Skip to main content
SpringerLink
Log in

Aging of Immune System Organs

  • Chapter
  • First Online:
Book cover Immunopathology in Toxicology and Drug Development

Part of the book series: Molecular and Integrative Toxicology ((MOLECUL))

  • 1106 Accesses

Abstract

Aging of mammals has a negative effect on virtually all components of the immune system. Some, but not all, age-related immunological alterations are due to structural alterations in immune system organs or depletion of immunocyte populations. However, other age-related alterations involve dysregulation and failures in coordination of various immunological functions. Aging effects on the innate immune system may result in a pro-inflammatory status (‘inflamm-aging’) that consists of a paradoxical increase in the tendency to inflammation, but concurrently reduced ability to mount an effective inflammatory response. Many of the age-related alterations in adaptive immune responsiveness are a result of a decline in T cell function, which has a downstream effect on B cell functions and humoral immune responses.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

APC:

antigen-presenting cell

ARR :

antigen-responsive reticulum

BALT:

bronchus-associated lymphoid tissue

BLA:

basic lead acetate

BTLA:

B and T lymphocyte attenuator

CCR:

chemokine receptor

CD:

clusters of differentiation

CINC:

cytokine-induced neutrophil chemoattractant

CLP :

Common lymphocyte progenitor

CTLA-4:

cytotoxic T lymphocyte-associated protein 4

DC:

dentritic cell

DHEA:

dehydroxyepiandosterone

DHEAS:

dehydroepiandrosterone sulfate

DTH :

delayed type hypersensitivity

Fcγ:

fraction crystallizable γ

FDC :

follicular dendritic cell

GALT:

gut-associated lymphoid tissue

G-CSF:

granulocyte colony-stimulating factor

HSC:

Hematopoietic stem cell

IFNγ:

Interferon γ

IL-:

Interleukin

MALT:

mucosa-associated lymphoid tissue

MC:

mast cell

MHC:

major histocompatibility class

MIP:

macrophage inflammatory protein

MOCD:

monocyte-origin dentritic cells

NALT:

nasopharynx-associated lymphoid tissue

NET:

neutrophil extracellular trap

NK:

Natural killer

NKT:

NK cell with T cell receptor

PD-L1:

programmed death ligand 1

PECAM:

platelet-endothelial cell adhesion molecule

PI3K :

phosphoinositide 3 kinase

RANTES:

regulated on activation normal T cell expressed and secreted

TCR:

T cell receptor

TFH :

T follicular helper cell

TFN-α:

Tumor necrosis factor-α

TFR :

T follicular regulatory cell

TLR:

Toll-like receptor

TREM-1:

triggering receptor expressed on myeloid cells-1

References

  • Abo T (1993) Extrathymic pathways of T-cell differentiation: a primitive and fundamental immune system. Microbiol Immunol 37(4):247–258

    Article  CAS  PubMed  Google Scholar 

  • Abo T (2001) Extrathymic pathways of T-cell differentiation and immunomodulation. Int Immunopharmacol 1(7):1261–1273

    Article  CAS  PubMed  Google Scholar 

  • Ademokun A, Wu YC, Dunn-Walters D (2010) The ageing B cell population: composition and function. Biogerontology 11(2):125–137. doi:10.1007/s10522-009-9256-9

    Article  PubMed  Google Scholar 

  • 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(9):1929–1940. doi:10.1084/jem.20090896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agrawal A, Agrawal S, Gupta S (2007) Dendritic cells in human aging. Exp Gerontol 42(5):421–426. doi:10.1016/j.exger.2006.11.007

    Article  CAS  PubMed  Google Scholar 

  • Agrawal A, Agrawal S, Tay J, Gupta S (2008) Biology of dendritic cells in aging. J Clin Immunol 28(1):14–20. doi:10.1007/s10875-007-9127-6

    Article  PubMed  Google Scholar 

  • Aita M, Ammirati P, Falchetti R, Pezzella M (1981) Immunological and immunohistochemical properties of an anti-thymostimulin (TP.1) serum. Cell Mol Biol Incl Cyto Enzymol 27(4):369–375

    CAS  PubMed  Google Scholar 

  • Allen CD, Cyster JG (2008) Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function. Semin Immunol 20(1):14–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allman D, Miller JP (2005a) The aging of early B-cell precursors. Immunol Rev 205:18–29. doi:10.1111/j.0105-2896.2005.00269.x

    Article  CAS  PubMed  Google Scholar 

  • Allman D, Miller JP (2005b) B cell development and receptor diversity during aging. Curr Opin Immunol 17(5):463–467. doi:10.1016/j.coi.2005.07.002

    Article  CAS  PubMed  Google Scholar 

  • Almanzar G, Schwaiger S, Jenewein B, Keller M, Herndler-Brandstetter D, Wurzner R, Schonitzer D, Grubeck-Loebenstein B (2005) Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J Virol 79(6):3675–3683. doi:10.1128/JVI.79.6.3675-3683.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andrade MR, Yee J, Barry P, Spinner A, Roberts JA, Cabello PH, Leite JP, Lerche NW (2003) Prevalence of antibodies to selected viruses in a long-term closed breeding colony of rhesus macaques (Macaca mulatta) in Brazil. Am J Primatol 59(3):123–128. doi:10.1002/ajp.10069

    Article  PubMed  Google Scholar 

  • Andrew D, Aspinall R (2002) Age-associated thymic atrophy is linked to a decline in IL-7 production. Exp Gerontol 37(2–3):455–463

    Article  CAS  PubMed  Google Scholar 

  • Arpin C, Dechanet J, Van Kooten C, Merville P, Grouard G, Briere F, Banchereau J, Liu YJ (1995) Generation of memory B cells and plasma cells in vitro. Science 268(5211):720–722

    Article  CAS  PubMed  Google Scholar 

  • 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(7):882–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aspinall R (1997) Age-associated thymic atrophy in the mouse is due to a deficiency affecting rearrangement of the TCR during intrathymic T cell development. J Immunol 158(7):3037–3045

    CAS  PubMed  Google Scholar 

  • Asquith M, Haberthur K, Brown M, Engelmann F, Murphy A, Al-Mahdi Z, Messaoudi I (2012) Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta). Pathobiol Aging Age Relat Dis 2. doi:10.3402/pba.v2i0.18052

  • Aw D, Silva AB, Maddick M, von Zglinicki T, Palmer DB (2008) Architectural changes in the thymus of aging mice. Aging Cell 7(2):158–167. doi:10.1111/j.1474-9726.2007.00365.x

    Article  CAS  PubMed  Google Scholar 

  • Aydar Y, Balogh P, Tew JG, Szakal AK (2002) Age-related depression of FDC accessory functions and CD21 ligand-mediated repair of co-stimulation. Eur J Immunol 32(10):2817–2826. doi:10.1002/1521-4141(2002010)32:10<2817::AID-IMMU2817>3.0.CO;2-Z

    Article  CAS  PubMed  Google Scholar 

  • Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D, Rossi DJ (2010) Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A 107(12):5465–5470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benner R, Meima F, van der Meulen GM, van Muiswinkel WB (1974) Antibody formation in mouse bone marrow. I Evidence for the development of plaque-forming cells in situ Immunology. Immunology 26(2):247–255

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berek C, Berger A, Apel M (1991) Maturation of the immune response in germinal centers. Cell 67(6):1121–1129

    Article  CAS  PubMed  Google Scholar 

  • Bockman DE, Kirby ML (1985) Neural crest interactions in the development of the immune system. J Immunol 135(2 Suppl):766s–768s

    CAS  PubMed  Google Scholar 

  • Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B, Pena J, Solana R (1999) NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol 34(2):253–265

    Article  CAS  PubMed  Google Scholar 

  • Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535

    Article  CAS  PubMed  Google Scholar 

  • Brown KL, Wathne GJ, Sales J, Bruce ME, Mabbott NA (2009) The effects of host age on follicular dendritic cell status dramatically impair scrapie agent neuroinvasion in aged mice. J Immunol 183(8):5199–5207. doi:10.4049/jimmunol.0802695

    Article  CAS  PubMed  Google Scholar 

  • Bruunsgaard H (2002) Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. Eur Cytokine Netw 13(4):389–391

    CAS  PubMed  Google Scholar 

  • Bruunsgaard H, Pedersen AN, Schroll M, Skinhoj P, Pedersen BK (2001) Decreased natural killer cell activity is associated with atherosclerosis in elderly humans. Exp Gerontol 37(1):127–136

    Article  CAS  PubMed  Google Scholar 

  • Burek JD (1978) Pathology of aging rats. A morphological and experimental study of the age-associated lesions in aging BN/Bi, WAG.Rij, and (WAGxBN) F1 rats. CRC Press, Boca Raton

    Google Scholar 

  • Burns EA, Lum LG, L’Hommedieu G, Goodwin JS (1993) Specific humoral immunity in the elderly: in vivo and in vitro response to vaccination. J Gerontol 48(6):B231–B236

    Article  CAS  PubMed  Google Scholar 

  • Burns EA, Lum LG, Seigneuret MC, Giddings BR, Goodwin JS (1990) Decreased specific antibody synthesis in old adults: decreased potency of antigen-specific B cells with aging. Mech Ageing Dev 53(3):229–241

    Article  CAS  PubMed  Google Scholar 

  • Butcher S, Chahel H, Lord JM (2000) Review article: ageing and the neutrophil: no appetite for killing? Immunology 100(4):411–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(6):881–886

    CAS  PubMed  Google Scholar 

  • 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(6):319–324. doi:10.1111/j.1474-9726.2005.00178.x

    Article  CAS  PubMed  Google Scholar 

  • Cancro MP (2005) B cells and aging: gauging the interplay of generative, selective, and homeostatic events. Immunol Rev 205:48–59. doi:10.1111/j.0105-2896.2005.00272.x

    Article  CAS  PubMed  Google Scholar 

  • Cancro MP, Hao Y, Scholz JL, Riley RL, Frasca D, Dunn-Walters DK, Blomberg BB (2009) B cells and aging: molecules and mechanisms. Trends Immunol 30(7):313–318. doi:10.1016/j.it.2009.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Channappanavar R, Twardy BS, Krishna P, Suvas S (2009) Advancing age leads to predominance of inhibitory receptor expressing CD4 T cells. Mech Ageing Dev 130(10):709–712. doi:10.1016/j.mad.2009.08.006

    Article  CAS  PubMed  Google Scholar 

  • Chatta GS, Andrews RG, Rodger E, Schrag M, Hammond WP, Dale DC (1993) Hematopoietic progenitors and aging: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J Gerontol 48(5):M207–M212

    Article  CAS  PubMed  Google Scholar 

  • Chen J (2004) Senescence and functional failure in hematopoietic stem cells. Exp Hematol 32(11):1025–1032. doi:10.1016/j.exphem.2004.08.001

    Article  CAS  PubMed  Google Scholar 

  • Cheung HT, Nadakavukaren MJ (1983) Age-dependent changes in the cellularity and ultrastructure of the spleen of Fischer F344 rats. Mech Ageing Dev 22(1):23–33

    Article  CAS  PubMed  Google Scholar 

  • Chikuma S, Bluestone JA (2003) CTLA-4 and tolerance: the biochemical point of view. Immunol Res 28(3):241–253. doi:10.1385/IR:28:3:241

    Article  CAS  PubMed  Google Scholar 

  • Chilvers ER, Cadwallader KA, Reed BJ, White JF, Condliffe AM (2000) The function and fate of neutrophils at the inflamed site: prospects for therapeutic intervention. J R Coll Physicians Lond 34(1):68–74

    CAS  PubMed  Google Scholar 

  • Chong Y, Ikematsu H, Yamaji K, Nishimura M, Nabeshima S, Kashiwagi S, Hayashi J (2005) 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 17(4):383–390. doi:10.1093/intimm/dxh218

    Article  CAS  PubMed  Google Scholar 

  • Cicin-Sain L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, Tackitt S, Nikolich-Zugich D, Legasse A, Axthelm MK, Picker LJ, Mori M, Nikolich-Zugich J (2007) Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci U S A 104(50):19960–19965. doi:10.1073/pnas.0705905104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coe CL (2004) Biological and social predictors of immune senescence in the aged primate. Mech Ageing Dev 125(2):95–98. doi:10.1016/j.mad.2003.11.011

    Article  PubMed  Google Scholar 

  • Coe CL, Ershler WB (2001) Intrinsic and environmental influences on immune senescence in the aged monkey. Physiol Behav 73(3):379–384

    Article  CAS  PubMed  Google Scholar 

  • Coe CL, Ershler WB, Champoux M, Olson J (1992) Psychosocial factors and immune senescence in the aged primate. Ann N Y Acad Sci 650:276–282

    Article  CAS  PubMed  Google Scholar 

  • Colonna-Romano G, Bulati M, Aquino A, Scialabba G, Candore G, Lio D, Motta M, Malaguarnera M, Caruso C (2003) B cells in the aged: CD27, CD5, and CD40 expression. Mech Ageing Dev 124(4):389–393

    Article  CAS  PubMed  Google Scholar 

  • Colonna-Romano G, Bulati M, Aquino A, Vitello S, Lio D, Candore G, Caruso C (2008) B cell immunosenescence in the elderly and in centenarians. Rejuvenation Res 11(2):433–439. doi:10.1089/rej.2008.0664

    Article  CAS  PubMed  Google Scholar 

  • Cooper D, Lindberg FP, Gamble JR, Brown EJ, Vadas MA (1995) Transendothelial migration of neutrophils involves integrin-associated protein (CD47). Proc Natl Acad Sci U S A 92(9):3978–3982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dardenne M, Savino W, Bach JF (1988) Modulation of thymic endocrine function by thyroid and steroid hormones. Int J Neurosci 39(3–4):325–334

    Article  CAS  PubMed  Google Scholar 

  • Davis CF, Moore FD Jr, Rodrick ML, Fearon DT, Mannick JA (1987) Neutrophil activation after burn injury: contributions of the classic complement pathway and of endotoxin. Surgery 102(3):477–484

    CAS  PubMed  Google Scholar 

  • De la Fuente M, Baeza I, Guayerbas N, Puerto M, Castillo C, Salazar V, Ariznavarreta C, F-Tresguerres JA (2004) Changes with ageing in several leukocyte functions of male and female rats. Biogerontology 5(6):389–400. doi:10.1007/s10522-004-3201-8

    Article  CAS  PubMed  Google Scholar 

  • Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, Bernasconi S, Sironi M, Santoro A, Garlanda C, Facchetti F, Wymann MP, Vecchi A, Hirsch E, Mantovani A, Sozzani S (2004) Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-deficient mice. EMBO J 23(17):3505–3515. doi:10.1038/sj.emboj.7600361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Della Bella S, 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(2):220–228

    Article  CAS  PubMed  Google Scholar 

  • Didier ES, MacLean AG, Mohan M, Didier PJ, Lackner AA, Kuroda MJ (2016) Contributions of Nonhuman Primates to Research on Aging. Vet Pathol 53(2):277–290. doi:10.1177/0300985815622974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Didier ES, Sugimoto C, Bowers LC, Khan IA, Kuroda MJ (2012) Immune correlates of aging in outdoor-housed captive rhesus macaques (Macaca mulatta). Immun Ageing 9(1):25. doi:10.1186/1742-4933-9-25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dietert RR, DeWitt JC, Luebke RW (2012) Reducing the prevalence of immune-based chronic disease. In: Dietert RR, Luebke RW (eds) Immunotoxicity, Immune Dysfunction, and Chronic Disease Molecular and Integrative Toxicology. Springer, New York, pp 419–440. doi:10.1007/978-1-61779-812-2

    Chapter  Google Scholar 

  • Doria G, D’Agostaro G, Poretti A (1978) Age-dependent variations of antibody avidity. Immunology 35(4):601–611

    CAS  PubMed  PubMed Central  Google Scholar 

  • Doyle NA, Bhagwan SD, Meek BB, Kutkoski GJ, Steeber DA, Tedder TF, Doerschuk CM (1997) Neutrophil margination, sequestration, and emigration in the lungs of L-selectin-deficient mice. J Clin Invest 99(3):526–533. doi:10.1172/JCI119189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dykhuizen M, Ceman J, Mitchen J, Zayas M, MacDougall A, Helgeland J, Rakasz E, Pauza CD (2000) Importance of the CD3 marker for evaluating changes in rhesus macaque CD4/CD8 T-cell ratios. Cytometry 40(1):69–75

    Article  CAS  PubMed  Google Scholar 

  • Dykstra B, de Haan G (2008) Hematopoietic stem cell aging and self-renewal. Cell Tissue Res 331(1):91–101. doi:10.1007/s00441-007-0529-9

    Article  PubMed  Google Scholar 

  • Effros RB (2000) Costimulatory mechanisms in the elderly. Vaccine 18(16):1661–1665

    Article  CAS  PubMed  Google Scholar 

  • Effros RB, Cai Z, Linton PJ (2003) CD8 T cells and aging. Crit Rev Immunol 23(1–2):45–64

    Article  CAS  PubMed  Google Scholar 

  • Effros RB (2005) The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 205:147–157

    Google Scholar 

  • 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(6):308–316

    Article  CAS  PubMed  Google Scholar 

  • Engwerda CR, Handwerger BS, Fox BS (1994) Aged T cells are hyporesponsive to costimulation mediated by CD28. J Immunol 152(8):3740–3747

    CAS  PubMed  Google Scholar 

  • Ernst DN, Hobbs MV, Torbett BE, Glasebrook AL, Rehse MA, Bottomly K, Hayakawa K, Hardy RR, Weigle WO (1990) Differences in the expression 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 145(5):1295–1302

    CAS  PubMed  Google Scholar 

  • Ershler WB, Keller ET (2000) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51:245–270. doi:10.1146/annurev.med.51.1.245

    Article  CAS  PubMed  Google Scholar 

  • Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101(4):890–898. doi:10.1172/JCI1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P (2000) Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 95(9):2860–2868

    CAS  PubMed  Google Scholar 

  • Faunce DE, Palmer JL, Paskowicz KK, Witte PL, Kovacs EJ (2005) CD1d-restricted NKT cells contribute to the age-associated decline of T cell immunity. J Immunol 175(5):3102–3109

    Article  CAS  PubMed  Google Scholar 

  • 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(6):1173–1178. doi:10.1016/j.febslet.2007.02.029

    Article  CAS  PubMed  Google Scholar 

  • Foy TM, Shepherd DM, Durie FH, Aruffo A, Ledbetter JA, Noelle RJ (1993) In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. J Exp Med 178(5):1567–1575

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254

    Article  CAS  PubMed  Google Scholar 

  • Frasca D, Blomberg BB (2009) Effects of aging on B cell function. Curr Opin Immunol 21(4):425–430. doi:10.1016/j.coi.2009.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(4):217–226. doi:10.1111/j.1474-9728.2004.00110.x

    Article  CAS  PubMed  Google Scholar 

  • Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M (2005) Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 23:749–786. doi:10.1146/annurev.immunol.21.120601.141025

    Article  CAS  PubMed  Google Scholar 

  • Gao HM, Hong JS (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 29(8):357–365. doi:10.1016/j.it.2008.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • George AJ, Ritter MA (1996) Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today 17(6):267–272

    Article  CAS  PubMed  Google Scholar 

  • Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R, Kondeatis E, Nilsson BO, Wikby A, Kipling D, Dunn-Walters DK (2009) B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8(1):18–25. doi:10.1111/j.1474-9726.2008.00443.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gillespie GM, Wills MR, Appay V, O’Callaghan C, Murphy M, Smith N, Sissons P, Rowland-Jones S, Bell JI, Moss PA (2000) Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors. J Virol 74(17):8140–8150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginaldi L, Di Benedetto MC, De Martinis M (2005) Osteoporosis, inflammation and ageing. Immun Ageing 2:14. doi:10.1186/1742-4933-2-14

    Article  PubMed  PubMed Central  Google Scholar 

  • Goidl EA, Innes JB, Weksler ME (1976) Immunological studies of aging. II. Loss of IgG and high avidity plaque-forming cells and increased suppressor cell activity in aging mice. J Exp Med 144(4):1037–1048

    Article  CAS  PubMed  Google Scholar 

  • Goldsby R, Kindt T, Osborne B (2000) Kuby Immunology. W. H. Freeman and Company, New York

    Google Scholar 

  • Gomez CR, Acuna-Castillo C, Perez C, Leiva-Salcedo E, Riquelme DM, Ordenes G, Oshima K, Aravena M, Perez VI, Nishimura S, Sabaj V, Walter R, Sierra F (2008a) Diminished acute phase response and increased hepatic inflammation of aged rats in response to intraperitoneal injection of lipopolysaccharide. J Gerontol A Biol Sci Med Sci 63(12):1299–1306

    Article  PubMed  Google Scholar 

  • Gomez CR, Boehmer ED, Kovacs EJ (2005) The aging innate immune system. Curr Opin Immunol 17(5):457–462. doi:10.1016/j.coi.2005.07.013

    Article  CAS  PubMed  Google Scholar 

  • Gomez CR, Nomellini V, Baila H, Oshima K, Kovacs EJ (2009) Comparison of the effects of aging and IL-6 on the hepatic inflammatory response in two models of systemic injury: scald injury versus i.p. LPS administration. Shock 31(2):178–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez CR, Nomellini V, Faunce DE, Kovacs EJ (2008b) Innate immunity and aging. Exp Gerontol 43(8):718–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goncharova ND, Lapin BA (2004) Age-related endocrine dysfunction in nonhuman primates. Ann N Y Acad Sci 1019:321–325. doi:10.1196/annals.1297.054

    Article  CAS  PubMed  Google Scholar 

  • 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(24):12182–12187. doi:10.1128/JVI.75.24.12182-12187.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goronzy JJ, Weyand CM (2005) T cell development and receptor diversity during aging. Curr Opin Immunol 17(5):468–475. doi:10.1016/j.coi.2005.07.020

    Article  CAS  PubMed  Google Scholar 

  • Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548. doi:10.1146/annurev.immunol.23.021704.115611

    Article  PubMed  CAS  Google Scholar 

  • Grizzi F, Franceschini B, Gagliano N, Moscheni C, Annoni G, Vergani C, Hermonat PL, Chiriva-Internati M, Dioguardi N (2003) Mast cell density, hepatic stellate cell activation and TGF-beta1 transcripts in the aging Sprague-Dawley rat during early acute liver injury. Toxicol Pathol 31(2):173–178

    CAS  PubMed  Google Scholar 

  • Grolleau-Julius A, Harning EK, Abernathy LM, Yung RL (2008) Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res 68(15):6341–6349. doi:10.1158/0008-5472.CAN-07-5769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haberthur K, Engelman F, Barron A, Messaoudi I (2010) Immune senescence in aged nonhuman primates. Exp Gerontol 45(9):655–661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han S, Hathcock K, Zheng B, Kepler TB, Hodes R, Kelsoe G (1995a) Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J Immunol 155(2):556–567

    CAS  PubMed  Google Scholar 

  • Han S, Zheng B, Dal Porto J, Kelsoe G (1995b) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance. J Exp Med 182(6):1635–1644

    Article  CAS  PubMed  Google Scholar 

  • 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(3):352–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hartsock RJ, Smith EB, Petty CS (1965) Normal variations with aging of the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. A study made from 177 cases of sudden death examined by necropsy. Am J Clin Pathol 43:326–331

    Article  CAS  PubMed  Google Scholar 

  • Hasegawa Y, Sawada M, Ozaki N, Inagaki T, Suzumura A (2000) Increased soluble tumor necrosis factor receptor levels in the serum of elderly people. Gerontology 46(4):185–188 doi:22157

    Article  CAS  PubMed  Google Scholar 

  • Haynes L, Eaton SM, Burns EM, Randall TD, Swain SL (2003) CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc Natl Acad Sci U S A 100(25):15053–15058. doi:10.1073/pnas.2433717100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hazeldine J, Arlt W, Lord JM (2010) Dehydroepiandrosterone as a regulator of immune cell function. J Steroid Biochem Mol Biol 120(2–3):127–136. doi:10.1016/j.jsbmb.2009.12.016

    Article  CAS  PubMed  Google Scholar 

  • Hazeldine J, Harris P, Chapple IL, Grant M, Greenwood H, Livesey A, Sapey E, Lord JM (2014) Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals. Aging Cell 13(4):690–698. doi:10.1111/acel.12222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henson SM, Macaulay R, Kiani-Alikhan S, Akbar AN (2008) The use of the inhibitory receptors for modulating the immune responses. Curr Pharm Des 14(26):2643–2650

    Article  CAS  PubMed  Google Scholar 

  • 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(2–3):389–394

    Article  CAS  PubMed  Google Scholar 

  • Hilmer SN, Cogger VC, Le Couteur DG (2007) Basal activity of Kupffer cells increases with old age. J Gerontol A Biol Sci Med Sci 62(9):973–978

    Article  PubMed  Google Scholar 

  • Hirokawa K, Kubo S, Utsuyama M, Kurashima C, Sado T (1986) Age-related change in the potential of bone marrow cells to repopulate the thymus and splenic T cells in mice. Cell Immunol 100(2):443–451

    Article  CAS  PubMed  Google Scholar 

  • Hirokawa K, McClure JE, Goldstein AL (1982) Age-related changes in localization of thymosin in the human thymus. Thymus 4(1):19–29

    CAS  PubMed  Google Scholar 

  • Hoffman CL, Higham JP, Heistermann M, Coe CL, Prendergast BJ, Maestripieri D (2011) Immune function and HPA axis activity in free-ranging rhesus macaques. Physiol Behav 104(3):507–514. doi:10.1016/j.physbeh.2011.05.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffman CL, Higham JP, Mas-Rivera A, Ayala JE, Maestripieri D (2010) Terminal investment and senescence in rhesus macaques (Macaca mulatta) on Cayo Santiago. Behav Ecol 21(5):972–978. doi:10.1093/beheco/arq098

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang H, Patel DD, Manton KG (2005) The immune system in aging: roles of cytokines, T cells and NK cells. Front Biosci 10:192–215

    Article  CAS  PubMed  Google Scholar 

  • Inui T, Nakagawa R, Ohkura S, Habu Y, Koike Y, Motoki K, Kuranaga N, Fukasawa M, Shinomiya N, Seki S (2002) Age-associated augmentation of the synthetic ligand- mediated function of mouse NK1.1 ag(+) T cells: their cytokine production and hepatotoxicity in vivo and in vitro. J Immunol 169(11):6127–6132

    Article  CAS  PubMed  Google Scholar 

  • Jacob J, Kelsoe G, Rajewsky K, Weiss U (1991) Intraclonal generation of antibody mutants in germinal centres. Nature 354(6352):389–392. doi:10.1038/354389a0

    Article  CAS  PubMed  Google Scholar 

  • Jankovic V, Messaoudi I, Nikolich-Zugich J (2003) Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4 and CD8 subsets. Blood 102(9):3244–3251. doi:10.1182/blood-2003-03-0927

    Article  CAS  PubMed  Google Scholar 

  • 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(10):777–784. doi:10.1016/j.humimm.2009.07.005

    Article  CAS  PubMed  Google Scholar 

  • Johnson SA, Cambier JC (2004) Ageing, autoimmunity and arthritis: senescence of the B cell compartment - implications for humoral immunity. Arthritis Res Ther 6(4):131–139. doi:10.1186/ar1180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones GV, Botham CA, Clarke AG, Kendall MD (1998) Immunoreactivity of neural crest-derived cells in thymic tissue developing under the rat kidney capsule. Brain Behav Immun 12(3):163–180. doi:10.1006/brbi.1998.0528

    Article  CAS  PubMed  Google Scholar 

  • Kaack MB, Harrison RM, Roberts JA (1998) Effect of age and hormonal state on cytokine synthesis in the monkey. Cytokine 10(3):236–239. doi:10.1006/cyto.1997.0281

    Article  CAS  PubMed  Google Scholar 

  • Kasper M, Haroske G (1996) Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol Histopathol 11(2):463–483

    CAS  PubMed  Google Scholar 

  • Kawabata T, Kinoshita M, Inatsu A, Habu Y, Nakashima H, Shinomiya N, Seki S (2008) Functional alterations of liver innate immunity of mice with aging in response to CpG-oligodeoxynucleotide. Hepatology 48(5):1586–1597

    Article  CAS  PubMed  Google Scholar 

  • Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA (2002) Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169(4):1984–1992

    Article  CAS  PubMed  Google Scholar 

  • Kishimoto S, Takahama T, Mizumachi H (1976) In vitro immune response to the 2,4,6-trinitrophenyl determinant in aged C57BL/6J mice:changes in the humoral immune response to, avidity for the TNP determinant and responsiveness to LPS effect with aging. J Immunol 116(2):294–300

    CAS  PubMed  Google Scholar 

  • Kishimoto S, Tomino S, Mitsuya H, Fujiwara H, Tsuda H (1980) Age-related decline in the in vitro and in vivo syntheses of anti-tetanus toxoid antibody in humans. J Immunol 125(5):2347–2352

    CAS  PubMed  Google Scholar 

  • Kleinschmidt S, Meneses F, Nolte I, Hewicker-Trautwein M (2008) Distribution of mast cell subtypes and immune cell populations in canine intestines: evidence for age-related decline in T cells and macrophages and increase of IgA-positive plasma cells. Res Vet Sci 84(1):41–48. doi:10.1016/j.rvsc.2007.03.009

    Article  CAS  PubMed  Google Scholar 

  • Koch G, Osmond DG, Julius MH, Benner R (1981) The mechanism of thymus-dependent antibody formation in bone marrow. J Immunol 126(4):1447–1451

    CAS  PubMed  Google Scholar 

  • Koch S, Larbi A, Ozcelik D, Solana R, Gouttefangeas C, Attig S, Wikby A, Strindhall J, Franceschi C, Pawelec G (2007) Cytomegalovirus infection: a driving force in human T cell immunosenescence. Ann N Y Acad Sci 1114:23–35. doi:10.1196/annals.1396.043

    Article  CAS  PubMed  Google Scholar 

  • Kohler S, Wagner U, Pierer M, Kimmig S, Oppmann B, Mowes B, Julke K, Romagnani C, Thiel A (2005) Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol 35(6):1987–1994. doi:10.1002/eji.200526181

    Article  CAS  PubMed  Google Scholar 

  • Kosco MH, Burton GF, Kapasi ZF, Szakal AK, Tew JG (1989) Antibody-forming cell induction during an early phase of germinal centre development and its delay with ageing. Immunology 68(3):312–318

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kovacs EJ, Palmer JL, Fortin CF, Fulop T Jr, Goldstein DR, Linton PJ (2009) Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol 30(7):319–324. doi:10.1016/j.it.2009.03.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuper CF, Beems RB, Bruijntjes JP, Schuurman HJ, Vos JG (1992) Normal development, growth, and aging of the thymus. In: Mohr U, Dungworth DL, Capen CC (eds) Pathobiology of the aging rat. ILSI Press, Washington DC, pp 25–48

    Google Scholar 

  • Lansdorp PM, Dragowska W, Thomas TE, Little MT, Mayani H (1994) Age-related decline in proliferative potential of purified stem cell candidates. Blood Cells 20(2–3):376–380 discussion 380–371

    CAS  PubMed  Google Scholar 

  • Lazuardi L, Jenewein B, Wolf AM, Pfister G, Tzankov A, Grubeck-Loebenstein B (2005) Age-related loss of naive T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes. Immunology 114(1):37–43. doi:10.1111/j.1365-2567.2004.02006.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lehrer RI, Ganz T, Selsted ME (1988a) Oxygen-independent bactericidal systems. Mechanisms and disorders. Hematol Oncol Clin North Am 2(1):159–169

    CAS  PubMed  Google Scholar 

  • Lehrer RI, Ganz T, Selsted ME, Babior BM, Curnutte JT (1988b) Neutrophils and host defense. Ann Intern Med 109(2):127–142

    Article  CAS  PubMed  Google Scholar 

  • Leng S, Xue QL, Huang Y, Semba R, Chaves P, Bandeen-Roche K, Fried L, Walston J (2005) Total and differential white blood cell counts and their associations with circulating interleukin-6 levels in community-dwelling older women. J Gerontol A Biol Sci Med Sci 60(2):195–199

    Article  PubMed  Google Scholar 

  • Leng SX, Xue QL, Tian J, Huang Y, Yeh SH, Fried LP (2009) Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: results from the Women’s Health and Aging Studies I. Exp Gerontol 44(8):511–516. doi:10.1016/j.exger.2009.05.005

    Article  PubMed  Google Scholar 

  • Lerner A, Yamada T, Miller RA (1989) Pgp-1hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A. Eur J Immunol 19(6):977–982

    Article  CAS  PubMed  Google Scholar 

  • Libby P (2002) Inflammation in atherosclerosis. Nature 420(6917):868–874. doi:10.1038/nature01323

    Article  CAS  PubMed  Google Scholar 

  • Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105(9):1135–1143

    Article  CAS  PubMed  Google Scholar 

  • Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5(2):133–139

    Article  CAS  PubMed  Google Scholar 

  • Linton PJ, Haynes L, Klinman NR, Swain SL (1996) Antigen-independent changes in naive CD4 T cells with aging. J Exp Med 184(5):1891–1900

    Article  CAS  PubMed  Google Scholar 

  • Lloberas J, Celada A (2002) Effect of aging on macrophage function. Exp Gerontol 37(12):1325–1331

    Article  CAS  PubMed  Google Scholar 

  • Looney RJ, Falsey A, Campbell D, Torres A, Kolassa J, Brower C, McCann R, Menegus M, McCormick K, Frampton M, Hall W, Abraham GN (1999) Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol 90(2):213–219. doi:10.1006/clim.1998.4638

    Article  CAS  PubMed  Google Scholar 

  • Losco P, Harleman J (1992) Normal development, growth and aging of the lymph node. In: Mohr U, Dungworth DL, Capen CC (eds) Pathobiology of the aging rat. ILSI Press, Washington DC, pp 49–73

    Google Scholar 

  • Maizels N, Bothwell A (1985) The T-cell-independent immune response to the hapten NP uses a large repertoire of heavy chain genes. Cell 43(3 Pt 2):715–720

    Article  CAS  PubMed  Google Scholar 

  • Mariani E, Neri S, Cattini L, Mocchegiani E, Malavolta M, Dedoussis GV, Kanoni S, Rink L, Jajte J, Facchini A (2008) Effect of zinc supplementation on plasma IL-6 and MCP-1 production and NK cell function in healthy elderly: interactive influence of +647 MT1a and -174 IL-6 polymorphic alleles. Exp Gerontol 43(5):462–471

    Article  CAS  PubMed  Google Scholar 

  • Mathur SK, Schwantes EA, Jarjour NN, Busse WW (2008) Age-related changes in eosinophil function in human subjects. Chest 133(2):412–419. doi:10.1378/chest.07-2114

    Article  PubMed  PubMed Central  Google Scholar 

  • McDonald Pavelka MS (1994) The nonhuman primate perspective: Old age, kinship and social partners in a monkey society. J Cross Cult Gerontol 9(2):219–229. doi:10.1007/BF00972151

    Article  CAS  PubMed  Google Scholar 

  • Miller C, Stedra J, Kelsoe G, Cerny J (1995) Facultative role of germinal centers and T cells in the somatic diversification of IgVH genes. J Exp Med 181(4):1319–1331

    Article  CAS  PubMed  Google Scholar 

  • Miller JP, Allman D (2003) The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J Immunol 171(5):2326–2330

    Article  CAS  PubMed  Google Scholar 

  • Miller RA (1991) Aging and immune function. Int Rev Cytol 124:187–215

    Article  CAS  PubMed  Google Scholar 

  • Miller RA (2000) Effect of aging on T lymphocyte activation. Vaccine 18(16):1654–1660

    Article  CAS  PubMed  Google Scholar 

  • Miyaji C, Watanabe H, Toma H, Akisaka M, Tomiyama K, Sato Y, Abo T (2000) Functional alteration of granulocytes, NK cells, and natural killer T cells in centenarians. Hum Immunol 61(9):908–916

    Article  CAS  PubMed  Google Scholar 

  • Mocchegiani E, Giacconi R, Cipriano C, Malavolta M (2009) NK and NKT cells in aging and longevity: role of zinc and metallothioneins. J Clin Immunol 29(4):416–425

    Article  CAS  PubMed  Google Scholar 

  • 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(1):87–93. doi:10.1002/ijc.20998

    Article  CAS  PubMed  Google Scholar 

  • Montagna W, Carlisle K (1990) Structural changes in ageing skin. Br J Dermatol 122(Suppl 35):61–70

    Article  PubMed  Google Scholar 

  • Moro-Garcia MA, Alonso-Arias R, Lopez-Larrea C (2013) When Aging Reaches CD4+ T-Cells: Phenotypic and Functional Changes. Front Immunol 4:107. doi:10.3389/fimmu.2013.00107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muller WA, Weigl SA, Deng X, Phillips DM (1993) PECAM-1 is required for transendothelial migration of leukocytes. J Exp Med 178(2):449–460

    Article  CAS  PubMed  Google Scholar 

  • Nagelkerken L, Hertogh-Huijbregts A, Dobber R, Drager A (1991) Age-related changes in lymphokine production related to a decreased number of CD45RBhi CD4+ T cells. Eur J Immunol 21(2):273–281. doi:10.1002/eji.1830210206

    Article  CAS  PubMed  Google Scholar 

  • Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174(11):7446–7452

    Article  CAS  PubMed  Google Scholar 

  • Naylor PH, McClure JE, Spangelo BL, Low TL, Goldstein AL (1984) Immunochemical studies on thymosin: radioimmunoassay of thymosin beta 4. Immunopharmacology 7(1):9–16

    Article  CAS  PubMed  Google Scholar 

  • Nguyen M, Pace AJ, Koller BH (2005) Age-induced reprogramming of mast cell degranulation. J Immunol 175(9):5701–5707

    Article  CAS  PubMed  Google Scholar 

  • Nicoletti C, Borghesi-Nicoletti C, Yang XH, Schulze DH, Cerny J (1991) Repertoire diversity of antibody response to bacterial antigens in aged mice. II. Phosphorylcholine-antibody in young and aged mice differ in both VH/VL gene repertoire and in specificity. J Immunol 147(8):2750–2755

    CAS  PubMed  Google Scholar 

  • Nicoletti C, Yang X, Cerny J (1993) Repertoire diversity of antibody response to bacterial antigens in aged mice. III Phosphorylcholine antibody from young and aged mice differ in structure and protective activity against infection with Streptococcus pneumoniae. J Immunol 150(2):543–549

    CAS  PubMed  Google Scholar 

  • Nikolich-Zugich J (2008) Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8(7):512–522. doi:10.1038/nri2318

    Article  CAS  PubMed  Google Scholar 

  • Nociari MM, Telford W, Russo C (1999) Postthymic development of CD28-CD8+ T cell subset: age-associated expansion and shift from memory to naive phenotype. J Immunol 162(6):3327–3335

    CAS  PubMed  Google Scholar 

  • Nomellini V, Faunce DE, Gomez CR, Kovacs EJ (2008a) An age-associated increase in pulmonary inflammation after burn injury is abrogated by CXCR2 inhibition. J Leukoc Biol 83(6):1493–1501

    Article  CAS  PubMed  Google Scholar 

  • Nomellini V, Gomez CR, Kovacs EJ (2008b) Aging and impairment of innate immunity. Contrib Microbiol 15:188–205. doi:10.1159/000136358

    Article  CAS  PubMed  Google Scholar 

  • O’Mahony L, Holland J, Jackson J, Feighery C, Hennessy TP, Mealy K (1998) Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production. Clin Exp Immunol 113(2):213–219

    Article  PubMed  PubMed Central  Google Scholar 

  • 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(3):392–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osman F, Romics I, Nyirady P, Monos E, Nadasy GL (2009) Ureteral motility. Acta Physiol Hung 96(4):407–426. doi:10.1556/APhysiol.96.2009.4.2

    Article  CAS  PubMed  Google Scholar 

  • Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC (2009) Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 30(7):325–333. doi:10.1016/j.it.2009.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfister G, Weiskopf D, Lazuardi L, Kovaiou RD, Cioca DP, Keller M, Lorbeg B, Parson W, Grubeck-Loebenstein B (2006) Naive T cells in the elderly: are they still there? Ann N Y Acad Sci 1067:152–157. doi:10.1196/annals.1354.018

    Article  CAS  PubMed  Google Scholar 

  • Pitcher CJ, Hagen SI, Walker JM, Lum R, Mitchell BL, Maino VC, Axthelm MK, Picker LJ (2002) Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168(1):29–43

    Article  CAS  PubMed  Google Scholar 

  • Plackett TP, Boehmer ED, Faunce DE, Kovacs EJ (2004) Aging and innate immune cells. J Leukoc Biol 76(2):291–299. doi:10.1189/jlb.1103592

    Article  CAS  PubMed  Google Scholar 

  • Plecas-Solarovic B, Pesic V, Radojevic K, Leposavic G (2006) Morphometrical characteristics of age-associated changes in the thymus of old male Wistar rats. Anat Histol Embryol 35(6):380–386. doi:10.1111/j.1439-0264.2006.00695.x

    Article  CAS  PubMed  Google Scholar 

  • Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S (2004) Innate immunity in aging: impact on macrophage function. Aging Cell 3(4):161–167. doi:10.1111/j.1474-9728.2004.00102.x

    Article  CAS  PubMed  Google Scholar 

  • Radford DJ, Wang K, McNelis JC, Taylor AE, Hechenberger G, Hofmann J, Chahal H, Arlt W, Lord JM (2010) Dehydroepiandrosterone sulfate directly activates protein kinase C-beta to increase human neutrophil superoxide generation. Mol Endocrinol 24(4):813–821. doi:10.1210/me.2009-0390

    Article  CAS  PubMed  Google Scholar 

  • Rudd CE, Schneider H (2003) Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol 3(7):544–556. doi:10.1038/nri1131

    Article  CAS  PubMed  Google Scholar 

  • Rudd CE, Taylor A, Schneider H (2009) CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 229(1):12–26. doi:10.1111/j.1600-065X.2009.00770.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sage PT, Tan CL, Freeman GJ, Haigis M, Sharpe AH (2015) Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging. Cell Rep. doi:10.1016/j.celrep.2015.06.015

    Google Scholar 

  • Sainte-Marie G, Peng FS (1986) Diffusion of a lymph-carried antigen in the fiber network of the lymph node of the rat. Cell Tissue Res 245(3):481–486

    Article  CAS  PubMed  Google Scholar 

  • Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, Telera A, Lucchini G, Passeri G, Monti D, Franceschi C, Passeri M (2008) The immune system in extreme longevity. Exp Gerontol 43(2):61–65. doi:10.1016/j.exger.2007.06.008

    Article  CAS  PubMed  Google Scholar 

  • Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, Parson W, Bock G, Schonitzer D, Trannoy E, Grubeck-Loebenstein B (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(11):5893–5899

    Article  CAS  PubMed  Google Scholar 

  • Savino W, Dardenne M, Bach JF (1983a) Thymic hormone containing cells. II. Evolution of cells containing the serum thymic factor (FTS or thymulin) in normal and autoimmune mice, as revealed by anti-FTS monoclonal antibodies. Relationship with Ia bearing cells. Clin Exp Immunol 52(1):1–6

    CAS  PubMed  PubMed Central  Google Scholar 

  • Savino W, Dardenne M, Bach JF (1983b) Thymic hormone containing cells. III. Evidence for a feed-back regulation of the secretion of the serum thymic factor (FTS) by thymic epithelial cells. Clin Exp Immunol 52(1):7–12

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schmucker DL, Owen RL, Outenreath R, Thoreux K (2003) Basis for the age-related decline in intestinal mucosal immunity. Clin Dev Immunol 10(2–4):167–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schuurman HJ, Van de Wijngaert FP, Delvoye L, Broekhuizen R, McClure JE, Goldstein AL, Kater L (1985) Heterogeneity and age dependency of human thymus reticulo-epithelium in production of thymosin components. Thymus 7(1):13–23

    CAS  PubMed  Google Scholar 

  • Sebastian C, Espia M, Serra M, Celada A, Lloberas J (2005) MacrophAging: a cellular and molecular review. Immunobiology 210(2–4):121–126. doi:10.1016/j.imbio.2005.05.006

    Article  CAS  PubMed  Google Scholar 

  • Sharp A, Kukulansky T, Globerson A (1990) In vitro analysis of age-related changes in the developmental potential of bone marrow thymocyte progenitors. Eur J Immunol 20(12):2541–2546

    Article  CAS  PubMed  Google Scholar 

  • Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM (2010) Aging of the innate immune system. Curr Opin Immunol 22(4):507–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith KG, Light A, Nossal GJ, Tarlinton DM (1997) The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response. EMBO J 16(11):2996–3006. doi:10.1093/emboj/16.11.2996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solana R, Alonso MC, Pena J (1999) Natural killer cells in healthy aging. Exp Gerontol 34(3):435–443

    Article  CAS  PubMed  Google Scholar 

  • Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18(16):1613–1620

    Article  CAS  PubMed  Google Scholar 

  • Spaulding C, Guo W, Effros RB (1999) Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 34(5):633–644

    Article  CAS  PubMed  Google Scholar 

  • Stefanski SA, Elwell MR, Stromberg PC (1990) Spleen, Lymph Nodes and Thymus. In: Boorman GA, Eustis SL, Elwell MR, Montgomery CA, MacKenzie WF (eds) Pathology of the Fischer Rat. Academic Press, San Diego, pp 369–393

    Google Scholar 

  • Stephens L, Ellson C, Hawkins P (2002) Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. Curr Opin Cell Biol 14(2):203–213

    Article  CAS  PubMed  Google Scholar 

  • Stout-Delgado HW, Du W, Shirali AC, Booth CJ, Goldstein DR (2009) Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection. Cell Host Microbe 6(5):446–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strobel S, Miller HR, Ferguson A (1981) Human intestinal mucosal mast cells: evaluation of fixation and staining techniques. J Clin Pathol 34(8):851–858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stuber E, Neurath M, Calderhead D, Fell HP, Strober W (1995) Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells. Immunity 2(5):507–521

    Article  CAS  PubMed  Google Scholar 

  • Stuber E, Strober W (1996) The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response. J Exp Med 183(3):979–989

    Article  CAS  PubMed  Google Scholar 

  • Sudo K, Ema H, Morita Y, Nakauchi H (2000) Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 192(9):1273–1280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swift ME, Burns AL, Gray KL, DiPietro LA (2001) Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 117(5):1027–1035. doi:10.1046/j.0022-202x.2001.01539.x

    Article  CAS  PubMed  Google Scholar 

  • Szakal AK, Kosco MH, Tew JG (1988) A novel in vivo follicular dendritic cell-dependent iccosome-mediated mechanism for delivery of antigen to antigen-processing cells. J Immunol 140(2):341–353

    CAS  PubMed  Google Scholar 

  • Szakal AK, Taylor JK, Smith JP, Kosco MH, Burton GF, Tew JJ (1990) Kinetics of germinal center development in lymph nodes of young and aging immune mice. Anat Rec 227(4):475–485. doi:10.1002/ar.1092270411

    Article  CAS  PubMed  Google Scholar 

  • Takahashi Y, Dutta PR, Cerasoli DM, Kelsoe G (1998) In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection. J Exp Med 187(6):885–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor LD, Daniels CK, Schmucker DL (1992) Ageing compromises gastrointestinal mucosal immune response in the rhesus monkey. Immunology 75(4):614–618

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tesar BM, Du W, Shirali AC, Walker WE, Shen H, Goldstein DR (2009) Aging augments IL-17 T-cell alloimmune responses. Am J Transplant 9(1):54–63. doi:10.1111/j.1600-6143.2008.02458.x

    Article  CAS  PubMed  Google Scholar 

  • Tortorella C, Simone O, Piazzolla G, Stella I, Antonaci S (2007) Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins. Ageing Res Rev 6(2):81–93. doi:10.1016/j.arr.2006.10.001

    Article  CAS  PubMed  Google Scholar 

  • Trivedi SG, Lloyd CM (2007) Eosinophils in the pathogenesis of allergic airways disease. Cell Mol Life Sci 64(10):1269–1289. doi:10.1007/s00018-007-6527-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsaknaridis L, Spencer L, Culbertson N, Hicks K, LaTocha D, Chou YK, Whitham RH, Bakke A, Jones RE, Offner H, Bourdette DN, Vandenbark AA (2003) Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity. J Neurosci Res 74(2):296–308. doi:10.1002/jnr.10766

    Article  CAS  PubMed  Google Scholar 

  • Tyan ML (1977) Age-related decrease in mouse T cell progenitors. J Immunol 118(3):846–851

    CAS  PubMed  Google Scholar 

  • Utsuyama M, Hirokawa K, Kurashima C, Fukayama M, Inamatsu T, Suzuki K, Hashimoto W, Sato K (1992) Differential age-change in the numbers of CD4+CD45RA+ and CD4+CD29+ T cell subsets in human peripheral blood. Mech Ageing Dev 63(1):57–68

    Article  CAS  PubMed  Google Scholar 

  • Valenzuela HF, Effros RB (2002) Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol 105(2):117–125

    Article  CAS  PubMed  Google Scholar 

  • Vallejo AN (2005) CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev 205:158–169. doi:10.1111/j.0105-2896.2005.00256.x

    Article  CAS  PubMed  Google Scholar 

  • Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM (1994) Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci U S A 91(21):9857–9860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Videla LA, Tapia G, Fernandez V (2001) Influence of aging on Kupffer cell respiratory activity in relation to particle phagocytosis and oxidative stress parameters in mouse liver. Redox Rep 6(3):155–159

    Article  CAS  PubMed  Google Scholar 

  • Weisel KC, Bautz F, Seitz G, Yildirim S, Kanz L, Mohle R (2009) Modulation of CXC chemokine receptor expression and function in human neutrophils during aging in vitro suggests a role in their clearance from circulation. Mediators Inflamm 2009:790174. doi:10.1155/2009/790174

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weiskopf D, Weinberger B, Grubeck-Loebenstein B (2009) The aging of the immune system. Transpl Int 22(11):1041–1050

    Article  CAS  PubMed  Google Scholar 

  • Weksler MC, Innes JD, Goldstein G (1978) Immunological studies of aging. IV The contribution of thymic involution to the immune deficiencies of aging mice and reversal with thymopoietin. J Exp Med 148(4):996–1006

    Article  CAS  PubMed  Google Scholar 

  • Weksler ME (2000) Changes in the B-cell repertoire with age. Vaccine 18(16):1624–1628

    Article  CAS  PubMed  Google Scholar 

  • Weksler ME, Hutteroth TH (1974) Impaired lymphocyte function in aged humans. J Clin Invest 53(1):99–104. doi:10.1172/JCI107565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weksler ME, Szabo P (2000) The effect of age on the B-cell repertoire. J Clin Immunol 20(4):240–249

    Article  CAS  PubMed  Google Scholar 

  • Weng NP (2006) Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24(5):495–499. doi:10.1016/j.immuni.2006.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wenisch C, Patruta S, Daxbock F, Krause R, Horl W (2000) Effect of age on human neutrophil function. J Leukoc Biol 67(1):40–45

    CAS  PubMed  Google Scholar 

  • Wessels I, Jansen J, Rink L, Uciechowski P (2010) Immunosenescence of polymorphonuclear neutrophils. ScientificWorldJournal 10:145–160

    Article  CAS  PubMed  Google Scholar 

  • Wick G, Jansen-Durr P, Berger P, Blasko I, Grubeck-Loebenstein B (2000) Diseases of aging. Vaccine 18(16):1567–1583

    Article  CAS  PubMed  Google Scholar 

  • Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B (2005) An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci 60(5):556–565

    Article  PubMed  Google Scholar 

  • Yagi T, Sato A, Hayakawa H, Ide K (1997) Failure of aged rats to accumulate eosinophils in allergic inflammation of the airway. J Allergy Clin Immunol 99(1 Pt 1):38–47

    Article  CAS  PubMed  Google Scholar 

  • Yajima N, Sakamaki K, Yonehara S (2004) Age-related thymic involution is mediated by Fas on thymic epithelial cells. Int Immunol 16(7):1027–1035. doi:10.1093/intimm/dxh104

    Article  CAS  PubMed  Google Scholar 

  • Yamano T, DeCicco LA, Rikans LE (2000) Attenuation of cadmium-induced liver injury in senescent male fischer 344 rats: role of Kupffer cells and inflammatory cytokines. Toxicol Appl Pharmacol 162(1):68–75

    Article  CAS  PubMed  Google Scholar 

  • Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, Chandler NB, Rodesch CK, Albertine KH, Petti CA, Weyrich AS, Zimmerman GA (2009) Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood 113(25):6419–6427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng B, Han S, Takahashi Y, Kelsoe G (1997) Immunosenescence and germinal center reaction. Immunol Rev 160:63–77

    Article  CAS  PubMed  Google Scholar 

  • Zinkernagel RM (1996) Immunology taught by viruses. Science 271(5246):173–178

    Article  CAS  PubMed  Google Scholar 

  • Zissel G, Schlaak M, Muller-Quernheim J (1999) Age-related decrease in accessory cell function of human alveolar macrophages. J Investig Med 47(1):51–56

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Charles River Laboratories, Inc., 4025 Stirrup Creek Drive, Durham, NC, 27703, USA

    George A. Parker

Authors
  1. George A. Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George A. Parker .

Editor information

Editors and Affiliations

  1. Charles River Laboratories, Inc. , Hillsborough, North Carolina, USA

    George A. Parker

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Parker, G.A. (2017). Aging of Immune System Organs. In: Parker, G. (eds) Immunopathology in Toxicology and Drug Development. Molecular and Integrative Toxicology. Humana Press, Cham. https://doi.org/10.1007/978-3-319-47377-2_5

Download citation

Publish with us

Policies and ethics

Search

Navigation