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

In the paper

“More than 1600 genes are involved in innate and adaptive immune responses [1].”

What the sources say

• Not checked yetcites [1] Abbas AR et al. 2005 Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes Immun. 6, 319– 331. (10.1038/sj.gene.6364173) 15789058

In the paper

“Yet the immune system is relatively immature at birth and has to evolve during a life of exposure to multiple foreign challenges through childhood, via young and mature adulthood (including pregnancy), to the decline of old age (figure 1).”

In the paper

“A picture emerges of a child born with an immature, innate and adaptive immune system, which matures and acquires memory as he or she grows.”

In the paper

“Gut bacteria influence the development of Th17 cells [46], Treg cells [47] and memory T cells [48–50].”

What the sources say

• Not checked yetcites [46] Yang Y et al. 2014 Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152– 156. (10.1038/nature13279) 24739972 PMC4128479 source
• Not checked yetcites [47] Ivanov II et al. 2009 Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485– 498. (10.1016/j.cell.2009.09.033) 19836068 PMC2796826 source
• 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
• Not checked yetcites [49] Round JL, O'Connell RM, Mazmanian SK 2010 Coordination of tolerogenic immune responses by the commensal microbiota. J. Autoimmun. 34, J220– J225. (10.1016/j.jaut.2009.11.007) 19963349 PMC3155383
• Not checked yetcites [50] Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM 2013 Virus-specific CD4+ memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373– 383. (10.1016/j.immuni.2012.10.021) 23395677 PMC3626102 source

In the paper

“Thus, over time, protection provided by the immune response increases, and young adults suffer fewer infections.”

In the paper

“These T cells are important because they control the virus and their depletion, for instance by immunosuppressive therapy, can activate the infection (e.g. Mtb, EBV, CMV), with devastating consequences.”

In the paper

“Peripheral Treg represent around 3% of total CD4+ T cells at birth [20] and these cells persist for an extended period of time [21], giving the early-life immune response an anti-inflammatory profile [22].”

What the sources say

• Not checked yetcites [20] Takahata Y, Nomura A, Takada H, Ohga S, Furuno K, Hikino S, Nakayama H, Sakaguchi S, Hara T 2004 CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Exp. Hematol. 32, 622– 629. (10.1016/j.exphem.2004.03.012) 15246158
• Not checked yetcites [21] Burlingham WJ et al. 1998 The effect of tolerance to noninherited maternal HLA antigens on the survival of renal transplants from sibling donors. N. Engl. J. Med. 339, 1657– 1664. (10.1056/NEJM199812033392302) 9834302
• Not checked yetcites [22] Mackroth MS, Malhotra I, Mungai P, Koech D, Muchiri E, King CL 2011 Human cord blood CD4+CD25hi regulatory T cells suppress prenatally acquired T cell responses to Plasmodium falciparum antigens. J. Immunol. 186, 2780– 2791. (10.4049/jimmunol.1001188) 21278348

In the paper

“Very early-life adaptive T-cell immunity is thus characterized by tolerogeneic reactivity, reduced allo-antigen recognition and poor responses to foreign antigens.”

In the paper

“In preterm and newborn infants, classical monocytes and macrophages are also immature. They have reduced TLR4 expression [5] with impaired innate signalling pathways [6–8], resulting in diminished cytokine responses compared with adults.”

What the sources say

• Not checked yetcites [5] Forster-Waldl E et al. 2005 Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging. Pediatr. Res. 58, 121– 124. (10.1203/01.PDR.0000163397.53466.0F) 15879290
• Not checked yetcites [6] Yan SR, Qing G, Byers DM, Stadnyk AW, Al-Hertani W, Bortolussi R 2004 Role of MyD88 in diminished tumor necrosis factor alpha production by newborn mononuclear cells in response to lipopolysaccharide. Infect. Immun. 72, 1223– 1229. (10.1128/IAI.72.3.1223-1229.2004) 14977922 PMC355999
• Not checked yetcites [7] Sadeghi K, Berger A, Langgartner M, Prusa AR, Hayde M, Herkner K, Pollak A, Spittler A, Forster-Waldl E 2007 Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling. J. Infect. Dis. 195, 296– 302. (10.1086/509892) 17191175
• Not checked yetcites [8] Al-Hertani W, Yan SR, Byers DM, Bortolussi R 2007 Human newborn polymorphonuclear neutrophils exhibit decreased levels of MyD88 and attenuated p38 phosphorylation in response to lipopolysaccharide. Clin. Invest. Med. 30, E44– E53. 17716541

In the paper

“Together, these features contribute to blunted humoral immune responses with incomplete immunoglobulin class switching [35], although memory B cells are generated [36].”

What the sources say

• Not checked yetcites [35] Haase C, Yu L, Eisenbarth G, Markholst H 2010 Antigen-dependent immunotherapy of non-obese diabetic mice with immature dendritic cells. Clin. Exp. Immunol. 160, 331– 339. (10.1111/j.1365-2249.2010.04104.x) 20180832 PMC2883103
• Not checked yetcites [36] Gatto D, Pfister T, Jegerlehner A, Martin SW, Kopf M, Bachmann MF 2005 Complement receptors regulate differentiation of bone marrow plasma cell precursors expressing transcription factors Blimp-1 and XBP-1. J. Exp. Med. 201, 993– 1005. (10.1084/jem.20042239) 15767369 PMC2213108

In the paper

“Most childhood infections happen only once and then protection is lifelong.”

In the paper

“During childhood, Treg cell numbers decline, and memory Th1, Th17 and Th2 cells gradually increase to equal the number of naive T cells [51].”

What the sources say

• Not checked yetcites [51] Shearer WT et al. 2003 Lymphocyte subsets in healthy children from birth through 18 years of age: the pediatric AIDS clinical trials group P1009 study. J. Allergy Clin. Immunol. 112, 973– 980. (10.1016/j.jaci.2003.07.003) 14610491

In the paper

“However, neonatal T cells differ significantly from adult cells, reflecting the fetal life, where exposure to foreign antigens is largely restricted to non-inherited maternal alloantigens.”

In the paper

“Newborn serum concentrations of almost all circulating components are 10–80% lower than in adults [16], with diminished biological activity.”

What the sources say

• Not checked yetcites [16] McGreal EP, Hearne K, Spiller OB 2012 Off to a slow start: under-development of the complement system in term newborns is more substantial following premature birth. Immunobiology 217, 176– 186. (10.1016/j.imbio.2011.07.027) 21868122

In the paper

“The memory persists into old age [41] but then may fade.”

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

In the paper

“Compared with blood from children or adults, cord blood contains fewer myeloid-type dendritic cells (mDC). They express lower cell surface levels of HLA class II, CD80 and CD86 than adult mDC [10]. They secrete low concentrations of IL-12p70 in response to activating innate stimuli [11].”

What the sources say

• Not checked yetcites [10] Willems F, Vollstedt S, Suter M 2009 Phenotype and function of neonatal DC. Eur. J. Immunol. 39, 26– 35. (10.1002/eji.200838391) 19137537
• Not checked yetcites [11] De Wit D, Tonon S, Olislagers V, Goriely S, Boutriaux M, Goldman M, Willems F 2003 Impaired responses to toll-like receptor 4 and toll-like receptor 3 ligands in human cord blood. J. Autoimmun. 21, 277– 281. (10.1016/j.jaut.2003.08.003) 14599853

In the paper

“Consequently, the newborn, and especially premature infants, have impaired neutrophil functions [4], putting the child at risk of bacterial infections.”

What the sources say

• Not checked yetcites [4] Filias A, Theodorou GL, Mouzopoulou S, Varvarigou AA, Mantagos S, Karakantza M 2011 Phagocytic ability of neutrophils and monocytes in neonates. BMC Pediatr. 11, 29 (10.1186/1471-2431-11-29) 21492472 PMC3094219

In the paper

“Foreign antigen activation of late fetal or neonatal T cells results in a response skewed towards Th2 immunity [23], which is reinforced by neonatal dendritic cells and epigenetic features [24,25].”

What the sources say

• Not checked yetcites [23] Holt PG 2004 The role of genetic and environmental factors in the development of T-cell mediated allergic disease in early life. Paediatr. Respir. Rev. 5, S27– S30. (10.1016/S1526-0542(04)90006-1) 14980239
• Not checked yetcites [24] Goriely S, Van Lint C, Dadkhah R, Libin M, De Wit D, Demonte D, Willems F, Goldman M 2004 A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. J. Exp. Med. 199, 1011– 1016. (10.1084/jem.20031272) 15051764 PMC2211877
• Not checked yetcites [25] Hebel K et al. 2014 CD4+ T cells from human neonates and infants are poised spontaneously to run a nonclassical IL-4 program. J. Immunol. 192, 5160– 5170. (10.4049/jimmunol.1302539) 24778440

In the paper

“Overall, the innate immune system is muted at birth, a price probably paid by the fetus not only to tolerate non-shared maternal antigens but also to ignore the considerable amount of stress and remodelling that takes place during development.”

In the paper

“There are changes in innate cell numbers, with skewing of haematopoiesis towards the myeloid lineages [93,94].”

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
• 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

In the paper

“At the same time, the ageing immune system fails to maintain full tolerance to self-antigens, with an increased incidence of autoimmune diseases. [88].”

What the sources say

• Not checked yetcites [88] Goronzy JJ, Weyand CM 2003 Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity—catalysts of autoimmunity and chronic inflammation. Arthritis Res. Ther. 5, 225– 234. (10.1186/ar974) 12932282 PMC193735

In the paper

“This is probably due to lymphopaenia occurring with age, leading to excess homeostatic lymphocyte proliferation [89], as well as a decrease in regulatory T-cell function and decreased clearance of apoptotic cells by macrophages [81].”

What the sources say

• Not checked yetcites [89] Sheu TT, Chiang BL, Yen JH, Lin WC 2014 Premature CD4+ T cell aging and its contribution to lymphopenia-induced proliferation of memory cells in autoimmune-prone non-obese diabetic mice. PLoS ONE 9, e89379 (10.1371/journal.pone.0089379) 24586733 PMC3935863
• 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

In the paper

“As a consequence of this age-induced lymphopaenia, T cells proliferate and increase the ‘virtual memory’ compartment [91], but at the same time, the ability to establish immunological memory in response to de novo antigens is reduced, compromising vaccinations.”

What the sources say

• Not checked yetcites [91] Akue AD, Lee JY, Jameson SC 2012 Derivation and maintenance of virtual memory CD8 T cells. J. Immunol. 188, 2516– 2523. (10.4049/jimmunol.1102213) 22308307 PMC3294185

In the paper

“Thus pregnant women can show remissions of autoimmune disease [75], and are more susceptible to severe complications of influenza [76] and some other infections.”

What the sources say

• Not checked yetcites [75] Ostensen M, Villiger PM 2007 The remission of rheumatoid arthritis during pregnancy. Semin. Immunopathol. 29, 185– 191. (10.1007/s00281-007-0072-5) 17621703
• Not checked yetcites [76] Memoli MJ, Harvey H, Morens DM, Taubenberger JK 2013 Influenza in pregnancy. Influenza Other Respir. Viruses 7, 1033– 1039. (10.1111/irv.12055) 23170853 PMC3582707

In the paper

“It can be over-reactive and cause autoimmune disease or allergy, a price paid for the overall benefit.”

In the paper

“Immune senescence also results in reactivation of latent viruses, such as varicella-zoster virus, causing shingles and chronic neuralgia.”

In the paper

“While peripheral B-cell numbers do not decline with age, the composition of this compartment changes.”

In the paper

“However, the side effects of such therapy and of the passive transfer of anti-cancer T cells include autoimmune reactions, suggesting a balance between anti-self-immune reactions preventing cancer and causing autoimmunity [79].”

What the sources say

• Not checked yetcites [79] Zhong S et al. 2013 T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy. Proc. Natl Acad. Sci. USA 110, 6973– 6978. (10.1073/pnas.1221609110) 23576742 PMC3637771

In the paper

“Functions such as cytokine production by CD4 and CD8 T cells are impaired, the expression of key surface markers is altered and the CD4+ to CD8+ T-cell ratio is inverted [81].”

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

In the paper

“There are features at the trophoblast maternal interface at the site of initial implantation and in the placenta that subvert the normal graft rejection immune response. These include expression only of non-polymorphic non-classical HLA antigens on the trophoblast [71], local immune suppression mediated by infiltrating NK cells [72], monocytes and T regulatory cells [69,73], and inhibition of T-”

What the sources say

• Not checked yetcites [71] Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R 1990 A class I antigen, HLA-G, expressed in human trophoblasts. Science 248, 220– 223. (10.1126/science.2326636) 2326636
• Not checked yetcites [72] Moffett A, Colucci F 2014 Uterine NK cells: active regulators at the maternal–fetal interface. J. Clin. Invest. 124, 1872– 1879. (10.1172/JCI68107) 24789879 PMC4001528
• Not checked yetcites [69] Erlebacher A 2013 Immunology of the maternal–fetal interface. Annu. Rev. Immunol. 31, 387– 411. (10.1146/annurev-immunol-032712-100003) 23298207
• Not checked yetcites [73] Aluvihare VR, Kallikourdis M, Betz AG 2004 Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 5, 266– 271. (10.1038/ni1037) 14758358

In the paper

“The fading immune system in old age (see below) may ameliorate autoimmunity but at the expense of increased cancer risk.”

In the paper

“As the individual gets older, he or she develops an expanding repertoire comprising memory T and B cells triggered by previous infections and vaccinations, but also a naive-memory repertoire shaped by exposure to the microbiome, food antigens and inhaled antigens.”

In the paper

“As age advances, the immune system undergoes profound remodelling and decline, with major impact on health and survival [81,82].”

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
• 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

In the paper

“It not only protects against potentially lethal infections but also controls a number of persisting infections, some of which have the potential to cause cancer. It can also deal with mutant cells that have potential for becoming malignant.”

In the paper

“Many tumours turn off T cells specific for tumour antigens by binding to ‘check-point’ receptors such as PD-1 or CTLA4, and new treatments that block these receptor–ligand interactions have great therapeutic potential [77,78].”

What the sources say

• Not checked yetcites [77] Topalian SL et al. 2012 Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443– 2454. (10.1056/NEJMoa1200690) 22658127 PMC3544539 source
• Not checked yetcites [78] Pardoll DM 2012 Immunology beats cancer: a blueprint for successful translation. Nat. Immunol. 13, 1129– 1132. (10.1038/ni.2392) 23160205 PMC4659410

In the paper

“The expanded T-cell responses that keep latent viruses such as EBV and CMV under control reduces space for CD8+ T cells specific for other potentially lethal viruses [92], exacerbated by the reduced thymic naive T-cell output.”

What the sources say

• Not checked yetcites [92] De Martinis M, Franceschi C, Monti D, Ginaldi L 2005 Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett. 579, 2035– 2039. (10.1016/j.febslet.2005.02.055) 15811314

In the paper

“Similar to T cells, naive B cells are replaced by antigen-experienced memory cells, some of which are ‘exhausted’ (CD19+IgD− CD27−), and they display decreased affinity maturation and isotype switching [81].”

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

In the paper

“This immune impairment is in apparent contradiction to the increase in autoimmunity as anti-tumour responses can be directed against self; however, the general decline of the immune system probably prevails and tumours are no longer rejected as efficiently.”

In the paper

“Both the very young and old immune systems are therefore similarly compromised in coping with a typical viral infection such as influenza, whereas the young (non-pregnant) adult organism seems to be perfectly equipped for this challenge (figure 1).”

In the paper

“increased mitochondrial load/dysfunction and reactive oxygen species”

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 immune system has been primarily moulded by evolution to respond efficiently to acute infections in young people, to adapt to pregnancy and to transmit protection to infants, and is adapted to cope with many chronic infections lasting for decades.”

In the paper

“Together with DCs, they display reduced phagocytic function and HLA II expression [81].”

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

In the paper

“End-stage senescent CD27−CD28− T cells have the shortest telomeres and show decreased proliferation after activation, but nevertheless exhibit potent effector functions.”

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

In the paper

“Both memory T cells and HSCs characteristically divide rarely, to minimize telomere attrition, but reliably either in response to infection (memory lymphocytes) or for tissue renewal (stem cells) throughout the entire lifespan.”

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

“As proposed by Hayflick [108], ageing may be an artefact of civilization, and hence changes in the ageing immune system might just be a consequence of evolutionary unpredicted antigenic exposure over the lifetime of an individual.”

What the sources say

• Not checked yetcites [108] Hayflick L 2000 The future of ageing. Nature 408, 267– 269. (10.1038/35041709) 11089985

In the paper

“The output of naive lymphoid cells and the ability to form new immunological memory becomes increasingly less important as the older individual will have encountered and established a memory bank to many pathogens over its lifetime.”

In the paper

“The evolution of the immune system within an individual possibly reflects the central role of the young adult in the survival of the species for its procreative potential.”

In the paper

“These features impact on mitotically active cells by depletion or arrested division (e.g. haematopoietic stem cells—HSCs or T cells), and on post-mitotic immune cells by causing cellular dysfunction (e.g. neutrophils).”

In the paper

“As a long-lived species, humans have evolved mechanisms of innate immunity and immunological memory to survive recurrent infections.”

In the paper

“However, over the lifetime of an individual, these immune mechanisms change, first to adapt to the change from fetus to infant, and then to mature and expand during growth, subtly changing in pregnancy and finally decreasing in senescence.”

In the paper

“Indeed, when senescent cells were removed from aged mice artificially, the animals lived longer and were healthier [96].”

What the sources say

• Not checked yetcites [96] Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM 2011 Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 479, 232– 236. (10.1038/nature10600) 22048312 PMC3468323 source

In the paper

“The resulting low-grade inflammation probably contributes to atherosclerosis, dementia and cancer, inextricably linking inflammation and ageing of other tissues [84,98].”

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
• Not checked yetcites [98] Gangemi S et al. 2003 Increased circulating Interleukin-18 levels in centenarians with no signs of vascular disease: another paradox of longevity? Exp. Gerontol. 38, 669– 672. (10.1016/S0531-5565(03)00061-5) 12814802

In the paper

“Assuming an absence of a major selective pressure on humans beyond reproductive age, we may have to pay for genetic traits selected to ensure early-life fitness by the later development of immunological phenotypes such as chronic inflammation.”

In the paper

“Oxidative stress causes DNA breaks and may be the cause of telomere attrition, which links the first two causes of ageing.”

In the paper

“In some aspects, the immune system of the aged organism resembles that of the newborn, with reduced antimicrobial activity by neutrophils and macrophages, reduced antigen presentation by DCs and decreased NK killing, and somewhat compromised adaptive lymphocyte responses.”