炎性腸病腸道免疫學的研究進展_《中國普外基礎與臨床雜志》

作者：

徐超 ¹ , 宋海峰 ² , 王光陸 ¹

1.解放軍第522醫院外科(河南洛陽 471000);;
2.解放軍63880部隊后勤部衛生處(河南洛陽 471003);

關鍵詞：

炎性腸病潰瘍性結腸炎克羅恩病免疫學

視頻：

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目的總結有關炎性腸病腸道免疫學領域的最新進展。方法采用文獻復習的方法，對炎性腸病包括潰瘍性結腸炎及克羅恩病免疫學領域的相關文獻進行綜述。結果潰瘍性結腸炎和克羅恩病是炎性腸病的兩種主要類型，兩者的臨床和病理特征既有重疊又有區別。免疫學的研究表明，易感個體對腸道微生物“過激”的炎癥反應以及機體與微生物之間的相互作用在炎性腸病發生、發展中發揮重要作用。這一領域的突出成果包括發現了核苷酸結合寡聚化結構域2(NOD2)基因、自體吞噬基因、微RNA、白細胞介素23/Th17通路等。腸道細菌、腸上皮、腸道免疫細胞以及腸道微血管的功能異常在炎性腸病的病程進展中起關鍵作用。目前一些單克隆抗體已被用來治療炎性腸病，并取得良好效果。結論對炎性腸病發病過程中腸道黏膜免疫基礎和分子網絡調控的研究，將為炎性腸病的防治提供理論依據; 對炎性腸病相關基因的研究，又可為炎性腸病治療提供更多的基因治療靶點。

引用本文： 徐超,宋海峰,王光陸. 炎性腸病腸道免疫學的研究進展. 中國普外基礎與臨床雜志, 2011, 18(10): 1122-1126. doi: 復制

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.

《中國普外基礎與臨床雜志》

炎性腸病腸道免疫學的研究進展

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

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《中國普外基礎與臨床雜志》

炎性腸病腸道免疫學的研究進展

摘要 全文 圖表 視頻 參考文獻 施引文獻 補充材料

Format

Content

摘要全文圖表視頻參考文獻施引文獻補充材料