Progress of Intestinal Immunity in Inflammatory Bowel Disease_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

XU Chao ¹ , SONG Haifeng ² , WANG Guanglu. ¹

1.Department of Surgery, The 522nd Hospital of PLA, Luoyang 471000, Henan Province, China;;
2.Division of Health Care, The 63880th Troops of PLA, Luoyang 471003, Henan Province, China;

Corresponding author：

Keywords：

Inflammatory bowel disease; Ulcerative colitis; Crohn disease; Immunology

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ObjectiveTo summarize the recent progress in studies of intestinal immunity in inflammatory bowel disease (IBD). MethodsThe literatures on studying the intestinal immunity in IBD, including ulcerative colitis and Crohn disease were reviewed and analyzed. ResultsIBD comprised two main diseases that cause inflammation of the intestines: ulcerative colitis and Crohn disease. Although the diseases had some features in common, there were some important differences in clinical symptoms and pathological features. Accumulating evidence suggested that IBD results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Immunity studies highlighted the importance of host-microbe interactions in the pathogenesis of these diseases. Prominent among these findings were genomic regions containing nucleotide oligomerization domain 2 (NOD2), autophagy genes, miRNAs, and components of the interleukin-23/type 17 helper T-cell (Th17) pathway. The disfunction of the intestinal microbiome, intestinal epithelium, intestinal immune cells, and the intestinal vasculature played a key role in the process of IBD. The treatment with monoclonal antibody had been introduced to treat IBD and had been certificated effective. ConclusionThe study of basic intestinal immunity and regulation network of molecules in pathogenic process of IBD provides theory basis on prevention of IBD, while related genes of IBD can offer more gene therapy targets.

Citation： XU Chao,SONG Haifeng,WANG Guanglu.. Progress of Intestinal Immunity in Inflammatory Bowel Disease. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(10): 1122-1126. doi: Copy

1.	Abraham C, Cho JH. Inflammatory bowel disease [J]. N Engl J Med, 2009, 361(21): 20662078.
2.	Cho JH, Weaver CT. The genetics of inflammatory bowel disease [J]. Gastroenterology, 2007, 133(4): 13271339.
3.	Weinstock JV. Helminths and mucosal immune modulation [J]. Ann N Y Acad Sci, 2006, 1072: 356364.
4.	Frank DN, St Amand AL, Feldman RA, et al. Molecularphylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases [J]. Proc Natl Acad Sci U S A, 2007, 104(34): 1378013785.
5.	Turner JR. Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application [J]. Am J Pathol, 2006, 169(6): 19011909.
6.	Dahan S, Roda G, Pinn D, et al. Epithelial: lamina propria lymphocyte interactions promote epithelial cell differentiation [J]. Gastroenterology, 2008, 134(1): 192203.
7.	McVay LD, Keilbaugh SA, Wong TM, et al. Absence of bacterially induced RELMbeta reduces injury in the dextran sodium sulfate model of colitis [J]. J Clin Invest, 2006, 116(11): 29142923.
8.	Habtezion A, Toivola DM, Butcher EC, et al. Keratin8deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment [J]. J Cell Sci, 2005, 118(Pt 9): 19711980.
9.	Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease [J]. Cell, 2008, 134(5): 743756.
10.	Kabashima K, Saji T, Murata T, et al. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut [J]. J Clin Invest, 2002, 109(7): 883893.
11.	Libioulle C, Louis E, Hansoul S, et al. Novel Crohn disease locus identified by genomewide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4 [J]. PLoS Genet, 2007, 3(4): e58.
12.	VijayKumar M, Sanders CJ, Taylor RT, et al. Deletion of TLR5 results in spontaneous colitis in mice [J]. J Clin Invest, 2007, 117(12): 39093921.
13.	Niess JH, Brand S, Gu X, et al. CX3CR1mediated dendritic cell access to the intestinal lumen and bacterial clearance [J]. Science, 2005, 307(5707): 254258.
14.	Johansson C, Kelsall BL. Phenotype and function of intestinal dendritic cells [J]. Semin Immunol, 2005, 17(4): 284294.
15.	Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation [J]. Immunol Rev, 2006, 212: 256271.
16.	Elson CO, Cong Y, McCracken VJ, et al. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota [J]. Immunol Rev, 2005, 206: 260276.
17.	Hue S, Ahern P, Buonocore S, et al. Interleukin23 drives innate and T cellmediated intestinal inflammation [J]. J Exp Med, 2006, 203(11): 24732483.
18.	Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease [J]. Gut, 2008, 57(12): 16821689.
19.	Velázquez P, Wei B, Braun J. Surveillance B lymphocytes and mucosal immunoregulation [J]. Springer Semin Immunopathol, 2005, 26(4): 453462.
20.	Lodes NJ, Cong YZ, Elson CO, et al. Bacterial flagellin is a dominant antigen in Crohn disease [J]. J Clin Invest, 2004, 113(9): 12961306.
21.	Jaensson E, UronenHansson H, Pabst O, et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans [J]. J Exp Med, 2008, 205(9): 21392149.
22.	Hatoum OA, Heidemann J, Binion DG. The intestinal microvasculature as a therapeutic target in inflammatory bowel disease [J]. Ann N Y Acad Sci, 2006, 1072: 7897.
23.	Abraham C, Cho JH. Functional consequences of NOD2 (CARD15) mutations [J]. Inflamm Bowel Dis, 2006, 12(7): 641650.
24.	Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2dependent regulation of innate and adaptive immunity in the intestinal tract [J]. Science, 2005, 307(5710): 731734.
25.	Lesage S, Zouali H, Cézard JP, et al. CARD15/NOD2 mutational analysis and genotypephenotype correlation in 612 patients with inflammatory bowel disease [J]. Am J Hum Genet, 2002, 70(4): 845857.
26.	Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis [J]. Am J Gastroenterol, 2004, 99(12): 23932404.
27.	Watanabe T, Asano N, Murray PJ, et al. Muramyl dipeptide activation of nucleotidebinding oligomerization domain 2 protects mice from experimental colitis [J]. J Clin Invest, 2008, 118(2): 545559.
28.	Rioux JD, Xavier RJ, Taylor KD, et al. Genomewide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis [J]. Nat Genet, 2007, 39(5): 596604.
29.	Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene ATG16L1 in mouse and human intestinal Paneth cells [J]. Nature, 2008, 456(7219): 259263.
30.	Dalal SR, Kwon JH. The role of MicroRNA in inflammatory bowel disease [J]. Gastroenterol Hepatol (NY), 2010, 6(11): 714722.
31.	Wu F, Zikusoka M, Trindade A, et al. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide2 alpha [J]. Gastroenterology, 2008, 135(5): 16241635.
32.	Wu F, Zhang S, Dassopoulos T, et al. Identification of microRNAs associated with ileal and colonic Crohn’s disease [J]. Inflamm Bowel Dis, 2010, 16(10): 17291738.
33.	Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid [J]. Science, 2007, 317(5835): 256260.
34.	Nedjic J, Aichinger M, Emmerich J, et al. Autophagy in thymic epithelium shapes the Tcell repertoire and is essential for tolerance [J]. Nature, 2008, 455(7211): 396400.
35.	Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin10 receptor [J]. N Engl J Med, 2009, 361(21): 20332045.
36.	Izcue A, Hue S, Buonocore S, et al. Interleukin23 restrains regulatory T cell activity to drive T celldependent colitis [J]. Immunity, 2008, 28(4): 559570.
37.	Saruta M, Yu QT, Avanesyan A, et al. Phenotype and effector function of CC chemokine receptor 9expressing lymphocytes in small intestinal Crohn’s disease [J]. J Immunol, 2007, 178(5): 32933300.
38.	Burton PR, Clayton DG, Cardon LR, et al. Association scan of 14 500 nonsynonymous SNPs in four diseases identifies autoimmunity variants [J]. Nat Genet, 2007, 39(11): 13291337.
39.	Silverberg MS, Cho JH, Rioux JD, et al. Ulcerative colitisrisk loci on chromosomes 1p36 and 12q15 found by genomewide association study [J]. Nat Genet, 2009, 41(2): 216220.
40.	Fernando MM, Stevens CR, Walsh EC, et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis [J]. PLoS Genet, 2008, 4(4): e1000024.
41.	Mannon PJ, Fuss IJ, Mayer L, et al. Antiinterleukin12 antibody for active Crohn’s disease [J]. N Engl J Med, 2004, 351(20): 20692079.
42.	Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin12/23 monoclonal antibody, in patients with moderatetosevere Crohn’s disease [J]. Gastroenterology, 2008, 135(4): 11301141.
43.	Elson CO, Cong Y, Weaver CT, et al. Monoclonal antiinterleukin 23 reverses active colitis in a T cellmediated model in mice [J]. Gastroenterology, 2007, 132(7): 23592370.
44.	Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease [J]. Nature, 2008, 453(7195): 620625.

1. Abraham C, Cho JH. Inflammatory bowel disease [J]. N Engl J Med, 2009, 361(21): 20662078.
2. Cho JH, Weaver CT. The genetics of inflammatory bowel disease [J]. Gastroenterology, 2007, 133(4): 13271339.
3. Weinstock JV. Helminths and mucosal immune modulation [J]. Ann N Y Acad Sci, 2006, 1072: 356364.
4. Frank DN, St Amand AL, Feldman RA, et al. Molecularphylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases [J]. Proc Natl Acad Sci U S A, 2007, 104(34): 1378013785.
5. Turner JR. Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application [J]. Am J Pathol, 2006, 169(6): 19011909.
6. Dahan S, Roda G, Pinn D, et al. Epithelial: lamina propria lymphocyte interactions promote epithelial cell differentiation [J]. Gastroenterology, 2008, 134(1): 192203.
7. McVay LD, Keilbaugh SA, Wong TM, et al. Absence of bacterially induced RELMbeta reduces injury in the dextran sodium sulfate model of colitis [J]. J Clin Invest, 2006, 116(11): 29142923.
8. Habtezion A, Toivola DM, Butcher EC, et al. Keratin8deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment [J]. J Cell Sci, 2005, 118(Pt 9): 19711980.
9. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease [J]. Cell, 2008, 134(5): 743756.
10. Kabashima K, Saji T, Murata T, et al. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut [J]. J Clin Invest, 2002, 109(7): 883893.
11. Libioulle C, Louis E, Hansoul S, et al. Novel Crohn disease locus identified by genomewide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4 [J]. PLoS Genet, 2007, 3(4): e58.
12. VijayKumar M, Sanders CJ, Taylor RT, et al. Deletion of TLR5 results in spontaneous colitis in mice [J]. J Clin Invest, 2007, 117(12): 39093921.
13. Niess JH, Brand S, Gu X, et al. CX3CR1mediated dendritic cell access to the intestinal lumen and bacterial clearance [J]. Science, 2005, 307(5707): 254258.
14. Johansson C, Kelsall BL. Phenotype and function of intestinal dendritic cells [J]. Semin Immunol, 2005, 17(4): 284294.
15. Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation [J]. Immunol Rev, 2006, 212: 256271.
16. Elson CO, Cong Y, McCracken VJ, et al. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota [J]. Immunol Rev, 2005, 206: 260276.
17. Hue S, Ahern P, Buonocore S, et al. Interleukin23 drives innate and T cellmediated intestinal inflammation [J]. J Exp Med, 2006, 203(11): 24732483.
18. Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease [J]. Gut, 2008, 57(12): 16821689.
19. Velázquez P, Wei B, Braun J. Surveillance B lymphocytes and mucosal immunoregulation [J]. Springer Semin Immunopathol, 2005, 26(4): 453462.
20. Lodes NJ, Cong YZ, Elson CO, et al. Bacterial flagellin is a dominant antigen in Crohn disease [J]. J Clin Invest, 2004, 113(9): 12961306.
21. Jaensson E, UronenHansson H, Pabst O, et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans [J]. J Exp Med, 2008, 205(9): 21392149.
22. Hatoum OA, Heidemann J, Binion DG. The intestinal microvasculature as a therapeutic target in inflammatory bowel disease [J]. Ann N Y Acad Sci, 2006, 1072: 7897.
23. Abraham C, Cho JH. Functional consequences of NOD2 (CARD15) mutations [J]. Inflamm Bowel Dis, 2006, 12(7): 641650.
24. Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2dependent regulation of innate and adaptive immunity in the intestinal tract [J]. Science, 2005, 307(5710): 731734.
25. Lesage S, Zouali H, Cézard JP, et al. CARD15/NOD2 mutational analysis and genotypephenotype correlation in 612 patients with inflammatory bowel disease [J]. Am J Hum Genet, 2002, 70(4): 845857.
26. Economou M, Trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis [J]. Am J Gastroenterol, 2004, 99(12): 23932404.
27. Watanabe T, Asano N, Murray PJ, et al. Muramyl dipeptide activation of nucleotidebinding oligomerization domain 2 protects mice from experimental colitis [J]. J Clin Invest, 2008, 118(2): 545559.
28. Rioux JD, Xavier RJ, Taylor KD, et al. Genomewide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis [J]. Nat Genet, 2007, 39(5): 596604.
29. Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene ATG16L1 in mouse and human intestinal Paneth cells [J]. Nature, 2008, 456(7219): 259263.
30. Dalal SR, Kwon JH. The role of MicroRNA in inflammatory bowel disease [J]. Gastroenterol Hepatol (NY), 2010, 6(11): 714722.
31. Wu F, Zikusoka M, Trindade A, et al. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide2 alpha [J]. Gastroenterology, 2008, 135(5): 16241635.
32. Wu F, Zhang S, Dassopoulos T, et al. Identification of microRNAs associated with ileal and colonic Crohn’s disease [J]. Inflamm Bowel Dis, 2010, 16(10): 17291738.
33. Mucida D, Park Y, Kim G, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid [J]. Science, 2007, 317(5835): 256260.
34. Nedjic J, Aichinger M, Emmerich J, et al. Autophagy in thymic epithelium shapes the Tcell repertoire and is essential for tolerance [J]. Nature, 2008, 455(7211): 396400.
35. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin10 receptor [J]. N Engl J Med, 2009, 361(21): 20332045.
36. Izcue A, Hue S, Buonocore S, et al. Interleukin23 restrains regulatory T cell activity to drive T celldependent colitis [J]. Immunity, 2008, 28(4): 559570.
37. Saruta M, Yu QT, Avanesyan A, et al. Phenotype and effector function of CC chemokine receptor 9expressing lymphocytes in small intestinal Crohn’s disease [J]. J Immunol, 2007, 178(5): 32933300.
38. Burton PR, Clayton DG, Cardon LR, et al. Association scan of 14 500 nonsynonymous SNPs in four diseases identifies autoimmunity variants [J]. Nat Genet, 2007, 39(11): 13291337.
39. Silverberg MS, Cho JH, Rioux JD, et al. Ulcerative colitisrisk loci on chromosomes 1p36 and 12q15 found by genomewide association study [J]. Nat Genet, 2009, 41(2): 216220.
40. Fernando MM, Stevens CR, Walsh EC, et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis [J]. PLoS Genet, 2008, 4(4): e1000024.
41. Mannon PJ, Fuss IJ, Mayer L, et al. Antiinterleukin12 antibody for active Crohn’s disease [J]. N Engl J Med, 2004, 351(20): 20692079.
42. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin12/23 monoclonal antibody, in patients with moderatetosevere Crohn’s disease [J]. Gastroenterology, 2008, 135(4): 11301141.
43. Elson CO, Cong Y, Weaver CT, et al. Monoclonal antiinterleukin 23 reverses active colitis in a T cellmediated model in mice [J]. Gastroenterology, 2007, 132(7): 23592370.
44. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease [J]. Nature, 2008, 453(7195): 620625.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Progress of Intestinal Immunity in Inflammatory Bowel Disease

Abstract Full text Figures/Tables Video References Cited by

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