1932

Abstract

Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more severe in old than in young individuals and have a greater impact on health outcomes such as morbidity, disability, and mortality. Aging is characterized by increased low-grade chronic inflammation, so-called inflammaging, that represents a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we summarize current knowledge on age-associated changes in immune cells with special emphasis on B cells, which are more inflammatory and less responsive to infections and vaccines in the elderly. We highlight recent findings on factors and pathways contributing to inflammaging and how these lead to dysfunctional immune responses. We summarize recent published studies showing that adipose tissue, which increases in size with aging, contributes to inflammaging and dysregulated B cell function.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cellbio-011620-034148
2020-10-06
2024-10-03
Loading full text...

Full text loading...

/deliver/fulltext/cellbio/36/1/annurev-cellbio-011620-034148.html?itemId=/content/journals/10.1146/annurev-cellbio-011620-034148&mimeType=html&fmt=ahah

Literature Cited

  1. Ademokun A, Wu YC, Dunn-Walters D 2010. The ageing B cell population: composition and function. Biogerontology 11:125–37
    [Google Scholar]
  2. Adler H, Ferreira DM, Gordon SB, Rylance J 2017. Pneumococcal capsular polysaccharide immunity in the elderly. Clin. Vaccine Immunol. 24:e00004–17
    [Google Scholar]
  3. Adlowitz DG, Barnard J, Biear JN, Cistrone C, Owen T et al. 2015. Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of B cell depletion therapy, and biomarkers of response. PLOS ONE 10:e0128269
    [Google Scholar]
  4. Alpert A, Pickman Y, Leipold M, Rosenberg-Hasson Y, Ji X et al. 2019. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25:487–95
    [Google Scholar]
  5. Alter-Wolf S, Blomberg BB, Riley RL 2009. Deviation of the B cell pathway in senescent mice is associated with reduced surrogate light chain expression and altered immature B cell generation, phenotype, and light chain expression. J. Immunol. 182:138–47
    [Google Scholar]
  6. Amanna IJ, Carlson NE, Slifka MK 2007. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357:1903–15
    [Google Scholar]
  7. Andrew MK, Shinde V, Ye L, Hatchette T, Haguinet F et al. 2017. The importance of frailty in the assessment of influenza vaccine effectiveness against influenza-related hospitalization in elderly people. J. Infect. Dis. 216:405–14
    [Google Scholar]
  8. Andrews SF, Kaur K, Pauli NT, Huang M, Huang Y, Wilson PC 2015. High preexisting serological antibody levels correlate with diversification of the influenza vaccine response. J. Virol. 89:3308–17
    [Google Scholar]
  9. Anspach J, Poulsen G, Kaattari I, Pollock R, Zwollo P 2001. Reduction in DNA binding activity of the transcription factor Pax-5a in B lymphocytes of aged mice. J. Immunol. 166:2617–26
    [Google Scholar]
  10. Antonicelli R, Olivieri F, Bonafe M, Cavallone L, Spazzafumo L et al. 2005. The interleukin-6 −174 G>C promoter polymorphism is associated with a higher risk of death after an acute coronary syndrome in male elderly patients. Int. J. Cardiol. 103:266–71
    [Google Scholar]
  11. Antunes G, Evans SA, Lordan JL, Frew AJ 2002. Systemic cytokine levels in community-acquired pneumonia and their association with disease severity. Eur. Respir. J. 20:990–95
    [Google Scholar]
  12. Austrian R, Gold J. 1964. Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann. Intern. Med. 60:759–76
    [Google Scholar]
  13. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S et al. 2000. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18:767–811
    [Google Scholar]
  14. Bartlett DB, Fox O, McNulty CL, Greenwood HL, Murphy L et al. 2016. Habitual physical activity is associated with the maintenance of neutrophil migratory dynamics in healthy older adults. Brain Behav. Immun. 56:12–20
    [Google Scholar]
  15. Bennett NM, Buffington J, LaForce FM 1992. Pneumococcal bacteremia in Monroe County. New York: Am. J. Public Health 82:1513–16
    [Google Scholar]
  16. Berical AC, Harris D, Dela Cruz CS, Possick JD 2016. Pneumococcal vaccination strategies. An update and perspective. Ann. Am. Thorac. Soc. 13:933–44
    [Google Scholar]
  17. Biagi E, Nylund L, Candela M, Ostan R, Bucci L et al. 2010. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLOS ONE 5:e10667
    [Google Scholar]
  18. Bonten MJ, Huijts SM, Bolkenbaas M, Webber C, Patterson S et al. 2015. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N. Engl. J. Med. 372:1114–25
    [Google Scholar]
  19. Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R et al. 1999. NK phenotypic markers and IL2 response in NK cells from elderly people. Exp. Gerontol. 34:253–65
    [Google Scholar]
  20. Breiman RF, Spika JS, Navarro VJ, Darden PM, Darby CP 1990. Pneumococcal bacteremia in Charleston County, South Carolina. A decade later. Arch. Intern. Med. 150:1401–5
    [Google Scholar]
  21. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y et al. 2004. Neutrophil extracellular traps kill bacteria. Science 303:1532–35
    [Google Scholar]
  22. Bryl E, Vallejo AN, Weyand CM, Goronzy JJ 2001. Down-regulation of CD28 expression by TNF-α. J. Immunol. 167:3231–38
    [Google Scholar]
  23. Buffa S, Bulati M, Pellicano M, Dunn-Walters DK, Wu YC et al. 2011. B cell immunosenescence: different features of naive and memory B cells in elderly. Biogerontology 12:473–83
    [Google Scholar]
  24. Butcher SK, Chahal H, Nayak L, Sinclair A, Henriquez NV et al. 2001. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J. Leukoc. Biol. 70:881–86
    [Google Scholar]
  25. Camell CD, Gunther P, Lee A, Goldberg EL, Spadaro O et al. 2019. Aging induces an Nlrp3 inflammasome-dependent expansion of adipose B cells that impairs metabolic homeostasis. Cell Metab 30:1024–39.e6
    [Google Scholar]
  26. Campisi J. 2011. Cellular senescence: putting the paradoxes in perspective. Curr. Opin. Genet. Dev. 21:107–12
    [Google Scholar]
  27. Campos C, Pera A, Sanchez-Correa B, Alonso C, Lopez-Fernandez I et al. 2014. Effect of age and CMV on NK cell subpopulations. Exp. Gerontol. 54:130–37
    [Google Scholar]
  28. Castrucci MR. 2018. Factors affecting immune responses to the influenza vaccine. Hum. Vaccines Immunother. 14:637–46
    [Google Scholar]
  29. Cent. Dis. Control Prev. 2018. Adult obesity prevalence maps. Centers for Disease Control and Prevention. https://www.cdc.gov/obesity/data/prevalence-maps.html
  30. Cepinskas G, Sandig M, Kvietys PR 1999. PAF-induced elastase-dependent neutrophil transendothelial migration is associated with the mobilization of elastase to the neutrophil surface and localization to the migrating front. J. Cell Sci. 112:Part 121937–45
    [Google Scholar]
  31. Chang L-Y, Li Y, Kaplan DE 2016. Hepatitis C viraemia reversibly maintains subset of antigen-specific T-bet+ tissue-like memory B cells. J. Viral Hepat. 24:389–96
    [Google Scholar]
  32. Chidrawar SM, Khan N, Chan YL, Nayak L, Moss PA 2006. Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun. Ageing 3:10
    [Google Scholar]
  33. Claes N, Fraussen J, Vanheusden M, Hellings N, Stinissen P et al. 2016. Age-associated B cells with proinflammatory characteristics are expanded in a proportion of multiple sclerosis patients. J. Immunol. 197:4576–83
    [Google Scholar]
  34. Colonna-Romano G, Bulati M, Aquino A, Scialabba G, Candore G et al. 2003. B cells in the aged: CD27, CD5, and CD40 expression. Mech. Ageing Dev. 124:389–93
    [Google Scholar]
  35. Cooper MA, Fehniger TA, Caligiuri MA 2001. The biology of human natural killer-cell subsets. Trends Immunol 22:633–40
    [Google Scholar]
  36. Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB 2019. Immunosenescence and human vaccine immune responses. Immun. Ageing 16:25
    [Google Scholar]
  37. de Bourcy CFA, Lopez Angel CJ, Vollmers C, Dekker CL, Davis MM, Quake SR 2017. Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging. PNAS 114:1105–10
    [Google Scholar]
  38. Derhovanessian E, Maier AB, Hahnel K, McElhaney JE, Slagboom EP, Pawelec G 2014. Latent infection with cytomegalovirus is associated with poor memory CD4 responses to influenza A core proteins in the elderly. J. Immunol. 193:3624–31
    [Google Scholar]
  39. Derhovanessian E, Theeten H, Hähnel K, Van Damme P, Cools N, Pawelec G 2013. Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination. Vaccine 31:685–90
    [Google Scholar]
  40. Dhakal S, Klein SL. 2019. Host factors impact vaccine efficacy: implications for seasonal and universal influenza vaccine programs. J. Virol. 93:e00797–19
    [Google Scholar]
  41. Dunn-Walters DK, Ademokun AA. 2010. B cell repertoire and ageing. Curr. Opin. Immunol. 22:514–20
    [Google Scholar]
  42. Elisia I, Lam V, Hofs E, Li MY, Hay M et al. 2017. Effect of age on chronic inflammation and responsiveness to bacterial and viral challenges. PLOS ONE 12:e0188881
    [Google Scholar]
  43. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE 2005. Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352:1749–59
    [Google Scholar]
  44. Ferrucci L, Guralnik JM, Pahor M, Corti MC, Havlik RJ 1997. Hospital diagnoses, Medicare charges, and nursing home admissions in the year when older persons become severely disabled. JAMA 277:728–34
    [Google Scholar]
  45. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M et al. 2000. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908:244–54
    [Google Scholar]
  46. Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S 2017. Inflammaging and ‘Garb-aging. .’ Trends Endocrinol. Metab. 28:199–212
    [Google Scholar]
  47. Frasca D, Andrisani G, Diaz A, Felice C, Guidi L, Blomberg BB 2013a. AID in aging and autoimmune diseases. Autoimmunity 46:168–75
    [Google Scholar]
  48. Frasca D, Blomberg BB. 2016. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology 17:7–19
    [Google Scholar]
  49. Frasca D, Blomberg BB, Paganelli R 2017a. Aging, obesity, and inflammatory age-related diseases. Front. Immunol. 8:1745
    [Google Scholar]
  50. Frasca D, Diaz A, Romero M, Blomberg BB 2016a. The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations. Vaccine 34:2834–40
    [Google Scholar]
  51. Frasca D, Diaz A, Romero M, Blomberg BB 2017b. Human peripheral late/exhausted memory B cells express a senescent-associated secretory phenotype and preferentially utilize metabolic signaling pathways. Exp. Gerontol. 87:113–20
    [Google Scholar]
  52. Frasca D, Diaz A, Romero M, D'Eramo F, Blomberg BB 2017c. Aging effects on T-bet expression in human B cell subsets. Cell Immunol 321:68–73
    [Google Scholar]
  53. Frasca D, Diaz A, Romero M, Garcia D, Jayram D et al. 2020. Identification and characterization of adipose tissue-derived human antibodies with “anti-self” specificity. Front. Immunol. 11:392
    [Google Scholar]
  54. Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB 2011. Age effects on B cells and humoral immunity in humans. Ageing Res. Rev. 10:330–35
    [Google Scholar]
  55. Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB 2014. High TNF-α levels in resting B cells negatively correlate with their response. Exp. Gerontol. 54:116–22
    [Google Scholar]
  56. Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB 2015. Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine. Vaccine 33:1433–39
    [Google Scholar]
  57. Frasca D, Diaz A, Romero M, Landin AM, Phillips M et al. 2010. Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans. Vaccine 28:8077–84
    [Google Scholar]
  58. Frasca D, Diaz A, Romero M, Mendez NV, Landin AM, Blomberg BB 2013b. Effects of age on H1N1-specific serum IgG1 and IgG3 levels evaluated during the 2011–2012 influenza vaccine season. Immun. Ageing 10:14
    [Google Scholar]
  59. Frasca D, Diaz A, Romero M, Mendez NV, Landin AM et al. 2013c. Young and elderly patients with type 2 diabetes have optimal B cell responses to the seasonal influenza vaccine. Vaccine 31:3603–10
    [Google Scholar]
  60. Frasca D, Diaz A, Romero M, Phillips M, Mendez NV et al. 2012. Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine. Int. Immunol. 24:175–82
    [Google Scholar]
  61. Frasca D, Diaz A, Romero M, Thaller S, Blomberg BB 2018. Secretion of autoimmune antibodies in the human subcutaneous adipose tissue. PLOS ONE 13:e0197472
    [Google Scholar]
  62. Frasca D, Diaz A, Romero M, Thaller S, Blomberg BB 2019. Metabolic requirements of human pro-inflammatory B cells in aging and obesity. PLOS ONE 14:e0219545
    [Google Scholar]
  63. Frasca D, Diaz A, Romero M, Vazquez T, Blomberg BB 2017d. Obesity induces pro-inflammatory B cells and impairs B cell function in old mice. Mech. Ageing Dev. 162:91–99
    [Google Scholar]
  64. Frasca D, Ferracci F, Diaz A, Romero M, Lechner S, Blomberg BB 2016b. Obesity decreases B cell responses in young and elderly individuals. Obesity 24:615–25
    [Google Scholar]
  65. Frasca D, Landin AM, Alvarez JP, Blackshear PJ, Riley RL, Blomberg BB 2007. Tristetraprolin, a negative regulator of mRNA stability, is increased in old B cells and is involved in the degradation of E47 mRNA. J. Immunol. 179:918–27
    [Google Scholar]
  66. Frasca D, Landin AM, Lechner SC, Ryan JG, Schwartz R et al. 2008. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J. Immunol. 180:5283–90
    [Google Scholar]
  67. Frasca D, McElhaney J. 2019. Influence of obesity on pneumococcus infection risk in the elderly. Front. Endocrinol. 10:71
    [Google Scholar]
  68. Frasca D, Van der Put E, Landin AM, Gong D, Riley RL, Blomberg BB 2005. RNA stability of the E2A-encoded transcription factor E47 is lower in splenic activated B cells from aged mice. J. Immunol. 175:6633–44
    [Google Scholar]
  69. Frasca D, Van der Put E, Riley RL, Blomberg BB 2004. Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase. J. Immunol. 172:2155–62
    [Google Scholar]
  70. Freeman RB Jr 2009. The ‘indirect’ effects of cytomegalovirus infection. Am. J. Transplant. 9:2453–58
    [Google Scholar]
  71. Fulop T, Larbi A, Douziech N, Fortin C, Guerard KP et al. 2004. Signal transduction and functional changes in neutrophils with aging. Aging Cell 3:217–26
    [Google Scholar]
  72. Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S et al. 2019. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25:1822–32
    [Google Scholar]
  73. Furman D, Jojic V, Sharma S, Shen-Orr SS, Angel CJ et al. 2015. Cytomegalovirus infection enhances the immune response to influenza. Sci. Transl. Med. 7:281ra43
    [Google Scholar]
  74. Gensous N, Franceschi C, Blomberg BB, Pirazzini C, Ravaioli F et al. 2018. Responders and non-responders to influenza vaccination: a DNA methylation approach on blood cells. Exp. Gerontol. 105:94–100
    [Google Scholar]
  75. Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R et al. 2009. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8:18–25
    [Google Scholar]
  76. Goenka R, Scholz JL, Naradikian MS, Cancro MP 2014. Memory B cells form in aged mice despite impaired affinity maturation and germinal center kinetics. Exp. Gerontol. 54:109–15
    [Google Scholar]
  77. Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O'Fallon WM, Weyand CM 2001. Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J. Virol. 75:12182–87
    [Google Scholar]
  78. Gumá M, Angulo A, Vilches C, Gómez-Lozano N, Malats N, López-Botet M 2004. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104:3664–71
    [Google Scholar]
  79. Haber N. 2018. Respiratory syncytial virus infection in elderly adults. Med. Mal. Infect. 48:377–82
    [Google Scholar]
  80. Hao Y, O'Neill P, Naradikian MS, Scholz JL, Cancro MP 2011. A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood 118:1294–304
    [Google Scholar]
  81. Haq K, Fulop T, Tedder G, Gentleman B, Garneau H et al. 2017. Cytomegalovirus seropositivity predicts a decline in the T cell but not the antibody response to influenza in vaccinated older adults independent of type 2 diabetes status. J. Gerontol. A 72:1163–70
    [Google Scholar]
  82. Hazeldine J, Hampson P, Lord JM 2012. Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell 11:751–59
    [Google Scholar]
  83. Hirokawa K, Makinodan T. 1975. Thymic involution: effect on T cell differentiation. J. Immunol. 114:1659–64
    [Google Scholar]
  84. Illingworth J, Butler NS, Roetynck S, Mwacharo J, Pierce SK et al. 2013. Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J. Immunol. 190:1038–47
    [Google Scholar]
  85. Jain S, Self WH, Wunderink RG, Fakhran S, Balk R et al. 2015. Community-acquired pneumonia requiring hospitalization among U.S. adults. N. Engl. J. Med. 373:415–27
    [Google Scholar]
  86. Jiang N, He J, Weinstein JA, Penland L, Sasaki S et al. 2013. Lineage structure of the human antibody repertoire in response to influenza vaccination. Sci. Transl. Med. 5:171ra19
    [Google Scholar]
  87. Johnson SA, Rozzo SJ, Cambier JC 2002. Aging-dependent exclusion of antigen-inexperienced cells from the peripheral B cell repertoire. J. Immunol. 168:5014–23
    [Google Scholar]
  88. Kataoka K, Fukuyama Y, Briles DE, Miyake T, Fujihashi K 2017. Dendritic cell-targeting DNA-based nasal adjuvants for protective mucosal immunity to Streptococcus pneumoniae. Microbiol. . Immunol 61:195–205
    [Google Scholar]
  89. Khurana S, Frasca D, Blomberg B, Golding H 2012. AID activity in B cells strongly correlates with polyclonal antibody affinity maturation in-vivo following pandemic 2009-H1N1 vaccination in humans. PLOS Pathog 8:e1002920
    [Google Scholar]
  90. Kobie JJ, Zheng B, Bryk P, Barnes M, Ritchlin CT et al. 2011. Decreased influenza-specific B cell responses in rheumatoid arthritis patients treated with anti-tumor necrosis factor. Arthritis Res. Ther. 13:R209
    [Google Scholar]
  91. Krone CL, van de Groep K, Trzciński K, Sanders EA, Bogaert D 2014. Immunosenescence and pneumococcal disease: an imbalance in host–pathogen interactions. Lancet Respir. Med. 2:141–53
    [Google Scholar]
  92. Kyle RA, Rajkumar SV. 2006. Monoclonal gammopathy of undetermined significance. Br. J. Haematol. 134:573–89
    [Google Scholar]
  93. Labrie JE III, Sah AP, Allman DM, Cancro MP, Gerstein RM 2004. Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice. J. Exp. Med. 200:411–23
    [Google Scholar]
  94. Leggat DJ, Thompson RS, Khaskhely NM, Iyer AS, Westerink MA 2013. The immune response to pneumococcal polysaccharides 14 and 23F among elderly individuals consists predominantly of switched memory B cells. J. Infect. Dis. 208:101–8
    [Google Scholar]
  95. Lescale C, Dias S, Maes J, Cumano A, Szabo P et al. 2010. Reduced EBF expression underlies loss of B-cell potential of hematopoietic progenitors with age. Aging Cell 9:410–19
    [Google Scholar]
  96. Lio D, Scola L, Crivello A, Bonafè M, Franceschi C et al. 2002. Allele frequencies of +874T→A single nucleotide polymorphism at the first intron of interferon-γ gene in a group of Italian centenarians. Exp. Gerontol. 37:315–19
    [Google Scholar]
  97. Lopez-Sejas N, Campos C, Hassouneh F, Sanchez-Correa B, Tarazona R et al. 2016. Effect of CMV and aging on the differential expression of CD300a, CD161, T-bet, and Eomes on NK cell subsets. Front. Immunol. 7:476
    [Google Scholar]
  98. Mariani E, Mariani AR, Meneghetti A, Tarozzi A, Cocco L, Facchini A 1998. Age-dependent decreases of NK cell phosphoinositide turnover during spontaneous but not Fc-mediated cytolytic activity. Int. Immunol. 10:981–89
    [Google Scholar]
  99. Mariani E, Meneghetti A, Neri S, Ravaglia G, Forti P et al. 2002. Chemokine production by natural killer cells from nonagenarians. Eur. J. Immunol. 32:1524–29
    [Google Scholar]
  100. Marra F, Vadlamudi NK. 2019. Efficacy and safety of the pneumococcal conjugate-13 valent vaccine in adults. Aging Dis 10:404–18
    [Google Scholar]
  101. Martin V, Wu Y-CB, Kipling D, Dunn-Walters D 2015. Ageing of the B-cell repertoire. Philos. Trans. R. Soc. B 370:20140237
    [Google Scholar]
  102. McElhaney JE, Beran J, Devaster JM, Esen M, Launay O et al. 2013. AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Lancet Infect. Dis. 13:485–96
    [Google Scholar]
  103. McElhaney JE, Ewen C, Zhou X, Kane KP, Xie D et al. 2009. Granzyme B: correlates with protection and enhanced CTL response to influenza vaccination in older adults. Vaccine 27:2418–25
    [Google Scholar]
  104. McElhaney JE, Zhou X, Talbot HK, Soethout E, Bleackley RC et al. 2012. The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine 30:2060–67
    [Google Scholar]
  105. McKenna RW, Washington LT, Aquino DB, Picker LJ, Kroft SH 2001. Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood 98:2498–507
    [Google Scholar]
  106. McLaughlin B, O'Malley K, Cotter TG 1986. Age-related differences in granulocyte chemotaxis and degranulation. Clin. Sci. 70:59–62
    [Google Scholar]
  107. Merani S, Kuchel GA, Kleppinger A, McElhaney JE 2018. Influenza vaccine-mediated protection in older adults: impact of influenza infection, cytomegalovirus serostatus and vaccine dosage. Exp. Gerontol. 107:116–25
    [Google Scholar]
  108. Metcalf TU, Wilkinson PA, Cameron MJ, Ghneim K, Chiang C et al. 2017. Human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists. J. Immunol. 199:1405–17
    [Google Scholar]
  109. Miller JP, Allman D. 2003. The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J. Immunol. 171:2326–30
    [Google Scholar]
  110. Miller JP, Cancro MP. 2007. B cells and aging: balancing the homeostatic equation. Exp. Gerontol. 42:396–99
    [Google Scholar]
  111. Moir S, Ho J, Malaspina A, Wang W, DiPoto AC et al. 2008. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J. Exp. Med. 205:1797–805
    [Google Scholar]
  112. Mosterín Höpping A, McElhaney J, Fonville JM, Powers DC, Beyer WEP, Smith DJ 2016. The confounded effects of age and exposure history in response to influenza vaccination. Vaccine 34:540–46
    [Google Scholar]
  113. Muller-Sieburg CE, Sieburg HB, Bernitz JM, Cattarossi G 2012. Stem cell heterogeneity: implications for aging and regenerative medicine. Blood 119:3900–7
    [Google Scholar]
  114. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–63
    [Google Scholar]
  115. Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S et al. 2011. Systems biology of vaccination for seasonal influenza in humans. Nat. Immunol. 12:786–95
    [Google Scholar]
  116. Naylor K, Li G, Vallejo AN, Lee WW, Koetz K et al. 2005. The influence of age on T cell generation and TCR diversity. J. Immunol. 174:7446–52
    [Google Scholar]
  117. Nipper AJ, Smithey MJ, Shah RC, Canaday DH, Landay AL 2018. Diminished antibody response to influenza vaccination is characterized by expansion of an age-associated B-cell population with low PAX5. Clin. Immunol. 193:80–87
    [Google Scholar]
  118. Nuñez C, Nishimoto N, Gartland GL, Billips LG, Burrows PD et al. 1996. B cells are generated throughout life in humans. J. Immunol. 156:866–72
    [Google Scholar]
  119. Olivieri F, Bonafè M, Cavallone L, Giovagnetti S, Marchegiani F et al. 2002. The −174 C/G locus affects in vitro/in vivo IL-6 production during aging. Exp. Gerontol. 37:309–14
    [Google Scholar]
  120. Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J 2009. Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. PNAS 106:17031–36
    [Google Scholar]
  121. Ovsyannikova IG, White SJ, Larrabee BR, Grill DE, Jacobson RM, Poland GA 2014. Leptin and leptin-related gene polymorphisms, obesity, and influenza A/H1N1 vaccine-induced immune responses in older individuals. Vaccine 32:881–87
    [Google Scholar]
  122. Panda A, Qian F, Mohanty S, van Duin D, Newman FK et al. 2010. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J. Immunol. 184:2518–27
    [Google Scholar]
  123. Parish ST, Wu JE, Effros RB 2009. Modulation of T lymphocyte replicative senescence via TNF-α inhibition: role of caspase-3. J. Immunol. 182:4237–43
    [Google Scholar]
  124. Park S, Nahm MH. 2011. Older adults have a low capacity to opsonize pneumococci due to low IgM antibody response to pneumococcal vaccinations. Infect. Immun. 79:314–20
    [Google Scholar]
  125. Pawelec G, Barnett Y, Forsey R, Frasca D, Globerson A et al. 2002. T cells and aging, January 2002 update. Front. Biosci. 7:d1056–183
    [Google Scholar]
  126. Plouffe JF, Breiman RF, Facklam RR, Baird I, Barnishan J et al. 1996. Bacteremia with Streptococcus pneumoniae. Implications for therapy and prevention. JAMA 275:194–98
    [Google Scholar]
  127. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV 2000. A single nucleotide polymorphism in the first intron of the human IFN-γ gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-γ production. Hum. Immunol. 61:863–66
    [Google Scholar]
  128. Pritz T, Lair J, Ban M, Keller M, Weinberger B et al. 2015. Plasma cell numbers decrease in bone marrow of old patients. Eur. J. Immunol. 45:738–46
    [Google Scholar]
  129. Prosch S, Staak K, Stein J, Liebenthal C, Stamminger T et al. 1995. Stimulation of the human cytomegalovirus IE enhancer/promoter in HL-60 cells by TNFα is mediated via induction of NF-κB. Virology 208:197–206
    [Google Scholar]
  130. Puchta A, Naidoo A, Verschoor CP, Loukov D, Thevaranjan N et al. 2016. TNF drives monocyte dysfunction with age and results in impaired anti-pneumococcal immunity. PLOS Pathog 12:e1005368
    [Google Scholar]
  131. Pulko V, Davies JS, Martinez C, Lanteri MC, Busch MP et al. 2016. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat. Immunol. 17:966–75
    [Google Scholar]
  132. Ratliff M, Alter S, Frasca D, Blomberg BB, Riley RL 2013. In senescence, age-associated B cells secrete TNFα and inhibit survival of B-cell precursors. Aging Cell 12:303–11
    [Google Scholar]
  133. Redeker A, Remmerswaal EBM, van der Gracht ETI, Welten SPM, Höllt T et al. 2017. The contribution of cytomegalovirus infection to immune senescence is set by the infectious dose. Front. Immunol. 8:1953
    [Google Scholar]
  134. Riley RL, Blomberg BB, Frasca D 2005. B cells, E2A, and aging. Immunol. Rev. 205:30–47
    [Google Scholar]
  135. Rondy M, El Omeiri N, Thompson MG, Levêque A, Moren A, Sullivan SG 2017. Effectiveness of influenza vaccines in preventing severe influenza illness among adults: a systematic review and meta-analysis of test-negative design case-control studies. J. Infect. 75:381–94
    [Google Scholar]
  136. Rossi MI, Yokota T, Medina KL, Garrett KP, Comp PC et al. 2003. B lymphopoiesis is active throughout human life, but there are developmental age-related changes. Blood 101:576–84
    [Google Scholar]
  137. Rubtsov AV, Rubtsova K, Fischer A, Meehan RT, Gillis JZ et al. 2011. Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity. Blood 118:1305–15
    [Google Scholar]
  138. Ruderman N, Prentki M. 2004. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat. Rev. Drug Discov. 3:340–51
    [Google Scholar]
  139. Russell Knode LM, Naradikian MS, Myles A, Scholz JL, Hao Y et al. 2017. Age-associated B cells express a diverse repertoire of VH and Vκ genes with somatic hypermutation. J. Immunol. 198:1921–27
    [Google Scholar]
  140. Russell Knode LM, Park HS, Maul RW, Gearhart PJ 2019. B cells from young and old mice switch isotypes with equal frequencies after ex vivo stimulation. Cell Immunol 345:103966
    [Google Scholar]
  141. Sapey E, Greenwood H, Walton G, Mann E, Love A et al. 2014. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 123:239–48
    [Google Scholar]
  142. Sasaki S, He XS, Holmes TH, Dekker CL, Kemble GW et al. 2008. Influence of prior influenza vaccination on antibody and B-cell responses. PLOS ONE 3:e2975
    [Google Scholar]
  143. Sasaki S, Sullivan M, Narvaez CF, Holmes TH, Furman D et al. 2011. Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. J. Clin. Investig. 121:3109–19
    [Google Scholar]
  144. Saurwein-Teissl M, Lung TL, Marx F, Gschösser C, Asch E et al. 2002. Lack of antibody production following immunization in old age: association with CD8+CD28 T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J. Immunol. 168:5893–99
    [Google Scholar]
  145. Schirmer M, Smeekens SP, Vlamakis H, Jaeger M, Oosting M et al. 2016. Linking the human gut microbiome to inflammatory cytokine production capacity. Cell 167:1125–36.e8 Erratum. 2016 Cell 167:1897
    [Google Scholar]
  146. Shahid Z, Kleppinger A, Gentleman B, Falsey AR, McElhaney JE 2010. Clinical and immunologic predictors of influenza illness among vaccinated older adults. Vaccine 28:6145–51
    [Google Scholar]
  147. Shea KM, Edelsberg J, Weycker D, Farkouh RA, Strutton DR, Pelton SI 2014. Rates of pneumococcal disease in adults with chronic medical conditions. Open Forum Infect. Dis. 1:ofu024
    [Google Scholar]
  148. Sheridan PA, Paich HA, Handy J, Karlsson EA, Hudgens MG et al. 2012. Obesity is associated with impaired immune response to influenza vaccination in humans. Int. J. Obes. 36:1072–77
    [Google Scholar]
  149. Shi Y, Yamazaki T, Okubo Y, Uehara Y, Sugane K, Agematsu K 2005. Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell. J. Immunol. 175:3262–67
    [Google Scholar]
  150. Simell B, Vuorela A, Ekstrom N, Palmu A, Reunanen A et al. 2011. Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis. Vaccine 29:1929–34
    [Google Scholar]
  151. Simonsen L, Taylor RJ, Young-Xu Y, Haber M, May L, Klugman KP 2011. Impact of pneumococcal conjugate vaccination of infants on pneumonia and influenza hospitalization and mortality in all age groups in the United States. mBio 2:e00309–10
    [Google Scholar]
  152. Soysal P, Stubbs B, Lucato P, Luchini C, Solmi M et al. 2016. Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res. Rev. 31:1–8
    [Google Scholar]
  153. Spits H, Bernink JH, Lanier L 2016. NK cells and type 1 innate lymphoid cells: partners in host defense. Nat. Immunol. 17:758–64
    [Google Scholar]
  154. Stavnezer J, Guikema JE, Schrader CE 2008. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol. 26:261–92
    [Google Scholar]
  155. Stephan RP, Reilly CR, Witte PL 1998. Impaired ability of bone marrow stromal cells to support B-lymphopoiesis with age. Blood 91:75–88
    [Google Scholar]
  156. Stoecklin G, Anderson P. 2006. Posttranscriptional mechanisms regulating the inflammatory response. Adv. Immunol. 89:1–37
    [Google Scholar]
  157. Swain SL, Kugler-Umana O, Kuang Y, Zhang W 2017. The properties of the unique age-associated B cell subset reveal a shift in strategy of immune response with age. Cell Immunol 321:52–60
    [Google Scholar]
  158. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC et al. 2017. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21:455–66.e4
    [Google Scholar]
  159. Thevaranjan N, Whelan FJ, Puchta A, Ashu E, Rossi L et al. 2016. Streptococcus pneumoniae colonization disrupts the microbial community within the upper respiratory tract of aging mice. Infect. Immun. 84:906–16
    [Google Scholar]
  160. Thiery J, Keefe D, Boulant S, Boucrot E, Walch M et al. 2011. Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells. Nat. Immunol. 12:770–77
    [Google Scholar]
  161. Tseng CW, Kyme PA, Arruda A, Ramanujan VK, Tawackoli W, Liu GY 2012. Innate immune dysfunctions in aged mice facilitate the systemic dissemination of methicillin-resistant S. aureus. . PLOS ONE 7:e41454
    [Google Scholar]
  162. Vallejo AN. 2005. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol. Rev. 205:158–69
    [Google Scholar]
  163. Van Buynder P, Booy R 2018. Pneumococcal vaccination in older persons: Where are we today. ? Pneumonia 10:1
    [Google Scholar]
  164. van den Berg SPH, Warmink K, Borghans JAM, Knol MJ, van Baarle D 2019. Effect of latent cytomegalovirus infection on the antibody response to influenza vaccination: a systematic review and meta-analysis. Med. Microbiol. Immunol. 208:305–21
    [Google Scholar]
  165. Wehr C, Eibel H, Masilamani M, Illges H, Schlesier M et al. 2004. A new CD21low B cell population in the peripheral blood of patients with SLE. Clin. Immunol. 113:161–71
    [Google Scholar]
  166. Welten SPM, Redeker A, Toes REM, Arens R 2016. Viral persistence induces antibody inflation without altering antibody avidity. J. Virol. 90:4402–11
    [Google Scholar]
  167. Wenisch C, Patruta S, Daxbock F, Krause R, Horl W 2000. Effect of age on human neutrophil function. J. Leukoc. Biol. 67:40–45
    [Google Scholar]
  168. Wertheimer AM, Bennett MS, Park B, Uhrlaub JL, Martinez C et al. 2014. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192:2143–55
    [Google Scholar]
  169. Whelan FJ, Verschoor CP, Stearns JC, Rossi L, Luinstra K et al. 2014. The loss of topography in the microbial communities of the upper respiratory tract in the elderly. Ann. Am. Thorac. Soc. 11:513–21
    [Google Scholar]
  170. Whisler RL, Liu BQ, Newhouse YG, Walters JD, Breckenridge MB, Grants IS 1991. Signal transduction in human B cells during aging: alterations in stimulus-induced phosphorylations of tyrosine and serine/threonine substrates and in cytosolic calcium responsiveness. Lymphokine Cytokine Res 10:463–73
    [Google Scholar]
  171. Wikby A, Nilsson BO, Forsey R, Thompson J, Strindhall J et al. 2006. The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. Mech. Ageing Dev. 127:695–704
    [Google Scholar]
  172. Winer DA, Winer S, Shen L, Wadia PP, Yantha J et al. 2011. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat. Med. 17:610–17
    [Google Scholar]
  173. Wrammert J, Smith K, Miller J, Langley WA, Kokko K et al. 2008. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453:667–71
    [Google Scholar]
  174. Yao X, Hamilton RG, Weng NP, Xue QL, Bream JH et al. 2011. Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. Vaccine 29:5015–21
    [Google Scholar]
  175. Yende S, Tuomanen EI, Wunderink R, Kanaya A, Newman AB et al. 2005. Preinfection systemic inflammatory markers and risk of hospitalization due to pneumonia. Am. J. Respir. Crit. Care Med. 172:1440–46
    [Google Scholar]
  176. Young B, Zhao X, Cook AR, Parry CM, Wilder-Smith A, Chen MI-C 2017. Do antibody responses to the influenza vaccine persist year-round in the elderly? A systematic review and meta-analysis. Vaccine 35:212–21
    [Google Scholar]
/content/journals/10.1146/annurev-cellbio-011620-034148
Loading
  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error