Inborn Errors of Adaptive Immunity in Down Syndrome

Abstract

Down syndrome fits an immunophenotype of combined immunodeficiency with immunodysregulation, manifesting with increased susceptibility to infections, autoimmunity, autoinflammatory diseases, and hematologic malignancies. Qualitative and quantitative alterations in innate and adaptive immunity are found in most individuals with Down syndrome. However, there is substantial heterogeneity and no correlation between immunophenotype and clinical presentation. Previously, it was thought that the immunological changes in Down syndrome were caused by precocious aging. We emphasize in this review that the immune system in Down syndrome is intrinsically different from the very beginning. The overexpression of specific genes located on chromosome 21 contributes to immunodeficiency and immunodysregulation, but gene expression differs between genes located on chromosome 21 and depends on tissue and cell type. In addition, trisomy 21 results in gene dysregulation of the whole genome, reflecting the complex nature of this syndrome in comparison to well-known inborn errors of immunity that result from monogenic germline mutations. In this review, we provide an updated overview focusing on inborn errors of adaptive immunity in Down syndrome.

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

Fig. 1
Fig. 2

References

  1. 1.

    Verstegen RHJ, Chang KJJ, Kusters MAA. Clinical implications of immune-mediated diseases in children with Down syndrome. Pediatric allergy and immunology: official publication of the European Society of Pediatric Allergy and Immunology. 2020;31:117–23. https://doi.org/10.1111/pai.13133.

    Article  Google Scholar 

  2. 2.

    Schieve LA, Boulet SL, Boyle C, Rasmussen SA, Schendel D. Health of children 3 to 17 years of age with Down syndrome in the 1997-2005 national health interview survey. Pediatrics. 2009;123:e253–60. https://doi.org/10.1542/peds.2008-1440.

    Article  PubMed  Google Scholar 

  3. 3.

    Verstegen RH, van Hout RW, de Vries E. Epidemiology of respiratory symptoms in children with Down syndrome: a nationwide prospective web-based parent-reported study. BMC Pediatr. 2014;14:103. https://doi.org/10.1186/1471-2431-14-103.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Manikam L et al. Respiratory tract infection-related healthcare utilisation in children with Down’s syndrome. Infection. 2020. https://doi.org/10.1007/s15010-020-01408-5 .

  5. 5.

    Beckhaus AA, Castro-Rodriguez JA. Down syndrome and the risk of severe RSV infection: a meta-analysis. Pediatrics. 2018. https://doi.org/10.1542/peds.2018-0225.

  6. 6.

    Englund A, Jonsson B, Zander CS, Gustafsson J, Anneren G. Changes in mortality and causes of death in the Swedish Down syndrome population. Am J Med Genet. 2013;A161a:642–9. https://doi.org/10.1002/ajmg.a.35706.

  7. 7.

    Day SM, Strauss DJ, Shavelle RM, Reynolds RJ. Mortality and causes of death in persons with Down syndrome in California. Dev Med Child Neurol. 2005;47:171–6.

    Article  Google Scholar 

  8. 8.

    Guffroy A, Dieudonné Y, Uring-Lambert B, Goetz J, Alembik Y, Korganow AS. Infection risk among adults with down syndrome: a two group series of 101 patients in a tertiary center. Orphanet J Rare Dis. 2019;14:15. https://doi.org/10.1186/s13023-018-0989-x.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Nikolaev SI, Garieri M, Santoni F, Falconnet E, Ribaux P, Guipponi M, et al. Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations. Nat Commun. 2014;5:4654. https://doi.org/10.1038/ncomms5654.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hasle H, Friedman JM, Olsen JH, Rasmussen SA. Low risk of solid tumors in persons with Down syndrome. Genetics in medicine: official journal of the American College of Medical Genetics. 2016;18:1151–7. https://doi.org/10.1038/gim.2016.23.

    Article  Google Scholar 

  11. 11.

    Satge D, Seidel MG. The pattern of malignancies in Down syndrome and its potential context with the immune system. Front Immunol. 2018;9:3058. https://doi.org/10.3389/fimmu.2018.03058.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bull MJ. Health supervision for children with Down syndrome. Pediatrics. 2011;128:393–406. https://doi.org/10.1542/peds.2011-1605.

    Article  PubMed  Google Scholar 

  13. 13.

    McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med. 2006;3:e297. https://doi.org/10.1371/journal.pmed.0030297.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Veraldi S, Guanziroli E, Benzecry V, Nazzaro G. Hidradenitis suppurativa in patients with Down syndrome. J Eur Acad Dermatol Venereol. 2019;33(Suppl 6):34–5. https://doi.org/10.1111/jdv.15822.

    Article  PubMed  Google Scholar 

  15. 15.

    Foley CM, Deely DA, MacDermott EJ, Killeen OG. Arthropathy of Down syndrome: an under-diagnosed inflammatory joint disease that warrants a name change. RMD Open. 2019;5:e000890. https://doi.org/10.1136/rmdopen-2018-000890.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Lai F, Williams RS. A prospective study of Alzheimer disease in Down syndrome. Arch Neurol. 1989;46:849–53.

    CAS  Article  Google Scholar 

  17. 17.

    Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019;15:135–47. https://doi.org/10.1038/s41582-018-0132-6.

    Article  PubMed  Google Scholar 

  18. 18.

    Wilcock DM, Hurban J, Helman AM, Sudduth TL, McCarty KL, Beckett TL, et al. Down syndrome individuals with Alzheimer’s disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer’s disease. Neurobiol Aging. 2015;36:2468–74. https://doi.org/10.1016/j.neurobiolaging.2015.05.016.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Tangye SG, et al. Human Inborn Errors of Immunity: 2019 Update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020. https://doi.org/10.1007/s10875-019-00737-x.

  20. 20.

    Pelleri MC, Cattani C, Vitale L, Antonaros F, Strippoli P, Locatelli C, et al. Integrated quantitative transcriptome maps of human trisomy 21 tissues and cells. Front Genet. 2018;9:125. https://doi.org/10.3389/fgene.2018.00125.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Li CM, Guo M, Salas M, Schupf N, Silverman W, Zigman WB, et al. Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21. BMC medical genetics. 2006;7:24. https://doi.org/10.1186/1471-2350-7-24.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Mao R, Wang X, Spitznagel EL Jr, Frelin LP, Ting JC, Ding H, et al. Primary and secondary transcriptional effects in the developing human down syndrome brain and heart. Genome Biol. 2005;6:R107. https://doi.org/10.1186/gb-2005-6-13-r107.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Letourneau A, Santoni FA, Bonilla X, Sailani MR, Gonzalez D, Kind J, et al. Domains of genome-wide gene expression dysregulation in Down’s syndrome. Nature. 2014;508:345–50. https://doi.org/10.1038/nature13200.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Antonarakis SE. Down syndrome and the complexity of genome dosage imbalance. Nat Rev Genet. 2017;18:147–63. https://doi.org/10.1038/nrg.2016.154.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Xu Y, Li W, Liu X, Chen H, Tan K, Chen Y, et al. Identification of dysregulated microRNAs in lymphocytes from children with Down syndrome. Gene. 2013;530:278–86. https://doi.org/10.1016/j.gene.2013.07.055.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Moreira-Filho CA, et al. Modular transcriptional repertoire and microRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants. Oncotarget. 2016;7:7497–533. https://doi.org/10.18632/oncotarget.7120.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Elton TS, Sansom SE, Martin MM. Trisomy-21 gene dosage over-expression of miRNAs results in the haploinsufficiency of specific target proteins. RNA Biol. 2010;7:540–7. https://doi.org/10.4161/rna.7.5.12685.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Baltimore D, Boldin MP, O'Connell RM, Rao DS, Taganov KD. MicroRNAs: new regulators of immune cell development and function. Nat Immunol. 2008;9:839–45. https://doi.org/10.1038/ni.f.209.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    De Leon-Luis J, et al. Sonographic thymic measurements in Down syndrome fetuses. Prenat Diagn. 2011;31:841–5. https://doi.org/10.1002/pd.2783.

    Article  PubMed  Google Scholar 

  30. 30.

    Levin S, Schlesinger M, Handzel Z, Hahn T, Altman Y, Czernobilsky B, et al. Thymic deficiency in Down’s syndrome. Pediatrics. 1979;63:80–7.

    CAS  PubMed  Google Scholar 

  31. 31.

    Murphy M, Epstein LB. Down syndrome (trisomy 21) thymuses have a decreased proportion of cells expressing high levels of TCR alpha, beta and CD3. A possible mechanism for diminished T cell function in Down syndrome. Clinical immunology and immunopathology. 1990;55:453–67.

    CAS  Article  Google Scholar 

  32. 32.

    Larocca LM, Lauriola L, Ranelletti FO, Piantelli M, Maggiano N, Ricci R, et al. Morphological and immunohistochemical study of down syndrome thymus. Am J Med Genet Suppl. 1990;7:225–30.

    CAS  PubMed  Google Scholar 

  33. 33.

    Marcovecchio GE, Bortolomai I, Ferrua F, Fontana E, Imberti L, Conforti E, et al. Thymic epithelium abnormalities in DiGeorge and down syndrome patients contribute to dysregulation in T cell development. Front Immunol. 2019;10:447. https://doi.org/10.3389/fimmu.2019.00447.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Lima FA, et al. Decreased AIRE expression and global thymic hypofunction in Down syndrome. Journal of immunology (Baltimore, Md. : 1950). 2011;187:3422–30. https://doi.org/10.4049/jimmunol.1003053.

    CAS  Article  Google Scholar 

  35. 35.

    Ravkov E, Slev P, Heikal N. Thymic output: assessment of CD4(+) recent thymic emigrants and T-cell receptor excision circles in infants. Cytometry B Clin Cytom. 2017;92:249–57. https://doi.org/10.1002/cyto.b.21341.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Prada N, Nasi M, Troiano L, Roat E, Pinti M, Nemes E, et al. Direct analysis of thymic function in children with Down’s syndrome. Immun Ageing. 2005;2:4. https://doi.org/10.1186/1742-4933-2-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    McFarland RD, Douek DC, Koup RA, Picker LJ. Identification of a human recent thymic emigrant phenotype. Proc Natl Acad Sci U S A. 2000;97:4215–20. https://doi.org/10.1073/pnas.070061597.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bloemers BL, et al. Decreased thymic output accounts for decreased naive T cell numbers in children with Down syndrome, Journal of immunology (Baltimore, Md. : 1950). 2011;186:4500–7. https://doi.org/10.4049/jimmunol.1001700.

  39. 39.

    Kwan A, Church JA, Cowan MJ, Agarwal R, Kapoor N, Kohn DB, et al. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. J Allergy Clin Immunol. 2013;132:140–50. https://doi.org/10.1016/j.jaci.2013.04.024.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Verstegen RH, et al. Impact of Down syndrome on the performance of neonatal screening assays for severe primary immunodeficiency diseases. J Allergy Clin Immunol. 2014;133:1208–11. https://doi.org/10.1016/j.jaci.2013.10.010.

    Article  PubMed  Google Scholar 

  41. 41.

    Mohiddin G, et al. Oral Candidal and streptococcal carriage in Down syndrome patients. Journal of Natural Science, Biology, and Medicine. 2015;6:300–5. https://doi.org/10.4103/0976-9668.159983.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Soderbergh A, et al. Autoantibodies linked to autoimmune polyendocrine syndrome type I are prevalent in Down syndrome. Acta paediatrica (Oslo, Norway : 1992). 2006;95:1657–60. https://doi.org/10.1080/08035250600771466.

    Article  Google Scholar 

  43. 43.

    Skogberg G, et al. Altered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype. Journal of immunology (Baltimore, Md. : 1950). 2014;193:2187–95. https://doi.org/10.4049/jimmunol.1400742.

    CAS  Article  Google Scholar 

  44. 44.

    Gimenez-Barcons M, et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. Journal of immunology (Baltimore, Md. : 1950). 2014;193:3872–9. https://doi.org/10.4049/jimmunol.1400223.

    CAS  Article  Google Scholar 

  45. 45.

    Pellegrini FP, Marinoni M, Frangione V, Tedeschi A, Gandini V, Ciglia F, et al. Down syndrome, autoimmunity and T regulatory cells. Clin Exp Immunol. 2012;169:238–43. https://doi.org/10.1111/j.1365-2249.2012.04610.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Muche A, Arendt T, Schliebs R. Oxidative stress affects processing of amyloid precursor protein in vascular endothelial cells. PLoS One. 2017;12:e0178127. https://doi.org/10.1371/journal.pone.0178127.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Perluigi M, Butterfield DA. Oxidative stress and down syndrome: a route toward Alzheimer-like dementia. Curr Gerontol Geriatr Res. 2012;2012:724904–10. https://doi.org/10.1155/2012/724904.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Lott IT. Antioxidants in Down syndrome. Biochim Biophys Acta. 2012;1822:657–63. https://doi.org/10.1016/j.bbadis.2011.12.010.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Lorenzo LP, Shatynski KE, Clark S, Yarowsky PJ, Williams MS. Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome. Immunology. 2013;139:447–58. https://doi.org/10.1111/imm.12092.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Paz-Miguel JE, et al. Reactive oxygen intermediates during programmed cell death induced in the thymus of the Ts(1716)65Dn mouse, a murine model for human Down’s syndrome. Journal of immunology (Baltimore, Md. : 1950). 1999;163:5399–410.

    CAS  Google Scholar 

  51. 51.

    Laakso SM, Laurinolli TT, Rossi LH, Lehtoviita A, Sairanen H, Perheentupa J, et al. Regulatory T cell defect in APECED patients is associated with loss of naive FOXP3(+) precursors and impaired activated population. J Autoimmun. 2010;35:351–7. https://doi.org/10.1016/j.jaut.2010.07.008.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Schoch J, Rohrer TR, Kaestner M, Abdul-Khaliq H, Gortner L, Sester U, et al. Quantitative, phenotypical, and functional characterization of cellular immunity in children and adolescents with Down syndrome. J Infect Dis. 2017;215:1619–28. https://doi.org/10.1093/infdis/jix168.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Glick AB, Wodzinski A, Fu P, Levine AD, Wald DN. Impairment of regulatory T-cell function in autoimmune thyroid disease. Thyroid : official journal of the American Thyroid Association. 2013;23:871–8. https://doi.org/10.1089/thy.2012.0514.

    CAS  Article  Google Scholar 

  54. 54.

    Araya P, Waugh KA, Sullivan KD, Núñez NG, Roselli E, Smith KP, et al. Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity. Proc Natl Acad Sci U S A. 2019;116:24231–41. https://doi.org/10.1073/pnas.1908129116.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Lavaert M, Liang KL, Vandamme N, Park JE, Roels J, Kowalczyk MS, Li B, Ashenberg O, Tabaka M, Dionne D, Tickle TL, Slyper M, Rozenblatt-Rosen O, Vandekerckhove B, Leclercq G, Regev A, van Vlierberghe P, Guilliams M, Teichmann SA, Saeys Y, Taghon T. Integrated scRNA-Seq identifies human postnatal thymus seeding progenitors and regulatory dynamics of differentiating immature thymocytes. Immunity. 2020. https://doi.org/10.1016/j.immuni.2020.03.019.

  56. 56.

    Wang J, Sekai M, Matsui T, Fujii Y, Matsumoto M, Takeuchi O, et al. Hassall's corpuscles with cellular-senescence features maintain IFNα production through neutrophils and pDC activation in the thymus. Int Immunol. 2019;31:127–39. https://doi.org/10.1093/intimm/dxy073.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Papadopoulou AS, Dooley J, Linterman MA, Pierson W, Ucar O, Kyewski B, et al. The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptor. Nat Immunol. 2011;13:181–7. https://doi.org/10.1038/ni.2193.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34:798–804. https://doi.org/10.1136/jmg.34.10.798.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Gennery A. R. Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci. 2012;69:17–27. https://doi.org/10.1007/s00018-011-0842-z.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Morsheimer M, Brown Whitehorn TF, Heimall J, Sullivan KE. The immune deficiency of chromosome 22q11.2 deletion syndrome. Am J Med Genet A. 2017;173:2366–72. https://doi.org/10.1002/ajmg.a.38319.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Jawad AF, McDonald-Mcginn DM, Zackai E, Sullivan KE. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr. 2001;139:715–23. https://doi.org/10.1067/mpd.2001.118534.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Verstegen RH, Kusters MA, Gemen EF, De Vries E. Down syndrome B-lymphocyte subpopulations, intrinsic defect or decreased T-lymphocyte help. Pediatr Res. 2010;67:563–9. https://doi.org/10.1203/PDR.0b013e3181d4ecc1.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Halnon NJ, Cooper P, Chen DY, Boechat MI, Uittenbogaart CH. Immune dysregulation after cardiothoracic surgery and incidental thymectomy: maintenance of regulatory T cells despite impaired thymopoiesis. Clinical & developmental immunology. 2011;2011:915864–11. https://doi.org/10.1155/2011/915864.

    CAS  Article  Google Scholar 

  64. 64.

    Halnon NJ, Jamieson B, Plunkett M, Kitchen CMR, Pham T, Krogstad P. Thymic function and impaired maintenance of peripheral T cell populations in children with congenital heart disease and surgical thymectomy. Pediatr Res. 2005;57:42–8. https://doi.org/10.1203/01.Pdr.0000147735.19342.De.

    Article  PubMed  Google Scholar 

  65. 65.

    van Gent R, Schadenberg AWL, Otto SA, Nievelstein RAJ, Sieswerda GT, Haas F, et al. Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration? Blood. 2011;118:627–34. https://doi.org/10.1182/blood-2011-03-341396.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Kusters MA, Gemen EF, Verstegen RH, Wever PC, DE. Vries. E. Both normal memory counts and decreased naive cells favor intrinsic defect over early senescence of Down syndrome T lymphocytes. Pediatr Res. 2010;67:557–62. https://doi.org/10.1203/PDR.0b013e3181d4eca3.

    Article  PubMed  Google Scholar 

  67. 67.

    Kusters MA, Verstegen RH, Gemen EF, de Vries E. Intrinsic defect of the immune system in children with Down syndrome: a review. Clin Exp Immunol. 2009;156:189–93. https://doi.org/10.1111/j.1365-2249.2009.03890.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    de Hingh YC, et al. Intrinsic abnormalities of lymphocyte counts in children with Down syndrome. J Pediatr. 2005;147:744–7. https://doi.org/10.1016/j.jpeds.2005.07.022.

    Article  PubMed  Google Scholar 

  69. 69.

    Murphy M, Epstein LB. Down syndrome (DS) peripheral blood contains phenotypically mature CD3+TCR alpha, beta+ cells but abnormal proportions of TCR alpha, beta+, TCR gamma, delta+, and CD4+ CD45RA+ cells: evidence for an inefficient release of mature T cells by the DS thymus. Clin Immunol Immunopathol. 1992;62:245–51.

    CAS  Article  Google Scholar 

  70. 70.

    Bertotto A, et al. Lymphocytes bearing the gamma/delta T-cell receptors in Down’s syndrome. Scand J Immunol. 1992;35:275–8.

    CAS  Article  Google Scholar 

  71. 71.

    Guazzarotti L, Trabattoni D, Castelletti E, Boldrighini B, Piacentini L, Duca P, et al. T lymphocyte maturation is impaired in healthy young individuals carrying trisomy 21 (Down syndrome). Am J Intellect Dev Disabil. 2009;114:100–9. https://doi.org/10.1352/2009.114.100-109.

    Article  PubMed  Google Scholar 

  72. 72.

    Nateghi Rostami M, Douraghi M, Miramin Mohammadi A, Nikmanesh B. Altered serum pro-inflammatory cytokines in children with Down’s syndrome. Eur Cytokine Netw. 2012;23:64–7. https://doi.org/10.1684/ecn.2012.0307.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Franciotta D, Verri A, Zardini E, Andreoni L, de Amici M, Moratti R, et al. Interferon-gamma- and interleukin-4-producing T cells in Down’s syndrome. Neurosci Lett. 2006;395:67–70. https://doi.org/10.1016/j.neulet.2005.10.048.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Jakubiuk-Tomaszuk A, Sobaniec W, Rusak M, Poskrobko E, Nędzi A, Olchowik B, et al. Decrease of interleukin (IL)17A gene expression in leucocytes and in the amount of IL-17A protein in CD4+ T cells in children with Down syndrome. Pharmacological reports : PR. 2015;67:1130–4. https://doi.org/10.1016/j.pharep.2015.04.008.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621–63. https://doi.org/10.1146/annurev-immunol-031210-101400.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Song W, Craft J. T follicular helper cell heterogeneity: time, space, and function. Immunol Rev. 2019;288:85–96. https://doi.org/10.1111/imr.12740.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Crotty S. T follicular helper cell biology: a decade of discovery and diseases. Immunity. 2019;50:1132–48. https://doi.org/10.1016/j.immuni.2019.04.011.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol. 2008;26:741–66. https://doi.org/10.1146/annurev.immunol.26.021607.090344.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Farroni C, Marasco E, Marcellini V, Giorda E, Valentini D, Petrini S, et al. Dysregulated miR-155 and miR-125b are related to impaired B-cell responses in Down syndrome. Front Immunol. 2018;9:2683. https://doi.org/10.3389/fimmu.2018.02683.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Ottaviano G, Gerosa J, Santini M, de Leo P, Vecchione A, Jofra T, et al. A prevalent CXCR3(+) phenotype of circulating follicular helper T cells indicates humoral dysregulation in children with Down syndrome. J Clin Immunol. 2020;40:447–55. https://doi.org/10.1007/s10875-020-00755-0.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Foley C, Floudas A, Canavan M, Biniecka M, MacDermott EJ, Veale DJ, Mullan RH, Killeen OG, Fearon U. Increased T cell plasticity with dysregulation of T follicular helper, T peripheral helper and T regulatory cell responses in children with JIA and Down syndrome-associated arthritis. Arthritis rheumatol. 2019. https://doi.org/10.1002/art.41150.

  82. 82.

    Sullivan KD et al. Trisomy 21 consistently activates the interferon response. eLife. 2016. https://doi.org/10.7554/eLife.16220.

  83. 83.

    Waugh KA, et al. Mass cytometry reveals global immune remodeling with multi-lineage hypersensitivity to type I interferon in Down syndrome. Cell reports. 2019;29:1893–1908.e1894. https://doi.org/10.1016/j.celrep.2019.10.038.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Maroun LE, Heffernan TN, Hallam DM. Partial IFN-alpha/beta and IFN-gamma receptor knockout trisomy 16 mouse fetuses show improved growth and cultured neuron viability. J Interf Cytokine Res. 2000;20:197–203. https://doi.org/10.1089/107999000312612.

    CAS  Article  Google Scholar 

  85. 85.

    Raziuddin S, Elawad ME. Immunoregulatory CD4+ CD45R+ suppressor/inducer T lymphocyte subsets and impaired cell-mediated immunity in patients with Down’s syndrome. Clin Exp Immunol. 1990;79:67–71.

    CAS  Article  Google Scholar 

  86. 86.

    Bertotto A, et al. T-cell response to anti-CD2 monoclonal antibodies in Down’s syndrome. Scand J Immunol. 1989;30:39–43.

    CAS  Article  Google Scholar 

  87. 87.

    Noble RL, Warren RP. Altered T-cell subsets and defective T-cell function in young children with Down syndrome (trisomy-21). Immunol Investig. 1987;16:371–82.

    CAS  Article  Google Scholar 

  88. 88.

    Serra A, Arpaia E, Bova R. Kinetics of 21-trisomic lymphocytes. I. In vitro response of 21-trisomic lymphocytes to PHA. Hum Genet. 1978;41:157–67.

    CAS  Article  Google Scholar 

  89. 89.

    Bertotto A, Arcangeli C, Crupi S, Marinelli I, Gerli R, Vaccaro R. T cell response to anti-CD3 antibody in Down’s syndrome. Arch Dis Child. 1987;62:1148–51.

    CAS  Article  Google Scholar 

  90. 90.

    Montagna D, Maccario R, Ugazio AG, Nespoli L, Pedroni E, Faggiano P, et al. Cell-mediated cytotoxicity in Down syndrome: impairment of allogeneic mixed lymphocyte reaction, NK and NK-like activities. Eur J Pediatr. 1988;148:53–7.

    CAS  Article  Google Scholar 

  91. 91.

    Philip R, et al. Abnormalities of the in vitro cellular and humoral responses to tetanus and influenza antigens with concomitant numerical alterations in lymphocyte subsets in Down syndrome (trisomy 21). Journal of immunology (Baltimore, Md. : 1950). 1986;136:1661–7.

    CAS  Google Scholar 

  92. 92.

    Lašťovička J, Rataj M, Bartůňková J. Assessment of lymphocyte proliferation for diagnostic purpose: comparison of CFSE staining, Ki-67 expression and (3)H-thymidine incorporation. Hum Immunol. 2016;77:1215–22. https://doi.org/10.1016/j.humimm.2016.08.012.

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Verstegen RHJ, Aui PM, Watson E, de Jong S, Bartol SJW, Bosco JJ, et al. Quantification of T-cell and B-cell replication history in aging, immunodeficiency, and newborn screening. Front Immunol. 2019;10:2084. https://doi.org/10.3389/fimmu.2019.02084.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Martinez E, et al. Altered immune parameters correlate with infection-related hospitalizations in children with Down syndrome. Hum Immunol. 2016;77:594–9. https://doi.org/10.1016/j.humimm.2016.05.004.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Verstegen RHJ, et al. Defective B-cell memory in patients with Down syndrome. The Journal of allergy and clinical immunology. 2014;134:1346–1353.e1349. https://doi.org/10.1016/j.jaci.2014.07.015.

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Mitwalli M, Wahba Y, Shaltout A, Gouida M. Lymphocyte subgroups and recurrent infections in children with Down syndrome - a prospective case control study. Central-European journal of immunology. 2018;43:248–54. https://doi.org/10.5114/ceji.2018.80042.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Carsetti R, Valentini D, Marcellini V, Scarsella M, Marasco E, Giustini F, et al. Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome. Eur J Immunol. 2015;45:903–14. https://doi.org/10.1002/eji.201445049.

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Seckin AN, Ozdemir H, Ceylan A, Artac H. Age-related alterations of the CD19 complex and memory B cells in children with Down syndrome. Clin Exp Med. 2018;18:125–31. https://doi.org/10.1007/s10238-017-0457-2.

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Broers CJ, et al. Frequency of lower respiratory tract infections in relation to adaptive immunity in children with Down syndrome compared to their healthy siblings. Acta paediatrica (Oslo, Norway : 1992). 2012;101:862–7. https://doi.org/10.1111/j.1651-2227.2012.02696.x.

    Article  Google Scholar 

  100. 100.

    Morawiec Z, Janik K, Kowalski M, Stetkiewicz T, Szaflik J, Morawiec-Bajda A, et al. DNA damage and repair in children with Down’s syndrome. Mutat Res. 2008;637:118–23. https://doi.org/10.1016/j.mrfmmm.2007.07.010.

    CAS  Article  PubMed  Google Scholar 

  101. 101.

    Driessen GJ, et al. Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. The Journal of allergy and clinical immunology. 2013;131:1367–1375.e1369. https://doi.org/10.1016/j.jaci.2013.01.053.

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    van der Burg M, Pac M, Berkowska MA, Goryluk-Kozakiewicz B, Wakulinska A, Dembowska-Baginska B, et al. Loss of juxtaposition of RAG-induced immunoglobulin DNA ends is implicated in the precursor B-cell differentiation defect in NBS patients. Blood. 2010;115:4770–7. https://doi.org/10.1182/blood-2009-10-250514.

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Gemen EF, Verstegen RH, Leuvenink J, de Vries E. Increased circulating apoptotic lymphocytes in children with Down syndrome. Pediatr Blood Cancer. 2012;59:1310–2. https://doi.org/10.1002/pbc.24246.

    Article  PubMed  Google Scholar 

  104. 104.

    Vallerskog T, Heimbürger M, Gunnarsson I, Zhou W, Wahren-Herlenius M, Trollmo C, et al. Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther. 2006;8:R167. https://doi.org/10.1186/ar2076.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Conti A, Fabbrini F, D'Agostino P, Negri R, Greco D, Genesio R, et al. Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy. BMC Genomics. 2007;8:268. https://doi.org/10.1186/1471-2164-8-268.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Helguera P, Seiglie J, Rodriguez J, Hanna M, Helguera G, Busciglio J. Adaptive downregulation of mitochondrial function in Down syndrome. Cell Metab. 2013;17:132–40. https://doi.org/10.1016/j.cmet.2012.12.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Dogliotti G, Galliera E, Dozio E, Vianello E, Villa RE, Licastro F, et al. Okadaic acid induces apoptosis in Down syndrome fibroblasts. Toxicology in vitro: an international journal published in association with BIBRA. 2010;24:815–21. https://doi.org/10.1016/j.tiv.2009.12.012.

    CAS  Article  Google Scholar 

  108. 108.

    Roat E, Prada N, Ferraresi R, Giovenzana C, Nasi M, Troiano L, et al. Mitochondrial alterations and tendency to apoptosis in peripheral blood cells from children with Down syndrome. FEBS Lett. 2007;581:521–5. https://doi.org/10.1016/j.febslet.2006.12.058.

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Chou J, Alazami AM, Jaber F, Hoyos-Bachiloglu R, Jones J, Weeks S, et al. Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation. J Allergy Clin Immunol. 2019. https://doi.org/10.1016/j.jaci.2019.12.004.

  110. 110.

    Berkowska MA, Driessen GJA, Bikos V, Grosserichter-Wagener C, Stamatopoulos K, Cerutti A, et al. Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways. Blood. 2011;118:2150–8. https://doi.org/10.1182/blood-2011-04-345579.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    von Bernuth H, Picard C, Puel A, Casanova JL. Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. Eur J Immunol. 2012;42:3126–35. https://doi.org/10.1002/eji.201242683.

    CAS  Article  Google Scholar 

  112. 112.

    Weller S, Bonnet M, Delagreverie H, Israel L, Chrabieh M, Maródi L, et al. IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients. Blood. 2012;120:4992–5001. https://doi.org/10.1182/blood-2012-07-440776.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Isnardi I, Ng YS, Srdanovic I, Motaghedi R, Rudchenko S, von Bernuth H, et al. IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. Immunity. 2008;29:746–57. https://doi.org/10.1016/j.immuni.2008.09.015.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114.

    van Zelm MC, Bartol SJW, Driessen GJ, Mascart F, Reisli I, Franco JL, et al. Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. J Allergy Clin Immunol. 2014;134:135–44. https://doi.org/10.1016/j.jaci.2013.11.015.

    CAS  Article  PubMed  Google Scholar 

  115. 115.

    Wardemann H, et al. Predominant autoantibody production by early human B cell precursors. Science (New York, N.Y.). 2003;301:1374–7. https://doi.org/10.1126/science.1086907.

    CAS  Article  Google Scholar 

  116. 116.

    Pugh-Bernard AE, Silverman GJ, Cappione AJ, Villano ME, Ryan DH, Insel RA, et al. Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance. J Clin Invest. 2001;108:1061–70. https://doi.org/10.1172/JCI12462.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117.

    van Schouwenburg PA, IJspeert H, Pico-Knijnenburg I, Dalm VASH, van Hagen PM, van Zessen D, et al. Identification of CVID patients with defects in immune repertoire formation or specification. Front Immunol. 2018;9:2545. https://doi.org/10.3389/fimmu.2018.02545.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Alivernini S, et al. MicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis. Nature communications. 2016;(7):12970. https://doi.org/10.1038/ncomms12970.

  119. 119.

    Rodriguez A, et al. Requirement of bic/microRNA-155 for normal immune function. Science (New York, N.Y.). 2007;316:608–11. https://doi.org/10.1126/science.1139253.

    CAS  Article  Google Scholar 

  120. 120.

    Isnardi I, Ng YS, Menard L, Meyers G, Saadoun D, Srdanovic I, et al. Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood. 2010;115:5026–36. https://doi.org/10.1182/blood-2009-09-243071.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Wehr C, et al. A new CD21low B cell population in the peripheral blood of patients with SLE. Clinical immunology (Orlando, Fla.). 2004;113:161–71. https://doi.org/10.1016/j.clim.2004.05.010.

    CAS  Article  Google Scholar 

  122. 122.

    Unger S, Seidl M, van Schouwenburg P, Rakhmanov M, Bulashevska A, Frede N, et al. The TH1 phenotype of follicular helper T cells indicates an IFN-gamma-associated immune dysregulation in patients with CD21low common variable immunodeficiency. J Allergy Clin Immunol. 2018;141:730–40. https://doi.org/10.1016/j.jaci.2017.04.041.

    CAS  Article  PubMed  Google Scholar 

  123. 123.

    Odnoletkova I, et al. The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet J Rare Dis. 2018;13:201. https://doi.org/10.1186/s13023-018-0941-0.

    Article  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Valentini D, Marcellini V, Bianchi S, Villani A, Facchini M, Donatelli I, et al. Generation of switched memory B cells in response to vaccination in Down syndrome children and their siblings. Vaccine. 2015;33:6689–96. https://doi.org/10.1016/j.vaccine.2015.10.083.

    CAS  Article  PubMed  Google Scholar 

  125. 125.

    Nisihara R, de Bem RS, Negreiros PHR, Utiyama SRR, Oliveira NP, Amarante H. Low hepatitis B vaccine response in children with Down syndrome from Brazil. Child Care Health Dev. 2014;40:607–9. https://doi.org/10.1111/cch.12099.

    CAS  Article  PubMed  Google Scholar 

  126. 126.

    Heijtink RA, De Jong P, Schalm SW, Masurel N. Hepatitis B vaccination in Down’s syndrome and other mentally retarded patients. Hepatology (Baltimore, Md.). 1984;4:611–4.

    CAS  Article  Google Scholar 

  127. 127.

    Eijsvoogel NB, Hollegien MI, Bok LA, Derksen-Lubsen G, Dikken FPJ, Leenders ACAP, et al. Lower percentage of allergic sensitization in children with Down syndrome. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2017;28:852–7. https://doi.org/10.1111/pai.12796.

    CAS  Article  Google Scholar 

  128. 128.

    Avanzini M, et al. Humoral immunodeficiency in Down syndrome: serum IgG subclass and antibody response to hepatitis B vaccine. American Journal Medical Genetics. 1990;7:231–3.

    CAS  Google Scholar 

  129. 129.

    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–67. https://doi.org/10.1056/NEJMra035092.

    CAS  Article  PubMed  Google Scholar 

  130. 130.

    Vajro P, et al. Vaccination against hepatitis B in preschool children with Down’s syndrome. Journal of intellectual disability research : JIDR. 1992;36(Pt 1):77–81.

    PubMed  Google Scholar 

  131. 131.

    Troisi CL, Heiberg DA, Hollinger FB. Normal immune response to hepatitis B vaccine in patients with Down’s syndrome. A basis for immunization guidelines. Jama. 1985;254:3196–9.

    CAS  Article  Google Scholar 

  132. 132.

    Kusters MA, et al. Functionality of the pneumococcal antibody response in Down syndrome subjects. Vaccine. 2013;31:6261–5. https://doi.org/10.1016/j.vaccine.2013.09.070.

    CAS  Article  PubMed  Google Scholar 

  133. 133.

    Kusters MA, Jol-van der Zijde CM, van Tol MJ, Bolz WE, Bok LA, Visser M, et al. Impaired avidity maturation after tetanus toxoid booster in children with Down syndrome. Pediatr Infect Dis J. 2011;30:357–9. https://doi.org/10.1097/INF.0b013e3181ff85a8.

    Article  PubMed  Google Scholar 

  134. 134.

    de Hingh, Y. C., PhD et al. Intrinsic abnormalities of lymphocyte counts in children with Down syndrome. Journal of Pediatrics 147, 744–747 (2005).

  135. 135.

    Cossarrizza A. Age-related expansion of functionally inefficient cells with markers of natural killer activity in Down’s syndrome. Blood. 1991;77:1263–70.

    Article  Google Scholar 

  136. 136.

    Burgio G, et al. Derangements of immunoglobuline levels, phytohemagglutinin responsiveness and T and B cell markers in Down’s syndrome at different ages. Eur J Immunol. 1975;5:600–3.

    CAS  Article  Google Scholar 

  137. 137.

    Ugazio A, Maccario R, Notarangelo L, Burgio G. Immunology of Down syndrome: a review. American Journal Medical Genetics supplement. 1990;7:204–12.

    CAS  Google Scholar 

  138. 138.

    Nespoli L, Burgio G, Ugazio A, Maccario R. Immunological features of Down’s syndrome: a review. J Intellect Disabil Res. 1993;37:543–51.

    Article  Google Scholar 

  139. 139.

    Loh RK, Harth SC, Thong YH, Ferrante A. Immunoglobulin G subclass deficiency and predisposition to infection in Down’s syndrome. Pediatr Infect Dis J. 1990;9:547–51.

    CAS  Article  Google Scholar 

  140. 140.

    Anneren G, Magnusson CG, Lilja G, Nordvall SL. Abnormal serum IgG subclass pattern in children with Down’s syndrome. Arch Dis Child. 1992;67:628–31.

    CAS  Article  Google Scholar 

  141. 141.

    Park E, et al. Partial impairment of immune functions in peripheral blood leukocytes from aged men with Down’s syndrome. Clinical immunology (Orlando, Fla.). 2000;95:62–9. https://doi.org/10.1006/clim.2000.4834.

    CAS  Article  Google Scholar 

  142. 142.

    Seger R, Buchinger G, Stroder J. On the influence of age on immunity in Down’s syndrome. Eur J Pediatr. 1977;124:77–87.

    CAS  Article  Google Scholar 

  143. 143.

    Weijerman ME, Brand PL, van Furth MA, Broers CJ, Gemke RJ. Recurrent wheeze in children with Down syndrome: is it asthma? Acta paediatrica. 2011;100:e194–197. https://doi.org/10.1111/j.1651-2227.2011.02367.x.

  144. 144.

    Mannan SE, Yousef E, Hossain J. Prevalence of positive skin prick test results in children with Down syndrome: a case-control study. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2009;102:205–9. https://doi.org/10.1016/s1081-1206(10)60082-8.

  145. 145.

    Hawkes RA, Boughton CR, Schroeter DR. The antibody response of institutionalized Down’s syndrome patients to seven microbial antigens. Clin Exp Immunol. 1978;31:298–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Hawkes RA, Philbrook SC, Boughton CR. The response of institutionalized Down’s syndrome subjects to enterovirus infections. J Hyg. 1980;84:433–41. https://doi.org/10.1017/s0022172400026978.

    CAS  Article  PubMed  Google Scholar 

  147. 147.

    Li Volti S, Mattina T, Mauro L, Bianca S, Anfuso S, Ursino A, et al. Safety and effectiveness of an acellular pertussis vaccine in subjects with Down’s syndrome. Child’s nervous system: ChNS: official journal of the International Society for Pediatric Neurosurgery. 1996;12:100–2.

    CAS  Article  Google Scholar 

  148. 148.

    Ferreira C, et al. Immunogenicity and safety of an inactivated hepatitis A vaccine in children with Down syndrome. J Pediatr Gastroenterol Nutr. 2004;39:337–40.

    CAS  Article  Google Scholar 

  149. 149.

    Kusters MA, Jol-Van Der Zijde EC, Gijsbers RH, de Vries E. Decreased response after conjugated meningococcal serogroup C vaccination in children with Down syndrome. Pediatr Infect Dis J. 2011;30:818–9. https://doi.org/10.1097/INF.0b013e31822233f9.

    Article  PubMed  Google Scholar 

  150. 150.

    Nurmi T, Leinonen M, Haiva VM, Tiilikainen A, Kouvalainen K. Antibody response to pneumococcal vaccine in patients with trisomy-21 (Down’s syndrome). Clin Exp Immunol. 1982;48:485–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Costa-Carvalho B, et al. Antibody response to pneumococcal capsular polysaccharide vaccine in Down syndrome patients. Brazilian Journal of medical Biology Research. 2006;39:1587–92.

    CAS  Article  Google Scholar 

  152. 152.

    Verstegen RH. J. Humoral immunity in children with Down syndrome - relevance to respiratory disease (PhD thesis). 2014. http://hdl.handle.net/1765/77471.

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ruud H.J. Verstegen.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Verstegen, R.H., Kusters, M.A. Inborn Errors of Adaptive Immunity in Down Syndrome. J Clin Immunol 40, 791–806 (2020). https://doi.org/10.1007/s10875-020-00805-7

Download citation

Keywords

  • Down syndrome
  • trisomy 21
  • immunodeficiency
  • adaptive immunity
  • T cells
  • B cells
  • immunodysregulation
  • gene expression dysregulation
  • immunology