Evolution of the immune system in humans from infancy to old age

In the paper

“The main reason is obviously the accumulation of cellular and genetic damage throughout life; however, given the role of the immune response in controlling cancers, reduced immune functions in the elderly must contribute to the higher risk [90].”

What the sources say

• Partly supported

  The Abstract proposes that age-related immune dysfunction could impair cancer immunosurveillance and increase cancer occurrence. But it explicitly calls the extent of this contribution controversial, so the citing sentence’s assertion that reduced immune function “must contribute” is stronger than the source supports. (LLM, conf=0.88)

  cites [90] Derhovanessian E, Solana R, Larbi A, Pawelec G 2008 Immunity, ageing and cancer. Immun. Ageing 5, 11 (10.1186/1742-4933-5-11) 18816370 PMC2564902 sourceExperimental — accuracy not yet measured

In the paper

“These cells develop and mature during fetal life, but at different times, and the function of all components of innate immunity is weak in newborns compared with later life.”

What the sources say

• Not checked yetcites [3] Nussbaum C, Gloning A, Pruenster M, Frommhold D, Bierschenk S, Genzel-Boroviczeny O, von Andrian UH, Quackenbush E, Sperandio M 2013 Neutrophil and endothelial adhesive function during human fetal ontogeny. J. Leukoc. Biol. 93, 175– 184. (10.1189/jlb.0912468) 23233729 PMC4050519 source

In the paper

“It then goes into decline in old age.”

In the paper

“However, newborn pDC are severely limited in secreting interferon α/β upon exposure to different viruses, despite expressing levels of TLR7 and TLR9 that are similar to adults [13].”

What the sources say

• Not checked yetcites [13] Schuller SS et al. 2013 Preterm neonates display altered plasmacytoid dendritic cell function and morphology. J. Leukoc. Biol. 93, 781– 788. (10.1189/jlb.1011525) 23401600 source

In the paper

“Critical early protection against many infectious diseases previously experienced by the mother is given by the passive IgG antibody transferred from the mother transplacentally and in milk.”

In the paper

“Furthermore, low levels of the receptor for complement C3d fragment (CD21) impede responses to polysaccharide–complement complexes [34].”

What the sources say

• Not checked yetcites [34] Griffioen AW, Rijkers GT, Janssens-Korpela P, Zegers BJ 1991 Pneumococcal polysaccharides complexed with C3d bind to human B lymphocytes via complement receptor type 2. Infect. Immun. 59, 1839– 1845. 1826897 PMC257924 source

In the paper

“Together with the impaired innate immunity, the weak Th1 and antibody responses amply explain why neonatal mortality can be high under conditions of increased pathogen exposure.”

In the paper

“Although some of these memory T cells could have been stimulated by infections with specific pathogens and by vaccinations, many may be primed by the microbiome, not only in the gut but also in the respiratory tract and skin.”

In the paper

“B cells from neonates and infants aged less than 2 months show decreased somatic hypermutation compared with adults, limiting affinity maturation of antibodies [37].”

What the sources say

• Not checked yetcites [37] Ridings J, Dinan L, Williams R, Roberton D, Zola H 1998 Somatic mutation of immunoglobulin VH6 genes in human infants. Clin. Exp. Immunol. 114, 33– 39. (10.1046/j.1365-2249.1998.00694.x) 9764600 PMC1905087 source

In the paper

“Thus animal data support the notion that the microbiome shapes the development of both memory T and B cells.”

In the paper

“For example, though fetal naive CD4+ T cells respond strongly to alloantigens, they tend to develop towards Foxp3+ CD25+ regulatory T cells (Treg) through the influence of TGF-β [19], and thus actively promote self-tolerance.”

What the sources say

• Not checked yetcites [19] Mold JE, Venkatasubrahmanyam S, Burt TD, Michaelsson J, Rivera JM, Galkina SA, Weinberg K, Stoddart CA, McCune JM 2010 Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330, 1695– 1699. (10.1126/science.1196509) 21164017 PMC3276679 source

In the paper

“The CMV-specific CD8 T-cell response can result in oligoclonal T-cell expansions reaching more than 10% of circulating CD8 T cells.”

In the paper

“This makes the newborn, and particularly the premature baby, relatively susceptible to bacterial and viral infections.”

In the paper

“Finally, there is a failure of early-life bone marrow stromal cells to support long-term plasmablast survival and differentiation to plasma cells, so that any IgG antibodies elicited rapidly decline after immunization, unlike in older children and adults [38].”

What the sources say

• Not checked yetcites [38] Pihlgren M, Friedli M, Tougne C, Rochat AF, Lambert PH, Siegrist CA 2006 Reduced ability of neonatal and early-life bone marrow stromal cells to support plasmablast survival. J. Immunol. 176, 165– 172. (10.4049/jimmunol.176.1.165) 16365407 source

In the paper

“Hence, the efficiency of the adaptive immune system to respond to T-cell-dependent antigens early is markedly impaired in neonates compared with older children and adults.”

In the paper

“The immune system gradually matures during infancy.”

In the paper

“The maintenance of long-term B-cell memory is remarkable given that IgG immunoglobulin has a half-life in vivo of around 25 days [61].”

What the sources say

• Not checked yetcites [61] Hinton PR, Xiong JM, Johlfs MG, Tang MT, Keller S, Tsurushita N 2006 An engineered human IgG1 antibody with longer serum half-life. J. Immunol. 176, 346– 356. (10.4049/jimmunol.176.1.346) 16365427 source

In the paper

“However, neonatal B cells express low levels of these co-receptors, limiting their capacity to respond [33].”

What the sources say

• Not checked yetcites [33] Kaur K, Chowdhury S, Greenspan NS, Schreiber JR 2007 Decreased expression of tumor necrosis factor family receptors involved in humoral immune responses in preterm neonates. Blood 110, 2948– 2954. (10.1182/blood-2007-01-069245) 17634409 source

In the paper

“EBV, CMV and Mtb provoke very strong CD4 and CD8 T-cell responses in humans.”

In the paper

“Consequently, innate immune responses to viruses such as respiratory syncytial virus, herpes simplex virus and cytomegalovirus are poor compared with later in life.”

In the paper

“Besides promoting recovery, such antigen stimulation results in immunological memory [41,42].”

What the sources say

• Not checked yetcites [41] Walker JM, Slifka MK 2010 Longevity of T-cell memory following acute viral infection. Adv. Exp. Med. Biol. 684, 96– 107. (10.1007/978-1-4419-6451-9_8) 20795543 source
• Not checked yetcites [42] Zinkernagel RM 2000 On immunological memory. Phil. Trans. R. Soc. Lond. B 355, 369– 371. (10.1098/rstb.2000.0576) 10794057 PMC1692736 source

In the paper

“As a result of an immune challenge, the responding T and B cells may expand transiently to very high numbers [65], sometimes more than 10% of all circulating T cells, but these decline rapidly as a result of activation-induced cell death and from attrition over a longer time period.”

What the sources say

• Not checked yetcites [65] Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, O'Callaghan CA, Steven N, McMichael AJ, Rickinson AB 1998 Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein–Barr virus in vivo. J. Exp. Med. 187, 1395– 1402. (10.1084/jem.187.9.1395) 9565632 PMC2212279 source

In the paper

“It is remarkable that a mother can transfer sufficient antibody to protect her infant when she was infected 20–30 years previously.”

In the paper

“Paradoxically, a mother who avoided a dangerous childhood infection, through herd immunity, may actually put her child at risk by being unable to transfer specific protective antibodies.”

In the paper

“These primed memory T cells may respond to subsequent infections through cross-reactions [48,52,53].”

What the sources say

• Not checked yetcites [48] Campion SL, Brodie TM, Fischer W, Korber BT, Rossetti A, Goonetilleke N, McMichael AJ, Sallusto F 2014 Proteome-wide analysis of HIV-specific naive and memory CD4+ T cells in unexposed blood donors. J. Exp. Med. 211, 1273– 1280. (10.1084/jem.20130555) 24958850 PMC4076590 source
• Not checked yetcites [52] Selin LK, Nahill SR, Welsh RM 1994 Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses. J. Exp. Med. 179, 1933– 1943. (10.1084/jem.179.6.1933) 8195718 PMC2191532 source
• Not checked yetcites [53] Su ZJ, Chen HB, Zhang JK, Xu L 2005 Effects of dendritic cells from cord blood CD34+ cells on human hepatocarcinoma cell line BEL-7402 in vitro and in SCID mice. World J. Gastroenterol. 11, 2502– 2507. (10.3748/wjg.v11.i16.2502) 15832426 PMC4305643 source

In the paper

“Given the great complexity of the T- and B-cell repertoires and a large stochastic element in choosing which cells will respond to a given stimulus, and somatic mutations in B cells, the precise composition will differ in each individual, even in monozygotic twins [66].”

What the sources say

• Not checked yetcites [66] Hawes GE, Struyk L, van den Elsen PJ 1993 Differential usage of T cell receptor V gene segments in CD4+ and CD8+ subsets of T lymphocytes in monozygotic twins. J. Immunol. 150, 2033– 2045. 8436833 source

In the paper

“Deterioration of the immune system with age may compromise the homeostatic equilibrium between microbiota and host.”

In the paper

“However, if immunity is impaired through ageing (see below), immunosuppressive therapy or certain infections, particularly HIV-1, these cancers emerge [80].”

What the sources say

• Not checked yetcites [80] Morath C, Mueller M, Goldschmidt H, Schwenger V, Opelz G, Zeier M 2004 Malignancy in renal transplantation. J. Am. Soc. Nephrol 15, 1582– 1588. (10.1097/01.ASN.0000126194.77004.9B) 15153569 source

In the paper

“Furthermore, aberrant immune responses in the aged can exacerbate inflammation, possibly contributing to other scourges of old age: cancer, cardiovascular disease, stroke, Alzheimer's disease and dementia [84].”

What the sources say

• Not checked yetcites [84] Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C 2009 Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res. Rev. 8, 18– 30. (10.1016/j.arr.2008.07.002) 18692159 PMC3782993 source

In the paper

“This immune senescence predisposes older adults to a higher risk of acute viral and bacterial infections.”

In the paper

“Specific T-cell responses normally hold these microbes in check.”

In the paper

“Add to this considerable genetic variability in how individuals respond, determined by the highly polymorphic HLA genes [67] and by the genes of innate immunity, and it is not surprising that the immune responses of any single adult vary considerably.”

What the sources say

• Not checked yetcites [67] Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC 1987 The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329, 512– 518. (10.1038/329512a0) 2443855 source

In the paper

“Thus as the pathogen is controlled and disappears, some memory T and B cells persist for a long time in numbers that far exceed the number of naive and ‘naive-memory’ T cells that were there before infection.”

In the paper

“Moreover, the increased inflammation found with age facilitates cancer emergence.”

In the paper

“The increase with age in pro-inflammatory pathobionts and the decrease in immune-modulatory species may promote and sustain inflammatory disorders [86].”

What the sources say

• Not checked yetcites [86] Biagi E, Candela M, Turroni S, Garagnani P, Franceschi C, Brigidi P 2013 Ageing and gut microbes: perspectives for health maintenance and longevity. Pharmacol. Res. 69, 11– 20. (10.1016/j.phrs.2012.10.005) 23079287 source

In the paper

“In general, the changes in the T- and B-cell compartments hamper the adequate immune response to new acute and latent viral infections and vaccinations.”

In the paper

“The increased morbidity due to the decline of the immune system is a direct consequence of dysregulated adaptive immunity in the elderly.”

In the paper

“Furthermore, poor immune responses account for diminished efficacy of vaccines [82,85].”

What the sources say

• Not checked yetcites [82] Jiang N et al. 2013 Lineage structure of the human antibody repertoire in response to influenza vaccination. Sci. Transl. Med. 5, 171ra19. (10.1126/scitranslmed.3004794) PMC3699344 23390249 source
• Not checked yetcites [85] Treanor JJ et al. 2012 Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains. Clin. Infect. Dis. 55, 951– 959. (10.1093/cid/cis574) 22843783 PMC3657521 source

In the paper

“This immune modulation, necessary for the well-being of the fetus, can occasionally be harmful to the mother.”

In the paper

“There is evidence that the mother changes the balance of her T-cell responses to Th2 rather than Th1 [68].”

What the sources say

• Not checked yetcites [68] Mor G, Cardenas I 2010 The immune system in pregnancy: a unique complexity. Am. J. Reprod. Immunol. 63, 425– 433. (10.1111/j.1600-0897.2010.00836.x) 20367629 PMC3025805 source

In the paper

“Moreover, deviations from the intestinal microbiota profile, which was established in youth, are associated with inflammatory bowel disease [87].”

What the sources say

• Not checked yetcites [87] Maslowski KM, Mackay CR 2011 Diet, gut microbiota and immune responses. Nat. Immunol. 12, 5– 9. (10.1038/ni0111-5) 21169997 source

In the paper

“Thus reduced bacterial diversity in the gut has been correlated with Clostridium difficile-associated diarrhoea, a major complication for the elderly in hospitals [86].”

What the sources say

• Not checked yetcites [86] Biagi E, Candela M, Turroni S, Garagnani P, Franceschi C, Brigidi P 2013 Ageing and gut microbes: perspectives for health maintenance and longevity. Pharmacol. Res. 69, 11– 20. (10.1016/j.phrs.2012.10.005) 23079287 source

In the paper

“The low number of naive T cells versus T cells [41,42] is a consequence of the reduced thymic output from the involuted thymus.”

What the sources say

• Not checked yetcites [41] Walker JM, Slifka MK 2010 Longevity of T-cell memory following acute viral infection. Adv. Exp. Med. Biol. 684, 96– 107. (10.1007/978-1-4419-6451-9_8) 20795543 source
• Not checked yetcites [42] Zinkernagel RM 2000 On immunological memory. Phil. Trans. R. Soc. Lond. B 355, 369– 371. (10.1098/rstb.2000.0576) 10794057 PMC1692736 source

In the paper

“A bigger puzzle is how the mother tolerates a semi-allogeneic graft without rejecting it and without the immunosuppression necessary to accept an organ transplant [70].”

What the sources say

• Not checked yetcites [70] Medawar P 1952 Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp. Soc. Exp. Biol. 7, 320– 338.

In the paper

“The innate immune response also declines with age.”

What the sources say

• Not checked yetcites [93] Tang Q, Koh LK, Jiang D, Schwarz H 2013 CD137 ligand reverse signaling skews hematopoiesis towards myelopoiesis during aging. Aging 5, 643– 652. 23945137 PMC3808697 source
• Not checked yetcites [94] Wang J, Geiger H, Rudolph KL 2011 Immunoaging induced by hematopoietic stem cell aging. Curr. Opin. Immunol. 23, 532– 536. (10.1016/j.coi.2011.05.004) 21872769 source
• Not checked yetcites [95] Fulop T Jr, Foris G, Worum I, Leovey A 1985 Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes. Clin. Exp. Immunol. 61, 425– 432. 2994926 PMC1577299
• Not checked yetcites [81] Weiskopf D, Weinberger B, Grubeck-Loebenstein B 2009 The aging of the immune system. Transplant Int. 22, 1041– 1050. (10.1111/j.1432-2277.2009.00927.x) 19624493 source

In the paper

“Moreover, the mortality rates of these infections are three times higher among elderly patients compared with younger adult patients [83].”

What the sources say

• Not checked yetcites [83] Yoshikawa TT 2000 Epidemiology and unique aspects of aging and infectious diseases. Clin. Infect. Dis. 30, 931– 933. (10.1086/313792) 10880303 source

In the paper

“Autophagy, degrading bulk cytoplasmic material by delivering it to the lysosomes, falls with age, including in human CD8+ T cells [105].”

What the sources say

• Not checked yetcites [105] Phadwal K et al. 2012 A novel method for autophagy detection in primary cells: impaired levels of macroautophagy in immunosenescent T cells. Autophagy 8, 677– 689. (10.4161/auto.18935) 22302009 PMC3405842 source

In the paper

“Possibly the most critical change in the ageing innate immune system is the increase in pro-inflammatory cytokines IL-1β, IL-6, IL-18 and TNFα [97].”

What the sources say

• Not checked yetcites [97] Franceschi C et al. 2007 Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92– 105. (10.1016/j.mad.2006.11.016) 17116321 source

In the paper

“Mice without autophagy in their haematopoietic system display a prematurely aged haematopoietic system [106].”

What the sources say

• Not checked yetcites [106] Mortensen M et al. 2011 The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455– 467. (10.1084/jem.20101145) 21339326 PMC3058574 source

In the paper

“telomere attrition accompanying each round of proliferation, leading to arrested cell division or ‘replicative senescence’”

What the sources say

• Not checked yetcites [99] Coppe JP, Desprez PY, Krtolica A, Campisi J 2010 The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99– 118. (10.1146/annurev-pathol-121808-102144) 20078217 PMC4166495 source

In the paper

“The immunological ‘silent’ removal of apoptotic and increasing numbers of senescent cells is therefore compromised”

In the paper

“While most of the data have been obtained in fibroblasts, senescent immune cells probably show similar features.”

In the paper

“The senescent neutrophil is less functional with decreased phagocytic ability and superoxide production partly due to decreased Fcγ receptor expression [95].”

What the sources say

• Not checked yetcites [95] Fulop T Jr, Foris G, Worum I, Leovey A 1985 Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes. Clin. Exp. Immunol. 61, 425– 432. 2994926 PMC1577299

In the paper

“The accumulation of oxidative damage could be due to a decline in lysosomal and autophagy function [104].”

What the sources say

• Not checked yetcites [104] Cuervo AM, Macian F 2014 Autophagy and the immune function in aging. Curr. Opin. Immunol. 29, 97– 104. (10.1016/j.coi.2014.05.006) 24929664 PMC4119564 source

In the paper

“Failing memory T cells' responses to flu vaccination observed in the elderly can be restored with an autophagy-inducing compound [107].”

What the sources say

• Not checked yetcites [107] Puleston DJ et al. 2014 Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 3, e03706 (10.7554/eLife.03706) PMC4225493 25385531 source

In the paper

“These cells accumulate in old age and in patients with autoimmune diseases and chronic viral infections [102].”

What the sources say

• Not checked yetcites [102] Akbar AN, Vukmanovic-Stejic M 2007 Telomerase in T lymphocytes: use it and lose it? J. Immunol. 178, 6689– 6694. (10.4049/jimmunol.178.11.6689) 17513711 source

In the paper

“A third more recent addition to these fundamental changes of aged cells is the acquisition of the SASP, contributing to increased pro-inflammatory cytokine secretion and low-grade inflammation [99].”

What the sources say

• Not checked yetcites [99] Coppe JP, Desprez PY, Krtolica A, Campisi J 2010 The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99– 118. (10.1146/annurev-pathol-121808-102144) 20078217 PMC4166495 source

In the paper

“Similarly, ageing macrophages have a decreased respiratory burst.”

What the sources say

• Not checked yetcites [81] Weiskopf D, Weinberger B, Grubeck-Loebenstein B 2009 The aging of the immune system. Transplant Int. 22, 1041– 1050. (10.1111/j.1432-2277.2009.00927.x) 19624493 source

In the paper

“Attrition of telomeres is a protective mechanism against cancer, as each round of proliferation is likely to introduce mutations [100].”

What the sources say

• Not checked yetcites [100] Hayflick L 2000 The illusion of cell immortality. Br. J. Cancer 83, 841– 846. (10.1054/bjoc.2000.1296) 10970682 PMC2374692 source

In the paper

“The second characteristic of aged cells is increased mitochondrial dysfunction and ensuing oxidative damage to proteins and DNA.”

What the sources say

• Not checked yetcites [103] Cannizzo ES et al. 2012 Age-related oxidative stress compromises endosomal proteostasis. Cell Rep. 2, 136– 149. (10.1016/j.celrep.2012.06.005) 22840404 PMC3408590 source
• Not checked yetcites [104] Cuervo AM, Macian F 2014 Autophagy and the immune function in aging. Curr. Opin. Immunol. 29, 97– 104. (10.1016/j.coi.2014.05.006) 24929664 PMC4119564 source

In the paper

“Only epithelial lymphocytes and stem cells including haemopoietic (HSCs) express the telomere-lengthening enzyme telomerase in the adult [101]”

What the sources say

• Not checked yetcites [101] Blackburn EH 2005 Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett. 579, 859– 862. (10.1016/j.febslet.2004.11.036) 15680963 source

In the paper

“DC function in aged mice can be restored through administration of anti-oxidants [103].”

What the sources say

• Not checked yetcites [103] Cannizzo ES et al. 2012 Age-related oxidative stress compromises endosomal proteostasis. Cell Rep. 2, 136– 149. (10.1016/j.celrep.2012.06.005) 22840404 PMC3408590 source

In the paper

“and may contribute to the pro-inflammatory phenotype.”