#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Crohn’s disease and ulcerative colitis – current view on genetic determination, immunopathogenesis and biologic therapy


Authors: M. Buc
Authors‘ workplace: Imunologický ústav, Lekárska fakulta UK, Bratislava, Slovenská republika
Published in: Epidemiol. Mikrobiol. Imunol. 66, 2017, č. 4, s. 189-197
Category: Review Article

Overview

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the intestine, also called inflammatory bowel diseases (IBD), which are not caused by pathogenic microorganisms but result from non-specific inflammatory processes in the bowel. IBD are polygenic diseases, as evidenced by the genome-wide association studies (GWAS), which have discovered more than 200 genes or genetic regions to be associated with IBD. Some of them are specific for CD or UC; however, there are 110 overlapping genes. In the pathogenesis of CD, activation of adaptive immunity mediated by TH1, TH17, or TH1/TH17 cells is induced because of disturbances in the mechanisms of innate immunity and autophagocytosis. By comparison, the major events that trigger autoimmune processes in UC are an increased translocation of commensal bacteria into the submucosa because of loose inter-epithelial connections with subsequent activation of ILC2, TH9, TH2, and NKT cells. Knowledge of the pathogenesis of a disease enables an effective therapy, which is especially true for biological therapy. It is noteworthy that monoclonal antibodies directed against the major protagonists underlying both CD and UC have failed. It points to the complexity of immunopathologic processes that run in both diseases. One can suppose that a blockade of one inflammatory pathway is circumvented by an alternative pathway. TNF is the principal pro-inflammatory cytokine that plays a major role in CD and UC as well. It was therefore decided to treat IBD patients with anti-TNF monoclonal antibodies, infliximab or adalimumab. Approximately one half of the CD patients and one third of the UC patients respond to this treatment.

Keywords:
Crohn – ulcerative colitis – autophagocytosis – autoantibodies – T cells subsets – innate lymphoid cells – anti-TNF treatment


Sources

1. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology, 2004;126(6): 1504–1517.

2. Chi KR. Epidemiology: Rising in the East. Nature, 2016;540(7634): S100–S102.

3. Oostenbrug LE, van Dullemen HM, te Meerman GJ, Jansen PL. IBD and genetics: new developments. Scand J Gastroenterol Suppl, 2003(239): 63–68.

4. Halme L, Paavola-Sakki P, Turunen U, et al. Family and twin studies in inflammatory bowel disease. World J Gastroenterol, 2006;12(23): 3668–3672.

5. Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut, 2011;60(12): 1739–1753.

6. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 2012;491(7422): 119–124.

7. Biancheri P, Powell N, Monteleone G, et al. The challenges of stratifying patients for trials in inflammatory bowel disease. Trends Immunol, 2013;34(11): 564–571.

8. Ahmad T, Marshall SE, Jewell D. Genetics of inflammatory bowel disease: the role of the HLA complex. World J Gastroenterol, 2006;12(23): 3628–3635.

9. Silverberg MS, Mirea L, Bull SB, Murphy JE, Steinhart AH, Greenberg GR, et al. A population- and family-based study of Canadian families reveals association of HLA DRB1*0103 with colonic involvement in inflammatory bowel disease. Inflam Bowel Dis, 2003;9(1): 1–9.

10. Abreu MT, Taylor KD, Lin YC, Hang T, Gaiennie J, Landers CJ, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn‘s disease. Gastroenterology, 2002;123(3): 679–688.

11. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol, 2010;11(1): 55–62.

12. Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet, 2007;39(2): 207–211.

13. Alenghat T, Osborne LC, Saenz SA, et al. Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature, 2013;504(7478): 153–157.

14. Kugelberg E. Immune homeostasis: balancing the gut. Nat Rev Immunol, 2013;13(12): 848–849.

15. Lee JC, Espeli M, Anderson CA, et al. Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway. Cell, 2013;155(1): 57–69.

16. Leavy O. Immunogenetics: SNPing at FOXO3 to limit inflammation. Nat Rev Immunol, 2013;13(11): 771.

17. Olaison G, Leandersson P, Sjodahl R, Tagesson C. Intestinal permeability to polyethyleneglycol 600 in Crohn‘s disease. Peroperative determination in a defined segment of the small intestine. Gut, 1988;29(2): 196–199.

18. Ukabam SO, Clamp JR, Cooper BT. Abnormal small intestinal permeability to sugars in patients with Crohn‘s disease of the terminal ileum and colon. Digestion, 1983;27(2): 70–74.

19. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn‘s disease. Nat Genet, 2008;40(8): 955–962.

20. Libioulle C, Louis E, Hansoul S, Sandor C, Farnir F, Franchimont D, et al. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet, 2007;3(4): e58.

21. Marks DJ, Harbord MW, MacAllister R, et al. Defective acute inflammation in Crohn‘s disease: a clinical investigation. Lancet, 2006;367(9511): 668–678.

22. Sewell GW, Marks DJ, Segal AW. The immunopathogenesis of Crohn‘s disease: a three-stage model. Curr Opin Immunol, 2009;21(5): 506–513.

23. Segal AW. Making sense of the cause of Crohn‘s − a new look at an old disease. F1000Res, 2016;5: 2510–2545.

24. MacDermott RP, Nash GS, Bertovich MJ, et al. Altered patterns of secretion of monomeric IgA and IgA subclass 1 by intestinal mononuclear cells in inflammatory bowel disease. Gastroenterology, 1986;91(2): 379–385.

25. Yoshida EM, Chan NH, Herrick RA, et al. Human immunodeficiency virus infection, the acquired immunodeficiency syndrome, and inflammatory bowel disease. J Clin Gastroenterol, 1996;23(1): 24–28.

26. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol, 2003;3(7): 521–533.

27. Pasparakis M. Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol, 2009;9(11): 778–788.

28. Watanabe T, Kitani A, Murray PJ, Strober W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol, 2004;5(8): 800–808.

29. Netea MG, Kullberg BJ, de Jong DJ, et al. NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn‘s disease. Eur J Immunol, 2004;34(7): 2052–2059.

30. Wehkamp J, Harder J, Weichenthal M, et al. Inducible and constitutive beta-defensins are differentially expressed in Crohn‘s disease and ulcerative colitis. Inflam Bowel Dis, 2003;9(4): 215–223.

31. Lukas D, Yogev N, Kel JM, et al. TGF-beta inhibitor Smad7 regulates dendritic cell-induced autoimmunity. Proc Ntl Acad Sci USA, 2017, v tlači.

32. Monteleone G, Pallone F, MacDonald TT. Smad7 in TGF-beta-mediated negative regulation of gut inflammation. Trends Immunol, 2004;25(10): 513–517.

33. Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature, 1997;389(6651): 631–635.

34. Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut, 2003;52(1): 65–70.

35. Neurath MF, Finotto S, Fuss I, et al. Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question. Trends Immunol, 2001;22(1): 21–26.

36. Verdier J, Begue B, Cerf-Bensussan N, Ruemmele FM. Compartmentalized expression of Th1 and Th17 cytokines in pediatric inflammatory bowel diseases. Inflamm Bowel Dis, 2012;18(7): 1260–1266.

37. Lee JS, Tato CM, Joyce-Shaikh B, et al. Interleukin-23-Independent IL-17 production regulates intestinal epithelial permeability. Immunity, 2015;43(4): 727–738.

38. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn‘s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut, 2012;61(12): 1693–1700.

39. Schiering C, Krausgruber T, Chomka A, et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature, 2014;513(7519): 564–568.

40. Kugelberg E. Regulatory T cells: alarmin(g) control. Nat Rev Immunol, 2014;14(9): 579.

41. Bernink JH, Peters CP, Munneke M, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol, 2013;14(3): 221–229.

42. Magri G, Miyajima M, Bascones S, et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol, 2014;15(4): 354–364.

43. Hepworth MR, Sonnenberg GF. Regulation of the adaptive immune system by innate lymphoid cells. Curr Opin Immunol, 2014;27: 75–82.

44. Cortez VS, Robinette ML, Colonna M. Innate lymphoid cells: new insights into function and development. Curr Opin Immunol, 2015;32C: 71–77.

45. Fuss IJ, Heller F, Boirivant M, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Cin Invest, 2004;113(10): 1490–1497.

46. Walker JA, Barlow JL, McKenzie AN. Innate lymphoid cells − how did we miss them? Nat Rev Immunol, 2013;13(2): 75–87.

47. Di Sabatino A, Biancheri P, Rovedatti L, et al. New pathogenic paradigms in inflammatory bowel disease. Inflamm Bowel Dis, 2012;18(2): 368–371.

48. Martin NT, Martin MU. Interleukin 33 is a guardian of barriers and a local alarmin. Nat Immunol, 2016;17(2): 122–131.

49. Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. Immunity, 2015;42(6): 1005–1019.

50. Sponheim J, Pollheimer J, Olsen T et al. Inflammatory bowel disease-associated interleukin-33 is preferentially expressed in ulceration-associated myofibroblasts. Am J Pathol, 2010;177(6): 2804–2815.

51. Palmer G, Gabay C. Interleukin-33 biology with potential insights into human diseases. Nat Rev Rheumatol, 2011;7(6): 321–329.

52. Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology, 2005;129(2): 550–564.

53. Licona-Limon P, Kim LK, Palm NW, Flavell RA. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol, 2013;14(6): 536–542.

54. Hufford MM, Kaplan MH. A gut reaction to IL-9. Nat Immunol, 2014;15(7): 599–600.

55. Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S, et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol, 2014;15(7): 676–686.

56. Leung JM, Davenport M, Wolff MJ, et al. IL-22-producing CD4+ cells are depleted in actively inflamed colitis tissue. Mucosal Immunol, 2014;7(1): 124–133.

57. Geremia A, Biancheri P, Allan P, et al. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev, 2014;13(1): 3–10.

58. Pastorelli L, Garg RR, Hoang SB, et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc Ntl Acad Sci USA, 2010;107(17): 8017–8022.

59. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 2012;491(7422): 119–124.

60. Joshi S, Lewis SJ, Creanor S, Ayling RM. Age-related faecal calprotectin, lactoferrin and tumour M2-PK concentrations in healthy volunteers. Ann Clin Biochem, 2009;47(3): 259–263.

61. Lewis JD. The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease. Gastroenterology, 2011;140(6): 1817–1826.

62. Poullis AP, Zar S, Sundaram KK, Moodie SJ, Risley P, Theodossi A, et al. A new, highly sensitive assay for C-reactive protein can aid the differentiation of inflammatory bowel disorders from constipation- and diarrhoea-predominant functional bowel disorders. Eur J Gastroenterol Hepatol, 2002;14(4): 409–412.

63. Reese GE, Constantinides VA, Simillis C, et al. Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Am J Gastroenterol, 2006;101(10): 2410–2422.

64. Roggenbuck D, Hausdorf G, Martinez-Gamboa L, et al. Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn‘s disease. Gut, 2009;58(12): 1620–1628.

65. Papp M, Altorjay I, Norman GL, et al. Seroreactivity to microbial components in Crohn‘s disease is associated with ileal involvement, noninflammatory disease behavior and NOD2/CARD15 genotype, but not with risk for surgery in a Hungarian cohort of IBD patients. Inflamm Bowel Dis, 2007;13(8): 984–992.

66. Wei B, Huang T, Dalwadi H, et al. Pseudomonas fluorescens encodes the Crohn‘s disease-associated I2 sequence and T-cell superantigen. Infect Immun, 2002;70(12): 6567–6575.

67. Reinisch W, Hommes DW, Van Assche G, et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn‘s disease. Gut, 2006;55(8): 1138–1144.

68. Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol, 2014;14(9): 585–600.

69. Biancheri P, Di Sabatino A, Ammoscato F, et al. Absence of a role for interleukin-13 in inflammatory bowel disease. Eur J Immunol, 2014;44(2): 370–385.

70. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn‘s disease. New Engl J Med, 2010;362(15): 1383–1395.

71. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. New Engl J Med, 2005;353(23): 2462–2476.

72. Neurath MF. New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol, 2014;7(1): 6–19.

73. Jurgens M, Mahachie John JM, Cleynen I, et al. Levels of C-reactive protein are associated with response to infliximab therapy in patients with Crohn‘s disease. Clin Gastroenterol Hepatol, 2011;9(5): 421–427.

74. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn‘s disease. N Engl J Med, 2012;367(16): 1519–1528.

75. Buc M. Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis. Mediators Inflamm, 2013;2013: 963748.

76. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. New Engl J Med, 2013;369(8): 699–710.

77. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med, 2012;367(7): 616–624.

78. Wickelgren I. Immunotherapy. Can worms tame the immune system? Science, 2004;305(5681): 170–171.

79. Weinstock JV, Elliott DE. Translatability of helminth therapy in inflammatory bowel diseases. Int J Parasitol, 2013;43(3–4): 245–251.

80. Garg SK, Croft AM, Bager P. Helminth therapy (worms) for induction of remission in inflammatory bowel disease. Cochrane Database Syst Rev, 2014;1: CD009400.

81. Bender E. Cell-based therapy: Cells on trial. Nature, 2016;540(7634): S106–S108.

82. Drew L. Microbiota: Reseeding the gut. Nature, 2016;540(7634): S109–S112.

Labels
Hygiene and epidemiology Medical virology Clinical microbiology
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#