提示: 手机请竖屏浏览!

炎性肠病的病理生理学
Pathophysiology of Inflammatory Bowel Diseases


John T. Chang ... 其他 • 2020.12.31
相关阅读
• 克罗恩病成人患者的治疗 • 维多珠单抗与阿达木单抗治疗中度至重度溃疡性结肠炎的比较 • 溃疡性结肠炎的治疗

炎性肠病(IBD)是慢性肠道疾病,一般分为克罗恩病和溃疡性结肠炎两种亚型1。溃疡性结肠炎局限于结肠,浅表黏膜炎症向近端连续延伸,可导致溃疡、大出血、中毒性巨结肠和暴发性结肠炎。而克罗恩病可累及消化道的任何部分,病变通常不连续,以透壁性炎症为特征,可导致纤维化狭窄、瘘管和脓肿等并发症。虽然我们已在溃疡性结肠炎和克罗恩病之间观察到可能具有重要意义的差异(如免疫细胞亚群的富集程度不同2,以及可增加克罗恩病风险,但可能有助于避免溃疡性结肠炎的遗传变异[如NODPTPN22])3,但对导致这些不同临床表现的基础病理生理机制仍缺乏全面了解。此外,除这两种IBD亚型外,可能还有其他异质性,如回肠和结肠克罗恩病可能属于不同的疾病,而结肠克罗恩病可能可以根据基因表达谱进一步分成多种亚型4

IBD的治疗手段(见补充附录表S1,补充附录与本文全文可在NEJM.org获取)包括非靶向疗法(如氨基水杨酸盐、糖皮质激素和免疫调节剂),以及通过以下机制之一发挥作用的靶向生物疗法:中和可促进炎症(如抗肿瘤坏死因子[TNF]抗体)或者驱动特化免疫细胞亚群分化和功能(抗白介素-12和抗白介素-23抗体)的细胞因子,阻断这些通路下游的信号传导级联(如Janus激酶[JAK]抑制剂),或者调节淋巴细胞迁移(如抗α4β7整合素抗体)。生物疗法对许多患者有效,但多达30%的患者接受初始治疗后无效,并且在多达50%的患者中,疗效会随着时间的推移消失。虽然药物浓度不够和对药物产生免疫原性是其中一些患者治疗失败的原因,但克罗恩病和溃疡性结肠炎这两个典型亚型之外的IBD异质性可能是另一个重要因素。IBD的病理生理学涉及复杂的遗传、环境、上皮、微生物和免疫因素。本综述未涵盖上述不同领域取得的所有突破,而是着重介绍了一些最新进展。

 

肠上皮


肠上皮由单层上皮细胞组成,上皮细胞通过紧密连接相连,并间插免疫细胞(图1和表S1)6。小肠上皮是高度动态的组织,由一系列突起(绒毛)和内陷(肠腺)组成。其主要功能包括协助吸收营养物质,作为隔离肠道内容物的物理屏障,并对来自肠道微生物群和免疫系统的信号做出应答。分泌细胞包括杯状细胞,杯状细胞可产生黏液,以及对肠腔内微生物有抑制作用的抗菌肽(如三叶因子和抗胰岛素蛋白样分子β)。早期研究提示,克罗恩病患者因杯状细胞减少而出现黏液层消失7;最近的一项单细胞RNA测序(scRNA-seq)研究表明,活动性溃疡性结肠炎患者的结肠杯状细胞分泌蛋白(乳清酸蛋白四二硫化物核心域2,WFDC2)下调可能导致黏液层形成过程异常、微生物群定植和入侵增加以及上皮屏障破坏8。这些发现提示WFDC2和杯状细胞产生的其他分子可能在溃疡性结肠炎中发挥保护作用。





作者信息

John T. Chang, M.D.
From the Department of Medicine, University of California San Diego, La Jolla, and the Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego. Address reprint requests to Dr. Chang at 9500 Gilman Dr., MC0063, La Jolla, CA 92093-0063, or at changj@ucsd.edu.

 

参考文献

1. Graham DB, Xavier RJ. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 2020;578:527-539.

2. Mitsialis V, Wall S, Liu P, et al. Single-cell analyses of colon and blood reveal distinct immune cell signatures of ulcerative colitis and Crohn’s disease. Gastroenterology 2020;159(2):591.e10-608.e10.

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

4. Weiser M, Simon JM, Kochar B, et al. Molecular classification of Crohn’s disease reveals two clinically relevant subtypes. Gut 2018;67:36-42.

5. McDonald BD, Jabri B, Bendelac A. Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat Rev Immunol 2018;18:514-525.

6. Kurashima Y, Kiyono H. Mucosal ecological network of epithelium and immune cells for gut homeostasis and tissue healing. Annu Rev Immunol 2017;35:119-147.

7. Pullan RD, Thomas GA, Rhodes M, et al. Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut 1994;35:353-359.

8. Parikh K, Antanaviciute A, Fawkner-Corbett D, et al. Colonic epithelial cell diversity in health and inflammatory bowel disease. Nature 2019;567:49-55.

9. Kinchen J, Chen HH, Parikh K, et al. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell 2018;175(2):372.e17-386.e17.

10. Furey TS, Sethupathy P, Sheikh SZ. Redefining the IBDs using genome-scale molecular phenotyping. Nat Rev Gastroenterol Hepatol 2019;16:296-311.

11. Crowley E, Muise A. Inflammatory bowel disease: what very early onset disease teaches us. Gastroenterol Clin North Am 2018;47:755-772.

12. West NR, Hegazy AN, Owens BMJ, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med 2017;23:579-589.

13. Martin JC, Chang C, Boschetti G, et al. Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 2019;178(6):1493.e20-1508.e20.

14. Smillie CS, Biton M, Ordovas-Montanes J, et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 2019;178(3):714.e22-730.e22.

15. Boland BS, He Z, Tsai MS, et al. Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses. Sci Immunol 2020;5(50):eabb4432-eabb4432.

16. Corridoni D, Antanaviciute A, Gupta T, et al. Single-cell atlas of colonic CD8+ T cells in ulcerative colitis. Nat Med 2020;26:1480-1490.

17. Round JL, Palm NW. Causal effects of the microbiota on immune-mediated diseases. Sci Immunol 2018;3(20):eaao1603-eaao1603.

18. Schirmer M, Garner A, Vlamakis H, Xavier RJ. Microbial genes and pathways in inflammatory bowel disease. Nat Rev Microbiol 2019;17:497-511.

19. Skelly AN, Sato Y, Kearney S, Honda K. Mining the microbiota for microbial and metabolite-based immunotherapies. Nat Rev Immunol 2019;19:305-323.

20. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407-415.

21. Costello SP, Hughes PA, Waters O, et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 2019;321:156-164.

22. Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015;149(1):102.e6-109.e6.

23. Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017;389:1218-1228.

24. Rossen NG, Fuentes S, van der Spek MJ, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 2015;149(1):110.e4-118.e4.

25. Britton GJ, Contijoch EJ, Mogno I, et al. Microbiotas from humans with inflammatory bowel disease alter the balance of gut Th17 and RORγt+ regulatory T cells and exacerbate colitis in mice. Immunity 2019;50(1):212.e4-224.e4.

26. Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013;500:232-236.

27. Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013;504:446-450.

28. Lim B, Zimmermann M, Barry NA, Goodman AL. Engineered regulatory systems modulate gene expression of human commensals in the gut. Cell 2017;169(3):547.e15-558.e15.

29. Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. New York: Garland Science, 2016.

30. Gerlach C, Moseman EA, Loughhead SM, et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 2016;45:1270-1284.

31. Milner JJ, Nguyen H, Omilusik K, et al. Delineation of a molecularly distinct terminally differentiated memory CD8 T cell population. Proc Natl Acad Sci U S A 2020;117:25667-25678.

32. Cerutti A. The regulation of IgA class switching. Nat Rev Immunol 2008;8:421-434.

33. Leiper K, Martin K, Ellis A, et al. Randomised placebo-controlled trial of rituximab (anti-CD20) in active ulcerative colitis. Gut 2011;60:1520-1526.

34. Uzzan M, Ko HM, Rosenstein AK, Pourmand K, Colombel J-F, Mehandru S. Efficient long-term depletion of CD20+ B cells by rituximab does not affect gut-resident plasma cells. Ann N Y Acad Sci 2018;1415:5-10.

35. Brandtzaeg P, Baklien K, Fausa O, Hoel PS. Immunohistochemical characterization of local immunoglobulin formation in ulcerative colitis. Gastroenterology 1974;66:1123-1136.

36. Kawamoto S, Maruya M, Kato LM, et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 2014;41:152-165.

37. Castro-Dopico T, Dennison TW, Ferdinand JR, et al. Anti-commensal IgG drives intestinal inflammation and type 17 immunity in ulcerative colitis. Immunity 2019;50(4):1099.e10-1114.e10.

38. Chang JT, Wherry EJ, Goldrath AW. Molecular regulation of effector and memory T cell differentiation. Nat Immunol 2014;15:1104-1115.

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

40. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2016;375:1946-1960.

41. Sandborn WJ, Gasink C, Gao L-L, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012;367:1519-1528.

42. Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2019;381:1201-1214.

43. Feagan BG, Sandborn WJ, D’Haens G, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 2017;389:1699-1709.

44. Sands BE, Chen J, Feagan BG, et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology 2017;153(1):77.e6-86.e6.

45. Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis. Gastroenterology 2020;158(3):537.e10-549.e10.

46. 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;61:1693-1700.

47. Lee JS, Tato CM, Joyce-Shaikh B, et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 2015;43:727-738.

48. Maxwell JR, Zhang Y, Brown WA, et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity 2015;43:739-750.

49. Chong WP, Mattapallil MJ, Raychaudhuri K, et al. The cytokine IL-17A limits Th17 pathogenicity via a negative feedback loop driven by autocrine induction of IL-24. Immunity 2020;53(2):384.e5-397.e5.

50. Puel A, Cypowyj S, Bustamante J, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011;332:65-68.

51. Wing JB, Tanaka A, Sakaguchi S. Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 2019;50:302-316.

52. Burzyn D, Kuswanto W, Kolodin D, et al. A special population of regulatory T cells potentiates muscle repair. Cell 2013;155:1282-1295.

53. DiSpirito JR, Zemmour D, Ramanan D, et al. Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci Immunol 2018;3(27):eaat5861-eaat5861.

54. Smigiel KS, Richards E, Srivastava S, et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med 2014;211:121-136.

55. Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 2012;119:4430-4440.

56. Ohnmacht C, Park J-H, Cording S, et al. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 2015;349:989-993.

57. Sefik E, Geva-Zatorsky N, Oh S, et al. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 2015;349:993-997.

58. Maul J, Loddenkemper C, Mundt P, et al. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 2005;128:1868-1878.

59. Wang J, Ioan-Facsinay A, van der Voort EIH, Huizinga TWJ, Toes REM. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007;37:129-138.

60. Hovhannisyan Z, Treatman J, Littman DR, Mayer L. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology 2011;140:957-965.

61. Spence A, Klementowicz JE, Bluestone JA, Tang Q. Targeting Treg signaling for the treatment of autoimmune diseases. Curr Opin Immunol 2015;37:11-20.

62. Trotta E, Bessette PH, Silveria SL, et al. A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism. Nat Med 2018;24:1005-1014.

63. Khoryati L, Pham MN, Sherve M, et al. An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice. Sci Immunol 2020;5(50):eaba5264-eaba5264.

64. Desreumaux P, Foussat A, Allez M, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology 2012;143(5):1207.e2-1217.e2.

65. Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 2009;10:524-530.

66. Park CO, Kupper TS. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat Med 2015;21:688-697.

67. Matos TR, O’Malley JT, Lowry EL, et al. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones. J Clin Invest 2017;127:4031-4041.

68. Rutgeerts P, Geboes K, Vantrappen G, Kerremans R, Coenegrachts JL, Coremans G. Natural history of recurrent Crohn’s disease at the ileocolonic anastomosis after curative surgery. Gut 1984;25:665-672.

69. Hegazy AN, West NR, Stubbington MJT, et al. Circulating and tissue-resident CD4+ T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation. Gastroenterology 2017;153(5):1320.e16-1337.e16.

70. Zundler S, Becker E, Spocinska M, et al. Hobit- and Blimp-1-driven CD4+ tissue-resident memory T cells control chronic intestinal inflammation. Nat Immunol 2019;20:288-300.

71. Kumar BV, Kratchmarov R, Miron M, et al. Functional heterogeneity of human tissue-resident memory T cells based on dye efflux capacities. JCI Insight 2018;3(22):e123568-e123568.

72. Kurd NS, He Z, Louis TL, et al. Early precursors and molecular determinants of tissue-resident memory CD8+ T lymphocytes revealed by single-cell RNA sequencing. Sci Immunol 2020;5(47):eaaz6894-eaaz6894.

73. Milner JJ, Toma C, He Z, et al. Heterogenous populations of tissue-resident CD8+ T cells are generated in response to infection and malignancy. Immunity 2020;52(5):808-824.e7.

74. Labarta-Bajo L, Nilsen SP, Humphrey GC, et al. Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection. J Exp Med 2020;217(12):e20192276-e20192276.

75. Fonseca R, Beura LK, Quarnstrom CF, et al. Developmental plasticity allows outside-in immune responses by resident memory T cells. Nat Immunol 2020;21:412-421.

76. Klicznik MM, Morawski PA, Höllbacher B, et al. Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy individuals. Sci Immunol 2019;4(37):eaav8995-eaav8995.

服务条款 | 隐私政策 | 联系我们