Innate immunesenescence: underlying mechanisms and clinical relevance

Biogerontology

Volumn 16, Issue 2, 2015, Pages 187-201

  Hazeldine, Jon ^a   Lord, Janet M ^a  

^a UNIVERSITY OF BIRMINGHAM   (United Kingdom)

Author keywords

Ageing; Innate immunesenescence; Innate immunity

Indexed keywords

CYTOKINE;

ANIMAL; BIOLOGICAL MODEL; HUMAN; IMMUNE SYSTEM; IMMUNOLOGY; IMMUNOSENESCENCE; INNATE IMMUNITY; LEUKOCYTE;

ANIMALS; CYTOKINES; HUMANS; IMMUNE SYSTEM; IMMUNITY, INNATE; IMMUNOSENESCENCE; LEUKOCYTES; MODELS, IMMUNOLOGICAL;

EID: 84939881933     PISSN: 13895729     EISSN: 15736768     Source Type: Journal    
DOI: 10.1007/s10522-014-9514-3     Document Type: Review

References (129)

1. Agius E, Lacy KE, Vukmanovic-Stejic M, Jagger AL, Papageorgiou AP, Hall S, Reed JR, Curnow SJ, Fuentes-Duculan J, Buckley CD, Salmon M, Taams LS, Krueger J, Greenwood J, Klein N, Rustin MH, Akbar AN (2009) Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4 + T cells during aging. J Exp Med 206:1929–1940
2. Agrawal A, Agrawal S, Cao JN, Su H, Osann K, Gupta S (2007) Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J Immunol 178:6912–6922
3. Albright JW, Albright JF (1985) Age-associated decline in natural killer (NK) activity reflects primarily a defect in function of NK cells. Mech Ageing Dev 31:295–306
4. Almeida-Oliveira A, Smith-Carvalho M, Porto LC, Cardoso-Oliveira J, Ribeiro AS, Falcao RR, Abdelhay E, Bouzas LF, Thuler LC, Ornellas MH, Diamond HR (2011) Age-related changes in natural killer cell receptors from childhood through old age. Hum Immunol 72:319–329
5. Alonso-Fernandez P, Puerto M, Mate I, Ribera JM, de la Fuente M (2008) Neutrophils of centenarians show function levels similar to those of young adults. J Am Geriatr Soc 56:2244–2251
6. Alvarez E, Ruiz-Gutierrez V, Sobrino F, Santa-Maria C (2001) Age-related changes in membrane lipid composition, fluidity and respiratory burst in rat peritoneal neutrophils. Clin Exp Immunol 124:95–102
7. Araki N, Johnson MT, Swanson JA (1996) A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J Cell Biol 135:1249–1260
8. Arranz E, O’Mahony S, Barton JR, Ferguson A (1992) Immunosenescence and mucosal immunity: significant effects of old age on secretory IgA concentrations and intraepithelial lymphocyte counts. Gut 33:882–886
9. Atsuta R, Akiyama K, Shirasawa T, Okumura K, Fukuchi Y, Ra C (1999) Atopic asthma is dominant in elderly onset asthmatics: possibility for an alteration of mast cell function by aging through Fc receptor expression. Int Arch Allergy Immunol 120(Suppl 1):76–81
10. Aw D, Silva AB, Palmer DB (2007) Immunosenescence: emerging challenges for an ageing population. Immunology 120:435–446
11. Beli E, Clinthorne JF, Duriancik DM, Hwang I, Kim S, Gardner EM (2011) Natural killer cell function is altered during the primary response of aged mice to influenza infection. Mech Ageing Dev 132:503–510
12. Bellavia D, Frada G, Di FP, Feo S, Franceschi C, Sansoni P, Brai M (1999) C4, BF, C3 allele distribution and complement activity in healthy aged people and centenarians. J Gerontol A Biol Sci Med Sci 54:B150–B153
13. Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336
14. Bhushan M, Cumberbatch M, Dearman RJ, Andrew SM, Kimber I, Griffiths CE (2002) Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing. Br J Dermatol 146:32–40
15. Biasi D, Bambara LM, Carletto A, Caramaschi P, Andrioli G, Urbani G, Bellavite P (1999) Neutrophil migration, oxidative metabolism and adhesion in early onset periodontitis. J Clin Periodontol 26:563–568
16. Biron CA, Byron KS, Sullivan JL (1989) Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 320:1731–1735
17. Boehmer ED, Goral J, Faunce DE, Kovacs EJ (2004) Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 75:342–349
18. Bonnema JD, Karnitz LM, Schoon RA, Abraham RT, Leibson PJ (1994) Fc receptor stimulation of phosphatidylinositol 3-kinase in natural killer cells is associated with protein kinase C-independent granule release and cell-mediated cytotoxicity. J Exp Med 180:1427–1435
19. Born J, Uthgenannt D, Dodt C, Nunninghoff D, Ringvolt E, Wagner T, Fehm HL (1995) Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Mech Ageing Dev 84:113–126
20. Bottazzi B, Doni A, Garlanda C, Mantovani A (2010) An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol 28:157–183
21. Braga PC, Sala MT, Dal SM, Mancini L, Sandrini MC, Annoni G (1998a) Influence of age on oxidative bursts (chemiluminescence) of polymorphonuclear neutrophil leukocytes. Gerontology 44:192–197
22. Braga PC, Sala MT, Dal SM, Pecile A, Annoni G, Vergani C (1998b) Age-associated differences in neutrophil oxidative burst (chemiluminescence). Exp Gerontol 33:477–484
23. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535
24. Brubaker AL, Rendon JL, Ramirez L, Choudhry MA, Kovacs EJ (2013) Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J. Immunol. 190:1746–1757
25. Butcher SK, Chahal H, Nayak L, Sinclair A, Henriquez NV, Sapey E, O’Mahony D, Lord JM (2001) Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol 70:881–886
26. Butcher SK, Killampalli V, Lascelles D, Wang K, Alpar EK, Lord JM (2005) Raised cortisol:dHEAS ratios in the elderly after injury: potential impact upon neutrophil function and immunity. Aging Cell 4:319–324
27. Chelvarajan RL, Liu Y, Popa D, Getchell ML, Getchell TV, Stromberg AJ, Bondada S (2006) Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages. J Leukoc Biol 79:1314–1327
28. Chiu BC, Stolberg VR, Chensue SW (2008) Mononuclear phagocyte-derived IL-10 suppresses the innate IL-12/IFN-gamma axis in lung-challenged aged mice. J. Immunol. 181:3156–3166
29. Cooper MA, Fehniger TA, Caligiuri MA (2001a) The biology of human natural killer-cell subsets. Trends Immunol 22:633–640
30. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA (2001b) Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 97:3146–3151
31. DelaRosa O, Tarazona R, Casado JG, Alonso C, Ostos B, Pena J, Solana R (2002) Valpha24+ NKT cells are decreased in elderly humans. Exp Gerontol 37:213–217
32. Della BS, Bierti L, Presicce P, Arienti R, Valenti M, Saresella M, Vergani C, Villa ML (2007) Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol 122:220–228
33. Di LG, Balistreri CR, Candore G, Cigna D, Colombo A, Romano GC, Colucci AT, Gervasi F, Listi F, Potestio M, Caruso C (1999) Granulocyte and natural killer activity in the elderly. Mech Ageing Dev 108:25–38
34. Dussault I, Miller SC (1994) Decline in natural killer cell-mediated immunosurveillance in aging mice–a consequence of reduced cell production and tumor binding capacity. Mech Ageing Dev 75:115–129
35. Emanuelli G, Lanzio M, Anfossi T, Romano S, Anfossi G, Calcamuggi G (1986) Influence of age on polymorphonuclear leukocytes in vitro: phagocytic activity in healthy human subjects. Gerontology 32:308–316
36. Emori TG, Banerjee SN, Culver DH, Gaynes RP, Horan TC, Edwards JR, Jarvis WR, Tolson JS, Henderson TS, Martone WJ (1991) Nosocomial infections in elderly patients in the United States, 1986-1990. National nosocomial infections surveillance system. Am J Med 91:289S–293S
37. Facchini A, Mariani E, Mariani AR, Papa S, Vitale M, Manzoli FA (1987) Increased number of circulating Leu 11+ (CD 16) large granular lymphocytes and decreased NK activity during human ageing. Clin Exp Immunol 68:340–347
38. Fang M, Roscoe F, Sigal LJ (2010) Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking. J Exp Med 207:2369–2381
39. Fleming DM, Elliot AJ (2005) The impact of influenza on the health and health care utilisation of elderly people. Vaccine 23(Suppl 1):S1–S9
40. Fortin CF, Lesur O, Fulop T Jr (2007) Effects of aging on triggering receptor expressed on myeloid cells (TREM)-1-induced PMN functions. FEBS Lett 581:1173–1178
41. Fulop T, Larbi A, Douziech N, Fortin C, Guerard KP, Lesur O, Khalil A, Dupuis G (2004) Signal transduction and functional changes in neutrophils with aging. Aging Cell 3:217–226
42. Gomez CR, Nomellini V, Faunce DE, Kovacs EJ (2008) Innate immunity and aging. Exp Gerontol 43:718–728
43. Gorina Y, Kelly T, Lubitz J, Hines Z (2008) Trends in influenza and pneumonia among older persons in the United States. Aging trends. U.S. Department of health and human services. Centers for disease control and prevention. National center for health statistics. http://www.cdc.gov/nchs/data/ahcd/agingtrends/08influenza.pdf
44. Grolleau-Julius A, Harning EK, Abernathy LM, Yung RL (2008) Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res 68:6341–6349
45. Hart PH, Grimbaldeston MA, Hosszu EK, Swift GJ, Noonan FP, Finlay-Jones JJ (1999) Age-related changes in dermal mast cell prevalence in BALB/c mice: functional importance and correlation with dermal mast cell expression of Kit. Immunology 98:352–356
46. Hayhoe RP, Henson SM, Akbar AN, Palmer DB (2010) Variation of human natural killer cell phenotypes with age: identification of a unique KLRG1-negative subset. Hum Immunol 71:676–681
47. Hazeldine J, Lord JM (2013) The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev 12:1069–1078
48. 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 11:751–759
49. Hazlett LD, Masinick-McClellan SA, Barrett RP (1999) Complement defects in aged mice compromise phagocytosis of Pseudomonas aeruginosa. Curr Eye Res 19:26–32
50. Hearps AC, Martin GE, Angelovich TA, Cheng WJ, Maisa A, Landay AL, Jaworowski A, Crowe SM (2012) Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11:867–875
51. Herrero C, Marques L, Lloberas J, Celada A (2001) IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice. J Clin Invest 107:485–493
52. Herrero C, Sebastian C, Marques L, Comalada M, Xaus J, Valledor AF, Lloberas J, Celada A (2002) Immunosenescence of macrophages: reduced MHC class II gene expression. Exp Gerontol 37:389–394
53. Ho JC, Chan KN, Hu WH, Lam WK, Zheng L, Tipoe GL, Sun J, Leung R, Tsang KW (2001) The effect of aging on nasal mucociliary clearance, beat frequency, and ultrastructure of respiratory cilia. Am J Respir Crit Care Med 163:983–988
54. Irimajiri N, Bloom ET, Makinodan T (1985) Suppression of murine natural killer cell activity by adherent cells from aging mice. Mech Ageing Dev 31:155–162
55. Janssens JP, Krause KH (2004) Pneumonia in the very old. Lancet Infect Dis 4:112–124
56. Jing Y, Gravenstein S, Chaganty NR, Chen N, Lyerly KH, Joyce S, Deng Y (2007) Aging is associated with a rapid decline in frequency, alterations in subset composition, and enhanced Th2 response in CD1d-restricted NKT cells from human peripheral blood. Exp Gerontol 42:719–732
57. Jing Y, Shaheen E, Drake RR, Chen N, Gravenstein S, Deng Y (2009) Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum Immunol 70:777–784
58. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M (1997) CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278:1626–1629
59. Kinjo Y, Illarionov P, Vela JL, Pei B, Girardi E, Li X, Li Y, Imamura M, Kaneko Y, Okawara A, Miyazaki Y, Gomez-Velasco A, Rogers P, Dahesh S, Uchiyama S, Khurana A, Kawahara K, Yesilkaya H, Andrew PW, Wong CH, Kawakami K, Nizet V, Besra GS, Tsuji M, Zajonc DM, Kronenberg M (2011) Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nat Immunol 12:966–974
60. Krishnaraj R, Bhooma T (1996) Cytokine sensitivity of human NK cells during immunosenescence. 2. IL2-induced interferon gamma secretion. Immunol Lett 50:59–63
61. Kutza J, Murasko DM (1994) Effects of aging on natural killer cell activity and activation by interleukin-2 and IFN-alpha. Cell Immunol 155:195–204
62. Laube S (2004) Skin infections and ageing. Ageing Res Rev 3:69–89
63. Le Garff-Tavernier M, Beziat V, Decocq J, Siguret V, Gandjbakhch F, Pautas E, Debre P, Merle-Beral H, Vieillard V (2010) Human NK cells display major phenotypic and functional changes over the life span. Aging Cell 9:527–535
64. Levy SM, Herberman RB, Lee J, Whiteside T, Beadle M, Heiden L, Simons A (1991) Persistently low natural killer cell activity, age, and environmental stress as predictors of infectious morbidity. Nat Immun Cell Growth Regul. 10:289–307
65. Lipschitz DA, Udupa KB, Indelicato SR, Das M (1991) Effect of age on second messenger generation in neutrophils. Blood 78:1347–1354
66. Lung TL, Saurwein-Teissl M, Parson W, Schonitzer D, Grubeck-Loebenstein B (2000) Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine 18:1606–1612
67. Lutz CT, Moore MB, Bradley S, Shelton BJ, Lutgendorf SK (2005) Reciprocal age related change in natural killer cell receptors for MHC class I. Mech Ageing Dev 126:722–731
68. Lutz CT, Karapetyan A, Al-Attar A, Shelton BJ, Holt KJ, Tucker JH, Presnell SR (2011) Human NK cells proliferate and die in vivo more rapidly than T cells in healthy young and elderly adults. J Immunol 186:4590–4598
69. MacGregor RR, Shalit M (1990) Neutrophil function in healthy elderly subjects. J Gerontol 45:M55–M60
70. Mahbub S, Deburghgraeve CR, Kovacs EJ (2012) Advanced age impairs macrophage polarization. J Interferon Cytokine Res 32:18–26
71. Mariani E, Sgobbi S, Meneghetti A, Tadolini M, Tarozzi A, Sinoppi M, Cattini L, Facchini A (1996) Perforins in human cytolytic cells: the effect of age. Mech Ageing Dev 92:195–209
72. 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 10:981–989
73. Mariani E, Pulsatelli L, Meneghetti A, Dolzani P, Mazzetti I, Neri S, Ravaglia G, Forti P, Facchini A (2001) Different IL-8 production by T and NK lymphocytes in elderly subjects. Mech Ageing Dev 122:1383–1395
74. Mariani E, Meneghetti A, Neri S, Ravaglia G, Forti P, Cattini L, Facchini A (2002a) Chemokine production by natural killer cells from nonagenarians. Eur J Immunol 32:1524–1529
75. Mariani E, Pulsatelli L, Neri S, Dolzani P, Meneghetti A, Silvestri T, Ravaglia G, Forti P, Cattini L, Facchini A (2002b) RANTES and MIP-1alpha production by T lymphocytes, monocytes and NK cells from nonagenarian subjects. Exp Gerontol 37:219–226
76. Marone G, Poto S, Di ML, Condorelli M (1986) Human basophil releasability. I. Age-related changes in basophil releasability. J Allergy Clin Immunol 77:377–383
77. Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461
78. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F (2004) Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol 5:1260–1265
79. Mathur SK, Schwantes EA, Jarjour NN, Busse WW (2008) Age-related changes in eosinophil function in human subjects. Chest 133:412–419
80. McLachlan JA, Serkin CD, Morrey KM, Bakouche O (1995) Antitumoral properties of aged human monocytes. J Immunol 154:832–843
81. McLaughlin B, O’Malley K, Cotter TG (1986) Age-related differences in granulocyte chemotaxis and degranulation. Clin Sci (Lond) 70:59–62
82. Mikael N, Mirza NM, Zaharian BI, Deulofeut H, Salazar M, Yunis EJ, Dubey DP (1994) Genetic control of the decline of natural killer cell activity in aging mice. Growth Dev Aging 58:3–12
83. Molling JW, Kolgen W, van der Vliet HJ, Boomsma MF, Kruizenga H, Smorenburg CH, Molenkamp BG, Langendijk JA, Leemans CR, von Blomberg BM, Scheper RJ, van den Eertwegh AJ (2005) Peripheral blood IFN-gamma-secreting Valpha24+Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer 116:87–93
84. Montagna W, Carlisle K (1979) Structural changes in aging human skin. J Invest Dermatol 73:47–53
85. Mysliwska J, Trzonkowski P, Szmit E, Brydak LB, Machala M, Mysliwski A (2004) Immunomodulating effect of influenza vaccination in the elderly differing in health status. Exp Gerontol 39:1447–1458
86. Nagaki K, Hiramatsu S, Inai S, Sasaki A (1980) The effect of aging on complement activity (CH50) and complement protein levels. J Clin Lab Immunol 3:45–50
87. Nguyen M, Pace AJ, Koller BH (2005) Age-induced reprogramming of mast cell degranulation. J Immunol 175:5701–5707
88. Niwa Y, Kasama T, Miyachi Y, Kanoh T (1989) Neutrophil chemotaxis, phagocytosis and parameters of reactive oxygen species in human aging: cross-sectional and longitudinal studies. Life Sci 44:1655–1664
89. Nomellini V, Faunce DE, Gomez CR, Kovacs EJ (2008) An age-associated increase in pulmonary inflammation after burn injury is abrogated by CXCR2 inhibition. J Leukoc Biol 83:1493–1501
90. Nyugen J, Agrawal S, Gollapudi S, Gupta S (2010) Impaired functions of peripheral blood monocyte subpopulations in aged humans. J Clin Immunol 30:806–813
91. Ogata K, Yokose N, Tamura H, An E, Nakamura K, Dan K, Nomura T (1997) Natural killer cells in the late decades of human life. Clin Immunol Immunopathol 84:269–275
92. Ogata K, An E, Shioi Y, Nakamura K, Luo S, Yokose N, Minami S, Dan K (2001) Association between natural killer cell activity and infection in immunologically normal elderly people. Clin Exp Immunol 124:392–397
93. Oyeyinka GO, Salimonu LS (1999) Levels of complement components, immunoglobulins and acute phase proteins in plasma during aging in Nigeria. Afr J Med Med Sci 28:177–180
94. Panda A, Qian F, Mohanty S, van Duin D, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E, Allore HG, Montgomery RR, Shaw AC (2010) Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol 184:2518–2527
95. Peralbo E, DelaRosa O, Gayoso I, Pita ML, Tarazona R, Solana R (2006) Decreased frequency and proliferative response of invariant Valpha24Vbeta11 natural killer T (iNKT) cells in healthy elderly. Biogerontology 7:483–492
96. Perez-Cabezas B, Naranjo-Gomez M, Fernandez MA, Grifols JR, Pujol-Borrell R, Borras FE (2007) Reduced numbers of plasmacytoid dendritic cells in aged blood donors. Exp Gerontol 42:1033–1038
97. Plett A, Murasko DM (2000) Genetic differences in the age-associated decrease in inducibility of natural killer cells by interferon-alpha/beta. Mech Ageing Dev 112:197–215
98. Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S (2004) Innate immunity in aging: impact on macrophage function. Aging Cell 3:161–167
99. Puchelle E, Zahm JM, Bertrand A (1979) Influence of age on bronchial mucociliary transport. Scand J Respir Dis 60:307–313
100. Qian F, Wang X, Zhang L, Chen S, Piecychna M, Allore H, Bockenstedt L, Malawista S, Bucala R, Shaw AC, Fikrig E, Montgomery RR (2012) Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging Cell 11:104–110
101. Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S (2002) Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 169:4697–4701
102. Rukavina D, Laskarin G, Rubesa G, Strbo N, Bedenicki I, Manestar D, Glavas M, Christmas SE, Podack ER (1998) Age-related decline of perforin expression in human cytotoxic T lymphocytes and natural killer cells. Blood 92:2410–2420
103. Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V (2013) Granule exocytosis mediates immune surveillance of senescent cells. Oncogene 32:1971–1977
104. Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, Insall RH, Stockley RA, Lord JM (2013) Phosphoinositide 3 kinase inhibition restores neutrophil accuracy in the elderly: towards targeted treatments for immunesenescence. Blood 123:239–248
105. Schwarzenbach HR, Nakagawa T, Conroy MC, de Weck AL (1982) Skin reactivity, basophil degranulation and IgE levels in ageing. Clin Allergy 12:465–473
106. Seidler S, Zimmermann HW, Bartneck M, Trautwein C, Tacke F (2010) Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol 11:30
107. Shodell M, Siegal FP (2002) Circulating, interferon-producing plasmacytoid dendritic cells decline during human ageing. Scand J Immunol 56:518–521
108. Simell B, Vuorela A, Ekstrom N, Palmu A, Reunanen A, Meri S, Kayhty H, Vakevainen M (2011) Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis. Vaccine 29:1929–1934
109. Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, Takeda K, van Dommelen SL, Degli-Esposti MA, Hayakawa Y (2005) Activation of NK cell cytotoxicity. Mol Immunol 42:501–510
110. Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T (2012) Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol 24:331–341
111. Sotsios Y, Ward SG (2000) Phosphoinositide 3-kinase: a key biochemical signal for cell migration in response to chemokines. Immunol Rev 177:217–235
112. Sridharan A, Esposo M, Kaushal K, Tay J, Osann K, Agrawal S, Gupta S, Agrawal A (2011) Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age (Dordr) 33:363–376
113. Svartengren M, Falk R, Philipson K (2005) Long-term clearance from small airways decreases with age. Eur Respir J 26:609–615
114. Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376
115. Thoren FB, Riise RE, Ousback J, Della CM, Alsterholm M, Marcenaro E, Pesce S, Prato C, Cantoni C, Bylund J, Moretta L, Moretta A (2012) Human NK Cells induce neutrophil apoptosis via an NKp46- and Fas-dependent mechanism. J Immunol 188:1668–1674
116. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci USA 104:19446–19451
117. Toapanta FR, Ross TM (2009) Impaired immune responses in the lungs of aged mice following influenza infection. Respir Res 10:112
118. 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
119. van Duin D, Allore HG, Mohanty S, Ginter S, Newman FK, Belshe RB, Medzhitov R, Shaw AC (2007a) Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J Infect Dis 195:1590–1597
120. van Duin D, Mohanty S, Thomas V, Ginter S, Montgomery RR, Fikrig E, Allore HG, Medzhitov R, Shaw AC (2007b) Age-associated defect in human TLR-1/2 function. J Immunol 178:970–975
121. Vignola AM, Bonanno A, Profita M, Riccobono L, Scichilone N, Spatafora M, Bousquet J, Bonsignore G, Bellia V (2003) Effect of age and asthma duration upon elastase and alpha1-antitrypsin levels in adult asthmatics. Eur Respir J 22:795–801
122. Vitale M, Della CM, Carlomagno S, Pende D, Arico M, Moretta L, Moretta A (2005) NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood 106:566–571
123. Walsh CM, Matloubian M, Liu CC, Ueda R, Kurahara CG, Christensen JL, Huang MT, Young JD, Ahmed R, Clark WR (1994) Immune function in mice lacking the perforin gene. Proc Natl Acad Sci USA 91:10854–10858
124. Wenisch C, Patruta S, Daxbock F, Krause R, Horl W (2000) Effect of age on human neutrophil function. J Leukoc Biol 67:40–45
125. Wong KL, Yeap WH, Tai JJ, Ong SM, Dang TM, Wong SC (2012) The three human monocyte subsets: implications for health and disease. Immunol Res 53:41–57
126. Yonemasu K, Kitajima H, Tanabe S, Ochi T, Shinkai H (1978) Effect of age on C1q and C3 levels in human serum and their presence in colostrum. Immunology 35:523–530
127. Zavala WD, Cavicchia JC (2006) Deterioration of the Langerhans cell network of the human gingival epithelium with aging. Arch Oral Biol 51:1150–1155
128. Zhang Y, Wallace DL, de Lara CM, Ghattas H, Asquith B, Worth A, Griffin GE, Taylor GP, Tough DF, Beverley PC, Macallan DC (2007) In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 121:258–265
129. Zhao J, Zhao J, Legge K, Perlman S (2011) Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest 121:4921–4930