Skip to main content
SpringerLink
Log in

Immune Dysregulation Associated with Very Early-Onset Inflammatory Bowel Disease

  • Chapter
  • First Online:
Book cover Pediatric Inflammatory Bowel Disease

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 occurring before the age of 5 represent a unique form of disease, termed very early-onset (VEO)-IBD, which is phenotypically and genetically distinct from older-onset IBD. VEO-IBD is associated with increased disease severity, aggressive progression, and poor responsiveness to most conventional therapies. Here we discuss the phenotypic nature of VEO-IBD, the recent identification of novel gene variants associated with disease, and the functional immunologic studies interrogating the contribution of specific genetic variants to the development of chronic intestinal inflammation.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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.

    Article  CAS  PubMed  PubMed Central  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jacobs J, Braun J. Host genes and their effect on the intestinal microbiome garden. Genome Med. 2014;6(12):119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. 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.

    Article  PubMed  CAS  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  PubMed  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  33. Glocker EO, et al. Infant colitis – It’s in the genes. Lancet. 2010;376(9748):1272.

    Article  PubMed  Google Scholar 

  34. 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.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  44. Benchimol EI, et al. Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterol. 2014;147(4):803–13 e7; quiz e14–5.

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  46. Kelsen JR, et al. Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease. Cell Mol Gastroenterol Hepatol. 2015;1(5):462–76.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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.

    Article  CAS  PubMed  Google Scholar 

  68. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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.

    Article  CAS  PubMed  Google Scholar 

  72. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  78. 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.

    Article  PubMed  Google Scholar 

  79. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  81. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  84. 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.

    Article  CAS  PubMed  Google Scholar 

  85. 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.

    Article  CAS  PubMed  Google Scholar 

  86. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 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.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  90. 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.

    Article  CAS  PubMed  Google Scholar 

  91. Nielsen C, et al. Immunodeficiency Associated with a Nonsense Mutation of IKBKB. J Clin Immunol. 2014;34(8):916–21.

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  93. 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.

    Article  CAS  PubMed  Google Scholar 

  94. 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.

    Google Scholar 

  95. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  104. 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 

  105. Zeissig S, et al. Early-onset Crohn’s disease and autoimmunity associated with a variant in CTLA-4. Gut. 2015;64(12):1889–97.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 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 

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

    Article  CAS  PubMed  Google Scholar 

  113. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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 

  115. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  117. 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.

    Article  CAS  PubMed  Google Scholar 

  118. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  120. 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 

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

    Article  CAS  PubMed  Google Scholar 

  122. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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.

    Article  CAS  PubMed  Google Scholar 

  125. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  133. 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.

    Article  CAS  PubMed  Google Scholar 

  134. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hepworth MR, et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science. 2015;348(6238):1031–5.

    Google Scholar 

  136. Okada Y, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376–81.

    Article  CAS  PubMed  Google Scholar 

  137. Ludvigsson JF, Neovius M, Hammarstrom L. Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study. J Clin Immunol. 2014;34(4):444–51.

    Article  CAS  PubMed  Google Scholar 

  138. Palm NW, et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell. 2014;158(5):1000–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  140. 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.

    Article  PubMed  Google Scholar 

  141. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  144. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  146. 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.

    Article  CAS  PubMed  Google Scholar 

  147. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  149. Li Q, et al. Variants in TRIM22 that affect NOD2 signaling are associated with very-early-onset inflammatory bowel disease. Gastroenterology. 2016;150(5):1196–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sawyer SL, Emerman M, Malik HS. Discordant evolution of the adjacent antiretroviral genes TRIM22 and TRIM5 in mammals. PLoS Pathog. 2007;3(12):e197.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Yu S, et al. Identification of tripartite motif-containing 22 (TRIM22) as a novel NF-kappaB activator. Biochem Biophys Res Commun. 2011;410(2):247–51.

    Article  CAS  PubMed  Google Scholar 

  152. Duan Z, et al. Identification of TRIM22 as a RING finger E3 ubiquitin ligase. Biochem Biophys Res Commun. 2008;374(3):502–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Judith Kelsen MD

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

    Kathleen Sullivan MD, PhD

Authors
  1. Judith Kelsen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathleen Sullivan MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Judith Kelsen MD .

Editor information

Editors and Affiliations

  1. Division of GI, Hepatology & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Petar Mamula

  2. Division of GI, Hepatology & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Andrew B. Grossman

  3. Division of GI, Hepatology & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Robert N. Baldassano

  4. Division of GI, Hepatology & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Judith R. Kelsen

  5. Division of Pediatric Gastroenterology & Nutrition, University of South Carolina School of Medicine - Greenville, Greenville, South Carolina, USA

    Jonathan E. Markowitz

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Kelsen, J., Sullivan, K. (2017). Immune Dysregulation Associated with Very Early-Onset Inflammatory Bowel Disease. In: Mamula, P., Grossman, A., Baldassano, R., Kelsen, J., Markowitz, J. (eds) Pediatric Inflammatory Bowel Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-49215-5_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-49215-5_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-49213-1

  • Online ISBN: 978-3-319-49215-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation