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Immune Dysregulation Associated with Very Early-Onset Inflammatory Bowel Disease

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Pediatric Inflammatory Bowel Disease

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Abstract

Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic microbes in the intestine, resulting in chronic intestinal inflammation. An emerging population of patients with IBD who present ≤5 years of age represent a unique form of disease, termed Very Early-Onset (VEO)-IBD, that can be phenotypically and genetically distinct from pediatric and adult-onset IBD. VEO-IBD may be associated with increased disease severity, aggressive progression, and poor responsiveness to most conventional therapies. Here, we discuss the phenotype of VEO-IBD, genetic variants associated with disease, and immunologic studies that can point to the contribution of specific genetic variants that lead to the development of this disease.

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References

  1. Stokkers PC, et al. HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis. Gut. 1999;45(3):395–401.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Goyette P, et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet. 2015;47(2):172–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Eggena M, et al. Identification of histone H1 as a cognate antigen of the ulcerative colitis-associated marker antibody pANCA. J Autoimmun. 2000;14(1):83–97.

    CAS  PubMed  Google Scholar 

  4. Saxon A, et al. A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease. J Allergy Clin Immunol. 1990;86(2):202–10.

    CAS  PubMed  Google Scholar 

  5. Sattler S, et al. IL-10-producing regulatory B cells induced by IL-33 (Breg(IL-33)) effectively attenuate mucosal inflammatory responses in the gut. J Autoimmun. 2014;50:107–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology. 2011;140(6):1704–12.

    CAS  PubMed  Google Scholar 

  8. Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Jacobs JP, Braun J. Immune and genetic gardening of the intestinal microbiome. FEBS Lett. 2014;588(22):4102–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. D'Inca R, et al. Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn’s disease. Aliment Pharmacol Ther. 2006;23(10):1455–61.

    CAS  PubMed  Google Scholar 

  11. Buhner S, et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut. 2006;55(3):342–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474(7351):298–306.

    CAS  PubMed  Google Scholar 

  13. Maynard CL, et al. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 2012;489(7415):231–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. 2010;10(3):159–69.

    CAS  PubMed  Google Scholar 

  15. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336(6086):1268–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lodes MJ, et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest. 2004;113(9):1296–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Baumgart M, et al. Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn’s disease involving the ileum. ISME J. 2007;1(5):403–18.

    CAS  PubMed  Google Scholar 

  20. Darfeuille-Michaud A, et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology. 2004;127(2):412–21.

    PubMed  Google Scholar 

  21. Dalwadi H, et al. The Crohn’s disease-associated bacterial protein I2 is a novel enteric t cell superantigen. Immunity. 2001;15(1):149–58.

    CAS  PubMed  Google Scholar 

  22. Walker AW, et al. High-throughput clone library analysis of the mucosa-associated microbiota reveals dysbiosis and differences between inflamed and non-inflamed regions of the intestine in inflammatory bowel disease. BMC Microbiol. 2011;11:7.

    PubMed  PubMed Central  Google Scholar 

  23. Willing B, et al. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn’s disease. Inflamm Bowel Dis. 2009;15(5):653–60.

    PubMed  Google Scholar 

  24. Willing BP, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology. 2010;139(6):1844–1854 e1.

    PubMed  Google Scholar 

  25. Martin HM, et al. Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterology. 2004;127(1):80–93.

    CAS  PubMed  Google Scholar 

  26. Benchimol EI, et al. Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data. Gut. 2009;58(11):1490–7.

    CAS  PubMed  Google Scholar 

  27. Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut. 2013;62(12):1795–805.

    CAS  PubMed  Google Scholar 

  28. Durandy A, Kracker S, Fischer A. Primary antibody deficiencies. Nat Rev Immunol. 2013;13(7):519–33.

    CAS  PubMed  Google Scholar 

  29. Glocker EO, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361(21):2033–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Glocker E, Grimbacher B. Inflammatory bowel disease: is it a primary immunodeficiency? Cell Mol Life Sci. 2012;69(1):41–8.

    CAS  PubMed  Google Scholar 

  31. Ruemmele FM, et al. Characteristics of inflammatory bowel disease with onset during the first year of life. J Pediatr Gastroenterol Nutr. 2006;43(5):603–9.

    PubMed  Google Scholar 

  32. Cannioto Z, et al. IBD and IBD mimicking enterocolitis in children younger than 2 years of age. Eur J Pediatr. 2009;168(2):149–55.

    CAS  PubMed  Google Scholar 

  33. de Ridder L, et al. Genetic susceptibility has a more important role in pediatric-onset Crohn’s disease than in adult-onset Crohn’s disease. Inflamm Bowel Dis. 2007;13(9):1083–92.

    PubMed  Google Scholar 

  34. Biank V, Broeckel U, Kugathasan S. Pediatric inflammatory bowel disease: clinical and molecular genetics. Inflamm Bowel Dis. 2007;13(11):1430–8.

    PubMed  Google Scholar 

  35. Glocker EO, et al. Infant colitis—it’s in the genes. Lancet. 2010;376(9748):1272.

    PubMed  Google Scholar 

  36. Worthey EA, et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med. 2011;13(3):255–62.

    PubMed  Google Scholar 

  37. Agarwal S, Mayer L. Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency. Clin Gastroenterol Hepatol. 2013;11(9):1050–63.

    PubMed  PubMed Central  Google Scholar 

  38. Mao H, et al. Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn’s disease. Genes Immun. 2012;13(5):437–42.

    CAS  PubMed  Google Scholar 

  39. Avitzur Y, et al. Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology. 2014;146(4):1028–39.

    CAS  PubMed  Google Scholar 

  40. Kammermeier J, et al. Targeted gene panel sequencing in children with very early onset inflammatory bowel disease-evaluation and prospective analysis. J Med Genet. 2014;51(11):748–55.

    CAS  PubMed  Google Scholar 

  41. Kelsen JR, et al. North American society for pediatric gastroenterology, hepatology, and nutrition position paper on the evaluation and management for patients with very early-onset inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2020;70(3):389–403.

    PubMed  Google Scholar 

  42. Muise AM, Snapper SB, Kugathasan S. The age of gene discovery in very early onset inflammatory bowel disease. Gastroenterology. 2012;143(2):285–8.

    PubMed  Google Scholar 

  43. Uhlig HH, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147(5):990–1007 e3.

    PubMed  Google Scholar 

  44. Kelsen JR, et al. The unique disease course of children with very early onset-inflammatory bowel disease. Inflamm Bowel Dis. 2020;26(6):909–18.

    PubMed  Google Scholar 

  45. Heyman MB, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr. 2005;146(1):35–40.

    PubMed  Google Scholar 

  46. Mamula P, et al. Inflammatory bowel disease in children 5 years of age and younger. Am J Gastroenterol. 2002;97(8):2005–10.

    PubMed  Google Scholar 

  47. Benchimol EI, et al. Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology. 2014;147(4):803–813 e7. quiz e14-5

    PubMed  Google Scholar 

  48. Aloi M, et al. Phenotype and disease course of early-onset pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(4):597–605.

    PubMed  Google Scholar 

  49. Bramuzzo M, et al. Efficacy and safety of infliximab in very early onset inflammatory bowel disease: a national comparative retrospective study. United European Gastroenterol J. 2019;7(6):759–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Chalaris A, et al. ADAM17-mediated shedding of the IL6R induces cleavage of the membrane stub by gamma-secretase. Biochim Biophys Acta. 2010;1803(2):234–45.

    CAS  PubMed  Google Scholar 

  51. Blaydon DC, et al. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med. 2011;365(16):1502–8.

    CAS  PubMed  Google Scholar 

  52. Karamchandani-Patel G, et al. Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels. Ann Allergy Asthma Immunol. 2011;107(1):50–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Zimmer KP, et al. Esophageal stenosis in childhood: dystrophic epidermolysis bullosa without skin blistering due to collagen VII mutations. Gastroenterology. 2002;122(1):220–5.

    PubMed  Google Scholar 

  54. Sadler E, et al. Novel KIND1 gene mutation in Kindler syndrome with severe gastrointestinal tract involvement. Arch Dermatol. 2006;142(12):1619–24.

    CAS  PubMed  Google Scholar 

  55. Ussar S, et al. Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genet. 2008;4(12):e1000289.

    PubMed  PubMed Central  Google Scholar 

  56. Kern JS, et al. Chronic colitis due to an epithelial barrier defect: the role of kindlin-1 isoforms. J Pathol. 2007;213(4):462–70.

    CAS  PubMed  Google Scholar 

  57. Campbell P, et al. Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR. J Invest Dermatol. 2014;134(10):2570–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Fiskerstrand T, et al. Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med. 2012;366(17):1586–95.

    CAS  PubMed  Google Scholar 

  59. Bianco AM, Girardelli M, Tommasini A. Genetics of inflammatory bowel disease from multifactorial to monogenic forms. World J Gastroenterol. 2015;21(43):12296–310.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Naviglio S, et al. Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling. J Crohns Colitis. 2014;8(8):770–4.

    PubMed  Google Scholar 

  61. Chalaris A, et al. Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice. J Exp Med. 2010;207(8):1617–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Nenci A, et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature. 2007;446(7135):557–61.

    CAS  PubMed  Google Scholar 

  63. Zaph C, et al. Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature. 2007;446(7135):552–6.

    CAS  PubMed  Google Scholar 

  64. Cheng LE, et al. Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol. 2009;132(1):124–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Luetteke NC, et al. TGF alpha deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice. Cell. 1993;73(2):263–78.

    CAS  PubMed  Google Scholar 

  66. Mann GB, et al. Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell. 1993;73(2):249–61.

    CAS  PubMed  Google Scholar 

  67. Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol. 2002;20:495–549.

    CAS  PubMed  Google Scholar 

  68. Hand TW, et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science. 2012;337(6101):1553–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Cong Y, et al. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc Natl Acad Sci U S A. 2009;106(46):19256–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Mombaerts P, et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68(5):869–77.

    CAS  PubMed  Google Scholar 

  71. Shinkai Y, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992;68(5):855–67.

    CAS  PubMed  Google Scholar 

  72. Peschon JJ, et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994;180(5):1955–60.

    CAS  PubMed  Google Scholar 

  73. Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol. 2013;131(4):959–71.

    CAS  PubMed  Google Scholar 

  74. Vetrie D, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361(6409):226–33.

    CAS  Google Scholar 

  75. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93(3):190–7.

    CAS  PubMed  Google Scholar 

  76. Alangari A, et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J Allergy Clin Immunol. 2012;130(2):481–8 e2.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Pai SY, Cowan MJ. Stem cell transplantation for primary immunodeficiency diseases: the North American experience. Curr Opin Allergy Clin Immunol. 2014;14(6):521–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Shearer WT, et al. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014;133(4):1092–8.

    PubMed  Google Scholar 

  79. Puel A, et al. Defective IL7R expression in T(−)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998;20(4):394–7.

    CAS  PubMed  Google Scholar 

  80. Dadi HK, Simon AJ, Roifman CM. Effect of CD3delta deficiency on maturation of alpha/beta and gamma/delta T-cell lineages in severe combined immunodeficiency. N Engl J Med. 2003;349(19):1821–8.

    CAS  PubMed  Google Scholar 

  81. Nielsen C, et al. Immunodeficiency associated with a nonsense mutation of IKBKB. J Clin Immunol. 2014;34(8):916–21.

    PubMed  Google Scholar 

  82. Derry JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell. 1994;79(5):922.

    PubMed  Google Scholar 

  83. Watanabe Y, et al. T-cell receptor ligation causes Wiskott-Aldrich syndrome protein degradation and F-actin assembly downregulation. J Allergy Clin Immunol. 2013;132(3):648–655 e1.

    CAS  PubMed  Google Scholar 

  84. Shimizu M, et al. Aberrant glycosylation of IgA in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. J Allergy Clin Immunol. 2013;131(2):587–90 e1-3.

    CAS  PubMed  Google Scholar 

  85. Westerberg LS, et al. Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function. Blood. 2012;119(17):3966–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Becker-Herman S, et al. WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J Exp Med. 2011;208(10):2033–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lanzi G, et al. A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J Exp Med. 2012;209(1):29–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Nguyen DD, et al. Lymphocyte-dependent and Th2 cytokine-associated colitis in mice deficient in Wiskott-Aldrich syndrome protein. Gastroenterology. 2007;133(4):1188–97.

    CAS  PubMed  Google Scholar 

  89. Maillard MH, et al. The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J Exp Med. 2007;204(2):381–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Nguyen DD, et al. Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice. Gastroenterology. 2012;143(3):719–29 e1-2.

    CAS  PubMed  Google Scholar 

  91. Ferrua F, et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 2019;6(5):e239–53.

    PubMed  PubMed Central  Google Scholar 

  92. Shin CR, et al. Outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome. Bone Marrow Transplant. 2012;47(11):1428–35.

    CAS  PubMed  Google Scholar 

  93. Chan AY, et al. Hematopoietic cell transplantation in patients with primary immune regulatory disorders (PIRD): a primary immune deficiency treatment consortium (PIDTC) survey. Front Immunol. 2020;11:239.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. de la Morena MT, et al. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation. J Allergy Clin Immunol. 2017;139(4):1282–92.

    PubMed  Google Scholar 

  95. Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2012. J Allergy Clin Immunol. 2013;131(3):675–82.

    PubMed  Google Scholar 

  96. Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol. 2012;3:211.

    PubMed  PubMed Central  Google Scholar 

  97. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol. 2007;2007:89017.

    PubMed  PubMed Central  Google Scholar 

  99. Zeissig S, et al. Early-onset Crohn’s disease and autoimmunity associated with a variant in CTLA-4. Gut. 2014;64(12):1889–97.

    PubMed  Google Scholar 

  100. Cebula A, et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature. 2013;497(7448):258–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Lathrop SK, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478(7368):250–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Chinen T, et al. A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota. J Exp Med. 2010;207(11):2323–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Schultz M, et al. IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation. Am J Phys. 1999;276(6 Pt 1):G1461–72.

    CAS  Google Scholar 

  104. Schiering C, et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature. 2014;513(7519):564–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Shim JO, et al. Interleukin-10 receptor mutations in children with neonatal-onset Crohn's disease and intractable ulcerating enterocolitis. Eur J Gastroenterol Hepatol. 2013;25(10):1235–40.

    CAS  PubMed  Google Scholar 

  106. Moore KW, et al. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.

    CAS  PubMed  Google Scholar 

  107. Hutchins AP, Diez D, Miranda-Saavedra D. The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges. Brief Funct Genomics. 2013;12(6):489–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Engelhardt KR, Grimbacher B. IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms. Curr Top Microbiol Immunol. 2014;380:1–18.

    CAS  PubMed  Google Scholar 

  109. Murray PJ. The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci U S A. 2005;102(24):8686–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Neven B, et al. A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency. Blood. 2013;122(23):3713–22.

    CAS  PubMed  Google Scholar 

  111. Engelhardt KR, et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013;131(3):825–30.

    CAS  PubMed  Google Scholar 

  112. Murugan D, et al. Very early onset inflammatory bowel disease associated with aberrant trafficking of IL-10R1 and cure by T cell replete haploidentical bone marrow transplantation. J Clin Immunol. 2014;34(3):331–9.

    CAS  PubMed  Google Scholar 

  113. Kuhn R, et al. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75(2):263–74.

    CAS  Google Scholar 

  114. Sellon RK, et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun. 1998;66(11):5224–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Rubtsov YP, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008;28(4):546–58.

    CAS  PubMed  Google Scholar 

  116. Roers A, et al. T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J Exp Med. 2004;200(10):1289–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Shouval DS, et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity. 2014;40(5):706–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Zigmond E, et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity. 2014;40(5):720–33.

    CAS  PubMed  Google Scholar 

  119. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 2011;12(5):383–90.

    CAS  PubMed  Google Scholar 

  120. Sonnenberg GF, Artis D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity. 2012;37(4):601–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Spits H, et al. Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13(2):145–9.

    CAS  PubMed  Google Scholar 

  122. Sonnenberg GF, et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science. 2012;336(6086):1321–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Hepworth MR, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 2013;498(7452):113–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Bernink JH, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. 2013;14(3):221–9.

    CAS  PubMed  Google Scholar 

  125. Geremia A, et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med. 2011;208(6):1127–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Takayama T, et al. Imbalance of NKp44(+)NKp46(−) and NKp44(−)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn’s disease. Gastroenterology. 2010;139(3):882–92. 892 e1–3

    CAS  PubMed  Google Scholar 

  127. Ciccia F, et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 2012;64(6):1869–78.

    CAS  PubMed  Google Scholar 

  128. Fuchs A, et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity. 2013;38(4):769–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Hepworth MR, et al. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science. 2015; https://doi.org/10.1126/science.aaa4812.

  130. Gunasekera DC, et al. The development of colitis in Il10(−/−) mice is dependent on IL-22. Mucosal Immunol. 2020;13(3):493–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Mizoguchi A, et al. Clinical importance of IL-22 cascade in IBD. J Gastroenterol. 2018;53(4):465–74.

    CAS  PubMed  Google Scholar 

  132. Kang EM, et al. Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2011;127(6):1319–26. quiz 1327-8

    PubMed  PubMed Central  Google Scholar 

  133. Abo A, et al. Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature. 1991;353(6345):668–70.

    CAS  PubMed  Google Scholar 

  134. Matute JD, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009;114(15):3309–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Marks DJ, et al. Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn’s disease. Am J Gastroenterol. 2009;104(1):117–24.

    CAS  PubMed  Google Scholar 

  136. Jones LB, et al. Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry. Clin Exp Immunol. 2008;152(2):211–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Rosenzweig SD. Inflammatory manifestations in chronic granulomatous disease (CGD). J Clin Immunol. 2008;28(Suppl. 1):S67–72.

    PubMed  Google Scholar 

  138. Foster CB, et al. Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease. J Clin Invest. 1998;102(12):2146–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Muise AM, et al. NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut. 2012;61(7):1028–35.

    CAS  PubMed  Google Scholar 

  140. Dhillon SS, et al. Variants in nicotinamide adenine dinucleotide phosphate oxidase complex components determine susceptibility to very early onset inflammatory bowel disease. Gastroenterology. 2014;147(3):680–689 e2.

    CAS  PubMed  Google Scholar 

  141. Roos D, Law SK. Hematologically important mutations: leukocyte adhesion deficiency. Blood Cells Mol Dis. 2001;27(6):1000–4.

    CAS  PubMed  Google Scholar 

  142. van de Vijver E, et al. Hematologically important mutations: leukocyte adhesion deficiency (first update). Blood Cells Mol Dis. 2012;48(1):53–61.

    PubMed  Google Scholar 

  143. Schmidt S, Moser M, Sperandio M. The molecular basis of leukocyte recruitment and its deficiencies. Mol Immunol. 2013;55(1):49–58.

    CAS  PubMed  Google Scholar 

  144. Davis MK, et al. Adalimumab for the treatment of Crohn-like colitis and enteritis in glycogen storage disease type Ib. J Inherit Metab Dis. 2008;31(Suppl. 3):505–9.

    PubMed  Google Scholar 

  145. Uzel G, et al. Complications of tumor necrosis factor-alpha blockade in chronic granulomatous disease-related colitis. Clin Infect Dis. 2010;51(12):1429–34.

    PubMed  PubMed Central  Google Scholar 

  146. Kato K, et al. Successful allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease with inflammatory complications and severe infection. Int J Hematol. 2011;94(5):479–82.

    PubMed  Google Scholar 

  147. de Luca A, et al. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc Natl Acad Sci U S A. 2014;111(9):3526–31.

    PubMed  PubMed Central  Google Scholar 

  148. Bianco AM, et al. Mevalonate kinase deficiency and IBD: shared genetic background. Gut. 2014;63(8):1367–8.

    PubMed  Google Scholar 

  149. Kuloglu Z, et al. An infant with severe refractory Crohn’s disease and homozygous MEFV mutation who dramatically responded to colchicine. Rheumatol Int. 2012;32(3):783–5.

    PubMed  Google Scholar 

  150. Beser OF, et al. Association of inflammatory bowel disease with familial Mediterranean fever in Turkish children. J Pediatr Gastroenterol Nutr. 2013;56(5):498–502.

    CAS  PubMed  Google Scholar 

  151. Mora AJ, Wolfsohn DM. The management of gastrointestinal disease in Hermansky-Pudlak syndrome. J Clin Gastroenterol. 2011;45(8):700–2.

    PubMed  Google Scholar 

  152. Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol. 2013;147(3):155–74.

    CAS  PubMed  Google Scholar 

  153. Speckmann C, et al. X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clin Immunol. 2013;149(1):133–41.

    CAS  PubMed  Google Scholar 

  154. Canna SW, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017;139(5):1698–701.

    CAS  PubMed  Google Scholar 

  155. Romberg N, Vogel TP, Canna SW. NLRC4 inflammasomopathies. Curr Opin Allergy Clin Immunol. 2017;17(6):398–404.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Latour S, Aguilar C. XIAP deficiency syndrome in humans. Semin Cell Dev Biol. 2015;39:115–23.

    CAS  PubMed  Google Scholar 

  157. Pedersen J, et al. Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation. Trends Mol Med. 2014;20(11):652–65.

    CAS  PubMed  Google Scholar 

  158. Aguilar C, Latour S. X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome. J Clin Immunol. 2015;35(4):331–8.

    CAS  PubMed  Google Scholar 

  159. Filipovich AH. The expanding spectrum of hemophagocytic lymphohistiocytosis. Curr Opin Allergy Clin Immunol. 2011;11(6):512–6.

    CAS  PubMed  Google Scholar 

  160. Okada Y. From the era of genome analysis to the era of genomic drug discovery: a pioneering example of rheumatoid arthritis. Clin Genet. 2014;86(5):432–40.

    CAS  PubMed  Google Scholar 

  161. Ludvigsson JF, et al. Journal of Clinical immunology. 2014;34(4):444–51. https://doi.org/10.1007/s10875-014-0009-4.

  162. Palm NW, et al. Cell. 2014;158(5):1000–1010. https://doi.org/10.1016/j.cell.2014.08.006.

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Authors and Affiliations

  1. Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Judith R. Kelsen & Trusha Patel

  2. Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Kathleen Sullivan

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  1. Judith R. Kelsen
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  2. Trusha Patel
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  3. Kathleen Sullivan
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Correspondence to Judith R. Kelsen .

Editor information

Editors and Affiliations

  1. Division of GI, Hepatology & Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Petar Mamula

  2. Division of GI, Hepatology & Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Judith R. Kelsen

  3. Division of GI, Hepatology & Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Andrew B. Grossman

  4. Division of GI, Hepatology & Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Robert N. Baldassano

  5. Division of Pediatric Gastroenterology, Prisma Health Children’s Hospital—Upstate, Greenville, SC, USA

    Jonathan E. Markowitz

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Kelsen, J.R., Patel, T., Sullivan, K. (2023). Immune Dysregulation Associated with Very Early-Onset Inflammatory Bowel Disease. In: Mamula, P., Kelsen, J.R., Grossman, A.B., Baldassano, R.N., Markowitz, J.E. (eds) Pediatric Inflammatory Bowel Disease. Springer, Cham. https://doi.org/10.1007/978-3-031-14744-9_5

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