontological studies: evaluation of the SENIEUR protocol. Mech. Aging Dev. 1990;55:89–105.

    Article  PubMed  CAS  Google Scholar 

  12. Wikby A, Johansson B, Ferguson F, Olsson J: Age-related changes in immune parameters in a very old population of Swedish people: a longitudinal study. Exp. Gerontol. 1994;29:531–541.

    Article  PubMed  CAS  Google Scholar 

  13. Brosche T, Platt D: Nutritional factors and age-associated changes in cellular immunity and phagocytosis: a mini-review. Aging Immunol. Infect. Dis. 1995; 6:31–42.

    Google Scholar 

  14. Horan MA, Gulati RS, Fox RA: Assessment of neutrophil function in the elderly using antibody coated polyacrylamide gel (immunobeads) and nitroblue tetrazolium (NTB) reduction as a combined test. Mech. Aging Dev. 1985;29: 29–33.

    Article  PubMed  CAS  Google Scholar 

  15. McLaughlin B, O’Malley K, Cotter TG: Age-related differences in granulocyte chemiotaxis and degranulation. Clin. Sci. 1986;70:59–62.

    PubMed  CAS  Google Scholar 

  16. Rabatic S, Sabioncello A, Dekaris D, Kardum I: Age-related changes in functions of peripheral blood phagocytes. Mech. Aging Dev. 1988;45:223–229.

    Article  PubMed  CAS  Google Scholar 

  17. Niwa Y, Kasama T, Miyachi Y, Kanoh T: Neutrophil chemotaxis, phagocytosis and parameters of reactive oxygen species in human aging: cross sectional and longitudinal studies. Life Sci. 1989;44: 1655–1664.

    Article  PubMed  CAS  Google Scholar 

  18. MacGregor RR, Shalit M: Neutrophil function in healthy elderly subjects. J. Gerontol. 1990;45: M55–60.

    PubMed  CAS  Google Scholar 

  19. Phair JP, Umeki S, Soejima R: Host defense activity in various hosts; human neutrophil NADPH oxidase activity. Chest 1992; 102: 1780–1786.

    Article  Google Scholar 

  20. Ortega E, Barriga C, De la Fuente M: Study of the phagocytic process in neutrophils from elite sports women. Eur. J. Appl. Physiol. 1993;66:37–42.

    Article  CAS  Google Scholar 

  21. Ligthart GJ, Schuit HRE, Hijmans W: Natural killer function is not diminished in the healthy aged and is proportional to the number of NK cells in the perypheral blood. Immunology 1989;68:396–402.

    PubMed  CAS  Google Scholar 

  22. Sansoni P, Cossarizza A, Brianti V, Fagnoni F, Snelli G, Monti D, Marcato A, Passed G, Ortolani C, Forti E, Fagiolo U, Passen M, Franceschi C: Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 1993;80:2767–2773.

    Google Scholar 

  23. Cossarizza A, Ortolani C, Monti D, Franceschi C: Cytometric analysis of immunosenescence. Cytometry 1997;27:297–313.

    Article  PubMed  CAS  Google Scholar 

  24. Cossarizza A, Monti D, Montagnani G, Ortolani C, Masi M, Zannotti M, Franceschi C: Precociuos aging of the immune system in Down’s syndrome: alterations of B-lymphocytes, Tlymphocyte subsets and of cells with NK markers. Am. J. Med. Genet. 1990;7:213–218.

    Article  CAS  Google Scholar 

  25. Cossarizza A, Ortolani C, Forti E, Montagnani G, Paganelli R, Zannotti M, Marini M, Monti D, Franceschi C: Age-related expansion of functionally inefficient cells with markers of NK activity in Down’s syndrome. Blood 1991;77:1263–1270.

    PubMed  CAS  Google Scholar 

  26. Levy SM, Herberman RB, Lee J, Whiteside T, Beadle M, Heiden L, Simons A: Persistently low natural killer cell activity, age, and environmental stress as predictors of infectious morbidity. Natl. Immunol. Cell Growth Regul. 1991; 10:289–307.

    CAS  Google Scholar 

  27. Franceschi C, Monti D, Sansoni P, Cossarizza A: The immunology of exceptional individuals: the lesson of centenarians. Immunol. Today 1995;16:12–16.

    Article  PubMed  CAS  Google Scholar 

  28. Voss SD, Sondel PM, Robb RJ: Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2Rg chain with the IL-2Rb chain in functional intermediate-affinity IL-2R. J. Exp. Med. 1992;176:531–540.

    Article  PubMed  CAS  Google Scholar 

  29. Trinchieri G: Biology of natural killer cells. Adv. Immunol. 1989; 47:187–196.

    Article  PubMed  CAS  Google Scholar 

  30. Kimball KA, Cornett LE, Seifen E, Kennedy RH: Aging: changes in cardiac alpha1 adrenoceptor responsiveness and expression. Eur. J.Pharmacol. 1991;208:231–238.

    Article  PubMed  CAS  Google Scholar 

  31. Krishnaraj R: Senescence and cytokines modulate the NK cell expression. Mech. Aging Dev. 1997;96:89–101.

    Article  PubMed  CAS  Google Scholar 

  32. Onsurd M: Age dependent changes in some human lymphocyte subpopulations. Acta Path. Microbiol. Scand. 1981;89:55–62.

    Google Scholar 

  33. Batory G, Benczur M, Varga M, Garam T, Onody C, Petranyi GG: Increased killer cell activity in aged humans. Immunobiology 1981;158:393–402.

    PubMed  CAS  Google Scholar 

  34. Kutza J, Murasko DM: Effects of aging on natural killer cell activity and activation by interleukin-2 and IFN-a. Cell Immunol. 1994; 155:195–204.

    Article  PubMed  CAS  Google Scholar 

  35. Baum LL, Krishnaraj R: Natural killer cells in host defense. Immunol. Allergy Clin. North. Am. 1993;13:535–550.

    Google Scholar 

  36. Bhooma T, Krishnaraj R, Svanborg A: Cytokine sensitivity of human NK cells during immunosenescence. I. IL-2-induced antitumor cytotoxicity. Aging Immunol. Infect. Dis. 1994; 5:83–97.

    Google Scholar 

  37. Kishimoto TK, Larson RS, Corbi AL, Dustin ML, Staunton DE, Springer TA: The leukocyte integrins. Adv. Immunol. 1989;46:149–182.

    PubMed  CAS  Google Scholar 

  38. Springer TA: Adhesion receptors of the immune system. Nature 1990;346:425–434.

    Article  PubMed  CAS  Google Scholar 

  39. Neubert R, Delgado I, Abraham K, Schuster C, Helge H: Evaluation of the age-dependent development of lymphocyte surface receptors in children. Life Sci. 1998;62: 1099,1100.

    Article  PubMed  CAS  Google Scholar 

  40. Okumura M, Fujii Y, Takeuchi Y, Inada K, Makahara K, Matsuda H: Age-related accumulation of LFA1high cells in CD8+ CD45RAhigh T cell population. Eur. J. Immunol. 1993;23:1057–1063.

    Article  PubMed  CAS  Google Scholar 

  41. Okumura M, Fujii Y, Takeuchi Y, Inada K, Makahara K, Matsuda H: Both CD45RA+ CD45RA-subpopulations of CD8+ T cells conatin cells with high levels of lymphocyte function associated antigen-1 expression, a phenotype of primed T cells. J. Immunol. 1993; 150:429–437.

    PubMed  CAS  Google Scholar 

  42. Beutler B, Cerami A: The biology of cachectin/TNF. A primary mediator of the host response. Annu. Rev. Immunol. 1989;7:625–655.

    PubMed  CAS  Google Scholar 

  43. Kingstone AE, Bergsteinsdottir K, Jessen KR, Van Der Meide PH, Colston MJ, Mirsky R: Schwann cells co-cultured with stimulated T cells and antigen express MHC class II determinants without interferon-g pretreatment: synergistic effects of interferon-g and tumor necrosis factor on MHC class II induction. Eur. J. Immunol. 1989;19:177–183.

    Article  Google Scholar 

  44. Dinarello CA: Interleukin-1 and interleukin-1 antagonism. Blood 1991;77:1627–1652.

    PubMed  CAS  Google Scholar 

  45. Farrar AM, Schreiber RD: The molecular cell biology of IFN-g and its receptor. 1993; 11:571–611.

    CAS  Google Scholar 

  46. Facchini A, Mariani E, Mariani AR, Papa S, Vitale ME, Manzoli FA: Increased number of circulating Leul 1c+ (CD 16) large granular lymphocytes and decreased NK activity during human aging. Clin. Exp. Immunol. 1987;68: 340–347.

    PubMed  CAS  Google Scholar 

  47. Licastro F, Morini MC, Chiricolo M, Belletti D, Malpassi P, Parente R, Carpenè E, Conte R: Functional assessment of cellular non-specific and specific immunity in selected healthy elderly. Arch. Gerontol. Geriatr. 1992;3:219–228.

    Article  CAS  Google Scholar 

  48. Chiricolo M, Morini M.C, Mancini R, Beltrandi E, Belletti D, Conte R: Cell adhesion molecules CD11a and CD18 in blood monocytes in old age and the consequences for immunological dysfunction. Gerontology 1995;41:227–234.

    PubMed  CAS  Google Scholar 

  49. Owen CA, Campbell EJ, Stockley RA: Monocyte adherence to fibronectin: role of CD11/CD18 integrins and relationship to other monocyte functions. J. Leukocyte Biol. 1992;51:400–408.

    PubMed  CAS  Google Scholar 

  50. Vyth-Dreese FA, Dellemijn TAM, Frijhoff A, van Kooyk Y, Figdor CG: Role of LFA-1/CAM-1 in interleukin-2-stimulated lymphocyte proliferation. Eur. J. Immunol. 1993;23:3292–3299.

    Article  PubMed  CAS  Google Scholar 

  51. Amadori A, Zanovello P, Cozzi E, Ciminale V, Borghesan F, Faggiolo U, Crepaldi G: Study of some early immunological parameters in aging humans. Gerontology 1988;34:277–283.

    Article  PubMed  CAS  Google Scholar 

  52. Schwab R, Pfeffer LM, Szabo P, Gamble G, Schnurr CM, Weksler ME: Defective expression of high affinity IL-2 receptors on activated T cells from aged humans. Int. Immunol. 1990;2:239–246.

    Article  PubMed  CAS  Google Scholar 

  53. Budd RC, Cerottini JC, Horvath C, Bron C, Pedrazzini T, Howe RC, McDonald HR: Distinction of virgin and memory T lymphocytes: stable acquisition of the Pgp-1 glycoprotein concomitant with antigenic stimulation. J. Immunol. 1987;138:3120–3129.

    PubMed  CAS  Google Scholar 

  54. Ernst DN, Hobbs MV, Torbett BE, Glaserbrook AL, Rehse MA, Bottomly K, et al.: Differences in the expressionn profiles of CD45RB, Pgp-1, and 3G11 membrane antigens and in the patterns of lymphokine secretion by splenic CD4+ T cells from young and aged mice. J. Immunol. 1990;145:1295–1302.

    PubMed  CAS  Google Scholar 

  55. Picker LJ, Butcher EC: Phisiological and molecular mechanisms of lymphocyte homing. Annu. Rev. Immunol. 1992; 10:561–591.

    Article  PubMed  CAS  Google Scholar 

  56. Fagiolo U, Cossarizza A, Scala E, Fenales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R: Increased cytokine production in mononuclear cells of healthy elderly people. Eur. J. Immunol. 1993;23:2375–2378.

    Article  PubMed  CAS  Google Scholar 

  57. Lerner A, Yamada T, Miller RA: Pgp-1hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A. Eur. J. Immunol. 1989;19:977–982.

    Article  PubMed  CAS  Google Scholar 

  58. Shearer GM: Th1/Th2 changes in aging. Mech. Aging Dev. 1997; 94:1–5.

    Article  PubMed  CAS  Google Scholar 

  59. Mountz JD, Wu J, Zhou TH, Hsu HC: Cell death and longevity: implications of Fas-mediated apoptosis in T-cell senescence. Immunol. Rev. 1997;160:19–30.

    Article  PubMed  CAS  Google Scholar 

  60. Linton PJ, Haynes L, Tsui L, Zhang X, Swain S: From naive to effector alterations with aging. Immunol. Rev. 1997;160:9–18.

    Article  PubMed  CAS  Google Scholar 

  61. Mosmann TR, Coffman RL: Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann. Rev. Immunol. 1989;7:145–173.

    Article  CAS  Google Scholar 

  62. Romagnani S: Human Th1 and Th2 subsets: doubt no more. Immunol. Today 1991;12:256–257.

    Article  PubMed  CAS  Google Scholar 

  63. Shearer GM:Th1/Th2 changes in aging. Mech. Aging Dev. 1997; 94:1–5.

    Article  PubMed  CAS  Google Scholar 

  64. Clerici M, Shearer GM: The Th1/ Th2 hypothesis of HIV infection: new insights. Immunol. Today 1994;15:575–581.

    Article  PubMed  CAS  Google Scholar 

  65. Cakman I, Rohwr J, Schutz RM, Kirchner H, Rink L: Dysregulation between TH1 and TH2 T cell subpopulations in the elderly. Mech. Aging Dev. 1996;87:197–209.

    Article  PubMed  CAS  Google Scholar 

  66. Thoman ML, Weigle WO: The cellular and subcellular bases of immunosenescence. Adv. Immunol. 1989;46:221–261.

    PubMed  CAS  Google Scholar 

  67. Riancho JA, Zarrabeitia MT, Amado JA, Olmos JM, Gonzalez-Macias J: Age-related differences in cytokine secretion. Gerontology 1994;40:8–12.

    PubMed  CAS  Google Scholar 

  68. Gillis S, Kozak R, Durante M, Weksler M: Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans. J. Clin. Invest. 1981; 67:937–942.

    PubMed  CAS  Google Scholar 

  69. Cossarizza A, Monti D, Cantini M, Paganalli R, Montagnani G, Cadossi R, Bersani F, Franceschi C: Extremely low frequency pulsed electromagnetic fields increase interleukin-2 (IL-2) utilization and IL-2 receptor expression in lymphocytes from old subjects. FEBS Lett. 1989 memory. J. Exp. Med. 1992;173:25–36.

    Google Scholar 

  70. Pahlavani MA, Richardson A: Agerelated decrease in the naive (0X22+) T cells in F344 rats. Mech. Aging Dev. 1994;74:171–176.

    Article  PubMed  CAS  Google Scholar 

  71. Papp I, Wieder KJ, Sablinski T, O’Connel PJ, Milford EL, Strom TB, Kupiec-Weglinski JW: Evidence for functional heterogeneity of rat CD4+ T cells in vivo. Differential expression of IL-2 and IL-4 mRNA in recipients of cardiac allografts. J. Immunol. 1992;148:1308–1314.

    PubMed  CAS  Google Scholar 

  72. Candore G, Di Lorenzo G, Caruso C, Modica MA, Colucci AT: Mitogen responsive T cell precursors in human beings is completely restored by interleukin-2. Mech. Aging Dev. 1992;63:297–307.

    Article  PubMed  CAS  Google Scholar 

  73. Pahlavani MA, Richardson A: The effect of age on the expression of interleukin-2. Mech. Aging Dev. 1996;89:125–154.

    Article  PubMed  CAS  Google Scholar 

  74. Prince HE, York J, Jensen ER: Phenotypic comparison of the three populations of human lymphocytes defined by CD45RO and CD45RA expression. Cell Immunol. 1992;145:254–262.

    Article  PubMed  CAS  Google Scholar 

  75. Akbar AN, Salmon M, Savill J, Janossy G: A possible role for bel-2 in regulating T cell memory: a balancing act between cell death and survival. Immunol. Today 1993;14:526–531.

    Article  PubMed  CAS  Google Scholar 

  76. Rea IM, Stewart M, Campbell P, Alexander HD, Crockard AD, Morris TCM: Changes in lymphocyte subsets, interleukin 2 and soluble interleukin 2 receptor in old and very old age. Gerontology 1986;42:69–78.

    Google Scholar 

  77. Catania A, Airaghi L, Motta P, Manfredi MG, Annoni G, Pettenati C, Brambilla F, Lipton J.M: Cytokine antagonists in aged subjects and their relation with cellular immunity. J. Gerontol. 1997;52A:B93–97.

    CAS  Google Scholar 

  78. Mbawuike I, Acuna CL, Walz KC, Atmar RL, Greenberg SB, Couch RB: Cytokines and impaired CD8+ CTL activity among elderly persons and the enhancing effect of IL-12. Mech. Aging Dev. 1997;94:25–39.

    Article  PubMed  CAS  Google Scholar 

  79. Castle S, Uyemura K, Wong W, Modlin R, Effros R: Evidence of enhanced type 2 immune response and impaired upregulation of a type 1 response in frail elderly nursing home resident. Mech. Aging Dev. 1997;94:7–16.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to L. Ginaldi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ginaldi, L., Martinis, M.D., D’Ostilio, A. et al. The immune system in the elderly. Immunol Res 20, 117–126 (1999). https://doi.org/10.1007/BF02786468

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02786468

Key words

Navigation