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Cited by 1,796T-cell and B-cell ImmunologyImmune responses and vaccinationsImmune Response and Inflammation

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

Open access
Simon, A. Katharina, Hollander, Georg A., McMichael, Andrew·2015·Proceedings of the Royal Society B: Biological Sciences
DOI 10.1098/rspb.2014.3085PMC PMC4707740
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Abstract

This article reviews the development of the immune response through neonatal, infant and adult life, including pregnancy, ending with the decline in old age. 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. It then goes into decline in old age. These changes are considered alongside the risks of different types of infection, autoimmune disease and malignancy.

AI snapshot

Written from the paper’s full text.

TL;DR

This review describes how the human immune system is immature at birth, matures with antigen exposure and immunological memory through childhood and adult life including pregnancy, then declines in old age. It links these changes to risks of infection, autoimmune disease, and malignancy.

Key findings

  • The newborn immune system is muted: complement components are 10–80% lower than adult levels, neonatal NK cytolytic function is about half adult level, Tregs are around 3% of CD4+ T cells at birth, and B1 cells comprise 40% of peripheral blood B cells at birth. Adaptive responses are skewed toward Th2/tolerance and poor T-cell-dependent antibody responses.
  • Immune maturation from childhood to adulthood is driven by infections, vaccinations, and the microbiome; approximately 20% of all lymphocytes reside in the gut. Historical UK infant mortality fell from 140 per 1000 in 1900 to 7 per 1000 by 2000, while many countries remain above 50 per 1000.
  • Pregnancy involves maternal immune modulation that tolerates the semi-allogeneic fetus, shifts toward Th2 responses, can remit autoimmune disease, and increases susceptibility to severe influenza complications.
  • Aging brings immune senescence: infection mortality is three times higher in elderly versus younger adults, about 90% of influenza-season excess deaths occur in people over 65, naive T cells decline with thymic involution, the CD4+:CD8+ ratio inverts, B cells become exhausted, innate responses decline, and inflammaging increases IL-1β, IL-6, IL-18, and TNFα. Cancer median diagnosis approaches age 70; one-third of Western humans develop cancer and 5–10% develop clinical autoimmune disease.

Methods

  • Narrative review, not a primary study; it synthesizes literature on immune development from fetal life through infancy, childhood, adulthood, pregnancy, and old age.
  • No systematic search strategy, sample, or primary data collection is described; evidence is drawn from cited human, animal, and in vitro studies.
  • Main analysis is a conceptual synthesis across the lifespan, supported by a schematic figure of immune responses and influenza mortality over age.

Limitations

  • The paper states that pregnancy immunology is beyond its detailed scope, that the cellular and molecular basis of immune senescence is still not well understood, and that most senescence data come from fibroblasts, though senescent immune cells probably show similar features.
  • Evident from the text: as a narrative review, it lacks a systematic search, quality appraisal, or quantitative synthesis, so conclusions depend on selected cited studies and reported numbers are illustrative rather than pooled estimates.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1098/rspb.2014.3085

Cites

110 of 110 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 100 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The function of all components of innate immunity is weak in newborns compared with later life.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Interpretationnone given

    The immune system goes into decline in old age.

    “It then goes into decline in old age.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Newborn pDC are severely limited in secreting interferon α/β upon exposure to different viruses, despite expressing TLR7 and TLR9 levels similar to adults.

    “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].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Premisenone given

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

    “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.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Low levels of CD21 impede responses to polysaccharide-complement complexes in neonates.

    “Furthermore, low levels of the receptor for complement C3d fragment (CD21) impede responses to polysaccharide–complement complexes [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim. 11
  • May combine two claims. 48

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More than 1600 genes are involved in innate and adaptive immune responses.

    “More than 1600 genes are involved in innate and adaptive immune responses [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The immune system is relatively immature at birth and evolves during life through childhood, adulthood including pregnancy, to old age.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    A child is born with an immature innate and adaptive immune system, which matures and acquires memory as he or she grows.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gut bacteria influence the development of Th17 cells, Treg cells and memory T cells.

    “Gut bacteria influence the development of Th17 cells [46], Treg cells [47] and memory T cells [48–50].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Over time, protection provided by the immune response increases, and young adults suffer fewer infections.

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

  • May combine two claims.

    Interpretationreasoning

    These T cells control the virus and their depletion can activate infection with devastating consequences.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Peripheral Treg represent around 3% of total CD4+ T cells at birth and persist for an extended period, giving early-life immune response an anti-inflammatory profile.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

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

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

  • May combine two claims.

    Premisecitation

    In preterm and newborn infants, classical monocytes and macrophages are immature, with reduced TLR4 expression and impaired innate signalling pathways, resulting in diminished cytokine responses compared with adults.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    These features contribute to blunted humoral immune responses with incomplete immunoglobulin class switching, although memory B cells are generated.

    “Together, these features contribute to blunted humoral immune responses with incomplete immunoglobulin class switching [35], although memory B cells are generated [36].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

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

    “Most childhood infections happen only once and then protection is lifelong.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

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

    “During childhood, Treg cell numbers decline, and memory Th1, Th17 and Th2 cells gradually increase to equal the number of naive T cells [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

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

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Newborn serum concentrations of almost all circulating complement components are 10-80% lower than in adults, with diminished biological activity.

    “Newborn serum concentrations of almost all circulating components are 10–80% lower than in adults [16], with diminished biological activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The memory persists into old age but then may fade.

    “The memory persists into old age [41] but then may fade.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cord blood contains fewer myeloid dendritic cells than blood from children or adults, and they express lower HLA class II, CD80 and CD86 and secrete low IL-12p70.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Newborn and especially premature infants have impaired neutrophil functions, putting them at risk of bacterial infections.

    “Consequently, the newborn, and especially premature infants, have impaired neutrophil functions [4], putting the child at risk of bacterial infections.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Foreign antigen activation of late fetal or neonatal T cells results in a response skewed towards Th2 immunity, reinforced by neonatal dendritic cells and epigenetic features.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Overall, the innate immune system is muted at birth, probably to tolerate maternal antigens and developmental stress/remodelling.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Changes in innate cell numbers occur with age, with skewing of haematopoiesis towards the myeloid lineages.

    “There are changes in innate cell numbers, with skewing of haematopoiesis towards the myeloid lineages [93,94].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    The ageing immune system fails to maintain full tolerance to self-antigens, with an increased incidence of autoimmune diseases.

    “At the same time, the ageing immune system fails to maintain full tolerance to self-antigens, with an increased incidence of autoimmune diseases. [88].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This is probably due to lymphopaenia occurring with age, leading to excess homeostatic lymphocyte proliferation, as well as decreased regulatory T-cell function and decreased clearance of apoptotic cells by macrophages.

    “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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    As a consequence of age-induced lymphopaenia, T cells proliferate and increase the virtual memory compartment, but the ability to establish immunological memory in response to de novo antigens is reduced, compromising vaccinations.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pregnant women can show remissions of autoimmune disease and are more susceptible to severe complications of influenza and some other infections.

    “Thus pregnant women can show remissions of autoimmune disease [75], and are more susceptible to severe complications of influenza [76] and some other infections.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The immune system can be over-reactive and cause autoimmune disease or allergy, a price paid for overall benefit.

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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

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

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

  • May combine two claims.

    Premisenone given

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

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

  • May combine two claims.

    Premisecitation

    Side effects of checkpoint therapy and passive transfer of anti-cancer T cells include autoimmune reactions, suggesting a balance between anti-self-immune reactions preventing cancer and causing autoimmunity.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

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

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Features at the trophoblast maternal interface and placenta subvert the normal graft rejection immune response, including non-polymorphic non-classical HLA antigens, local immune suppression by NK cells, monocytes and Tregs, and inhibition of T-cell activation by tryptophan catabolism.

    “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-”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The fading immune system in old age may ameliorate autoimmunity but at the expense of increased cancer risk.

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

  • May combine two claims.

    Interpretationnone given

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

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    As age advances, the immune system undergoes profound remodelling and decline, with major impact on health and survival.

    “As age advances, the immune system undergoes profound remodelling and decline, with major impact on health and survival [81,82].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The immune system protects against potentially lethal infections, controls persisting infections some of which can cause cancer, and can deal with mutant cells with malignant potential.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Many tumours turn off T cells specific for tumour antigens by binding to check-point receptors such as PD-1 or CTLA4, and treatments blocking these interactions have therapeutic potential.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [78] Pardoll DM 2012 Immunology beats cancer: a blueprint for successful translation. Nat. Immunol. 13, 1129– 1132. (10.1038/ni.2392) 23160205 PMC4659410

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expanded T-cell responses that keep latent viruses such as EBV and CMV under control reduce space for CD8+ T cells specific for other potentially lethal viruses, exacerbated by reduced thymic naive T-cell output.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Naive B cells are replaced by antigen-experienced memory cells, some exhausted, and display decreased affinity maturation and isotype switching.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Interpretationreasoning

    The general decline of the immune system probably prevails and tumours are no longer rejected as efficiently.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both the very young and old immune systems are 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.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Senescent cells have increased mitochondrial load/dysfunction and reactive oxygen species.

    “increased mitochondrial load/dysfunction and reactive oxygen species”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ageing macrophages and dendritic cells display reduced phagocytic function and HLA II expression.

    “Together with DCs, they display reduced phagocytic function and HLA II expression [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

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

    “End-stage senescent CD27−CD28− T cells have the shortest telomeres and show decreased proliferation after activation, but nevertheless exhibit potent effector functions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    As proposed by Hayflick, 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Hayflick L 2000 The future of ageing. Nature 408, 267– 269. (10.1038/35041709) 11089985

      Not checked in the free run.

    • Rests on an assumption: Massive ageing and advanced longevity are very recent phenomena occurring in an optimized environment.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

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

    “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).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

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

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

  • May combine two claims.

    Interpretationnone given

    Over the lifetime of an individual, 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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    When senescent cells were removed from aged mice artificially, the animals lived longer and were healthier.

    “Indeed, when senescent cells were removed from aged mice artificially, the animals lived longer and were healthier [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The resulting low-grade inflammation probably contributes to atherosclerosis, dementia and cancer, inextricably linking inflammation and ageing of other tissues.

    “The resulting low-grade inflammation probably contributes to atherosclerosis, dementia and cancer, inextricably linking inflammation and ageing of other tissues [84,98].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: There is an absence of a major selective pressure on humans beyond reproductive age.

  • May combine two claims.

    Interpretationreasoning

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

    “Oxidative stress causes DNA breaks and may be the cause of telomere attrition, which links the first two causes of ageing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim
55 of 55

  • The paper relies on this without support.

    Successful reproduction is of central evolutionary importance.

    “However, successful reproduction is of central evolutionary importance and there are immunological issues.”

  • The paper relies on this without support.

    The primary role of the immune system is probably to protect against infections.

    “The primary role of the immune system is probably to protect against infections.”

  • The paper relies on this without support.

    Microorganisms cause about a quarter of all cancers.

    “Microorganisms cause about a quarter of all cancers (e.g. EBV, hepatitis B and C viruses, human papilloma virus and Helicobacter pylori).”

  • The paper relies on this without support.

    In utero, the fetal environment demands that the immune system remains tolerant to maternal alloantigens.

    “In utero, the fetal environment demands that the immune system remains tolerant to maternal alloantigens.”

  • The paper relies on this without support.

    After birth, the sudden enormous exposure to environmental antigens calls for a rapid change to make distinct immune responses appropriate for early life.

    “After birth, the sudden enormous exposure to environmental antigens, many of them derived from intestinal commensal bacteria, calls for a rapid change to make distinct immune responses appropriate for early life.”

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    Infectious diseases are still the fourth most common cause of death among the elderly in the developed world.

    “Infectious diseases are still the fourth most common cause of death among the elderly in the developed world.”

  • The paper relies on this without support.

    During a regular influenza season, about 90% of the excess deaths occur in people aged over 65.

    “During a regular influenza season, about 90% of the excess deaths occur in people aged over 65.”

  • The paper relies on this without support.

    Cancer is most frequent in older people; the median age for cancer diagnosis in industrialized countries is approaching 70 years.

    “Cancer is most frequent in older people; the median age for cancer diagnosis in industrialized countries is approaching 70 years of age.”

  • The paper relies on this without support.

    In adult life, one-third of Western humans develop cancer, while 5–10% develop clinical autoimmune disease.

    “In adult life, the balance usually works, but one-third of Western humans develop cancer, usually later in life, while 5–10% develop clinical autoimmune disease, so the balance is finely set and may shift over time.”

  • The authors state this as an assumption.

    There is an absence of a major selective pressure on humans beyond reproductive age.

    “Assuming an absence of a major selective pressure on humans beyond reproductive age”

  • The paper relies on this without support.

    Massive ageing and advanced longevity are very recent phenomena occurring in an optimized environment.

    “Massive ageing and advanced longevity are very recent phenomena occurring in an optimized environment.”
12 of 12

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Prior to birth, babies lack significant antigenic exposure, have not acquired immunological memory, and their adaptive immunity is not fully developed.

    “Prior to birth, babies lack significant antigenic exposure and so have not yet acquired immunological memory and their adaptive immunity is not fully developed [5,10,11,19].”

    From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [19]

  • The innate immune system is functionally immature at birth.

    “The innate system is still functionally immature at birth, to allow the fetus to tolerate non-shared maternal antigens, but also so that it is not constantly triggered by the considerable amount of stress and remodeling that take place during development [19].”

    From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [19]

  • Young, non-pregnant adults seem well equipped to cope with immune challenges.

    “In general, young, non-pregnant adults seem to be well equipped to cope with immune challenges, which may reflect the procreative potential of young adults in the survival of the species [19].”

    From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [19]

  • As children grow, their immune systems continue to mature and acquire memory after exposure to multiple foreign challenges including pathogens, food, environmental components and vaccines.

    “As children grow and develop, their immune systems continue to mature and acquire memory after exposure to multiple foreign challenges including from pathogens, food and other environmental components and vaccines [19].”

    From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [19]

  • The incidence of autoimmune diseases increases in later life as the ageing immune system becomes unable to fully tolerate self-antigens.

    “The incidence of autoimmune diseases also increases in later life, as the ageing immune system becomes unable to fully tolerate self-antigens [19,37].”

    From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [19]

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Authors
Simon, A. K., Hollander, G. A., & McMichael, A.
Affiliations
  • University of Oxford (GB)
  • Department of Paediatrics, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Corresponding author
McMichael, Andrew
ORCID
Venue
Proceedings of the Royal Society B: Biological Sciences
Publisher
The Royal Society
Published
2015-12-22
Volume
282
Issue
1821
Pages
20143085
ISSN
  • 0080-4649 (ISSN-L)
  • 0962-8452
  • 1471-2954
DOI
10.1098/rspb.2014.3085
PMC
PMC4707740
OpenAlex
W2233660390
Cited by
1,796
References
110
Citations by year
2026: 106 · 2025: 185 · 2024: 183 · 2023: 195 · 2022: 212 · 2021: 275 · 2020: 254 · 2019: 150 · 2018: 135 · 2017: 70 · 2016: 25 · 2015: 2
FWCI
7.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the Royal Society B Biological Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
Funders
Wellcome Trust
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
immune system development, innate immunity, adaptive immunity, immunological memory, aging, immunosenescence, neonatal immunity, infant immunity, pregnancy, infection risk, autoimmune disease, cancer risk
MeSH terms
Aging, Autoimmune Diseases, Communicable Diseases, Biological Evolution, Female, Humans, Immune System, Immunity, Innate, Neoplasms, Pregnancy, Adaptive Immunity

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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