The aim of review

gastro-j

Российский журнал гастроэнтерологии, гепатологии, колопроктологии

Russian Journal of Gastroenterology, Hepatology, Coloproctology

1382-43762658-6673

«Gastro» LLC

gastro-j-1221

Research Article

НОВОСТИ КОЛОПРОКТОЛОГИИ

NEWS OF COLOPROCTOLOGY

Иммунопатогенез воспалительных заболеваний кишечника

Immunopathogenesis of inflammatory bowel diseases

Конович

Е. А.

Konovich

Ye. A.

Халиф

И. Л.

Khalif

I. L.

Шапина

М. В.

Shapina

M. V.

ФГБУ «Государственный научный центр колопроктологии» Минздрава РФРоссияFederal state-funded institution «State Scientific Center of Coloproctology» Ministry of healthcare of the Russian FederationRussian Federation

2013

22092013

2346978

2013

Конович Е.А., Халиф И.Л., Шапина М.В.

Konovich Y.A., Khalif I.L., Shapina M.V.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.gastro-j.ru/jour/article/view/1221

Цель обзора. Представить анализ данных по иммунопатогенезу воспалительных заболеваний кишечника.Основные положения. У генетически чувствительных животных воспалительные заболевания кишечника (ВЗК) развиваются при различных воздействиях на врожденную и адаптивную системы иммунитета (нокаутные и трансгенные мыши), вызывающих изменения экспрессии значимых иммунологических факторов с нарушением соотношения прои противовоспалительных клеток и молекул в их контактах со структурами микроорганизмов.Физиологическое состояние кишечника характеризуется сбалансированным взаимодействием эффекторных (Th1, Th2, Th17) и регуляторных (Treg) клеток, определяющих наличие иммунной толерантности к антигенам резидентной микрофлоры.Установленные в последние годы изменения в системе врожденного иммунитета, связанные с мутациями генов рецепторов бактериальных структур (NOD2, toll-подобных рецепторов, аутофагии), вызывают нарушение внутриклеточных сигнальных процессов и патологическую активацию клеток адаптивного иммунитета слизистой оболочки кишечника и соответствующего им профиля цитокинов с развитием хронического воспаления, которое опосредуется: при болезни Крона – Th1 и Th17клетками, цитокинами ИЛ-12, интерфероном-γ и др., при язвенном колите – Th2 и NKT-клетками, цитокинами ИЛ-4 и ИЛ-13 в сочетании с недостаточностью супрессорной функции регуляторных Т-клеток и их цитокинов TGF- (трансформирующий фактор роста) и ИЛ-10.Заключение. Исследования экспериментальных энтероколитов и ВЗК человека подтверждают иммунологическую гипотезу патогенеза: связь их развития с дефектами врожденной и адаптивной иммунной системы.

The aim of review

The aim of review. To present analysis of data on immunopathogenesis of inflammatory bowel diseases.

Key points

Key points. At genetically sensitive animals inflammatory bowel diseases (IBD) develop at various effects on innate and adaptive systems of immune defense (knock-out and transgenic mice), causing changes of expression of significant immunologic factors with distortion of pro- and anti-inflammatory cells and molecules ratio at their contact to microbiota structures. The physiological state of intestine is characterized by balanced interaction of effector (Th1, Th2, Th17) and regulatory (Treg) cells determining presence of immune tolerance to resident microflora antigens. Innate immunity changes revealed in last years, related to mutations of genes of bacterial structures receptors (NOD2, toll-like receptors, autophagy), cause disorder of endocellular signal processes and pathological activation of cells of adaptive immunodefense of intestinal mucosa and conforming profile of cytokines with development of chronic inflammation which will be mediated: at Crohn's disease – by Th1-and Th17-cells, cytokines IL-12, interferon-γ etc., at ulcerative colitis – by Th2-and NKT-cells, cytokines IL-4 and IL-3 in combination to incompetence of suppressor function of regulatory Т-cells and their cytokines TGF-β (transforming growth factor) and IL-10.

Conclusion

Conclusion. Investigations of experimental enterocolites and human IBD confirm immunologic hypothesis of pathogenesis: relation of their development to defects of innate and adaptive immune system.

воспалительные заболевания кишечникаиммунопатогенезврожденный и адаптивный иммунитетэкспериментальные модели

inflammatory bowel diseasesimmunopathogenesisinnate and adaptive immunodefensepilot models

References1

Караулов АВ, Быков СА, Быков АС. Иммунология,микробиология и иммунопатология кожи. – М., 2012.– С. 96–119.

Конович ЕА, Киркин БВ, Халиф ИЛ. IgG, IgM, IgA, секреторный IgA и комплемент C3, C4 и C9 в толстой кишке при неспецифическом язвенном колите и болезни Крона. Журн микробиол эпидемиол иммунол. 1987;1:71–5.

Фиокки К. Современные патогенетические аспекты воспалительных заболеваний кишечника. Байкальский форум по проблемам воспалительных заболеваний толстой кишки. – 2012:3–70.

Abreu MT, Fukata M, Breglio K. Innate immunity and its implications on pathogenesis of inflammatory bowel disease. In: Inflammatory bowel disease / Eds. Targan SR, Shanahan F, Karp LC. – 2010:64–81.

Broat H, Peppelenbosch MP, Hommes DW. Immunology of Crohn’s disease. Ann NY Acad Sci. 2006; 1072:135–54.

Cario E, Podolsky DK. Innate immune responses in inflammatory bowel disease. In: Immunoregulation in inflammatory bowel deseases. Falk sympos. 153 / Eds. Dignass A. et al. – 2006:3–11.

Cario E, Podolsky DK. Taking a tall on MD-2 in inflammatory bowel disease. In: Immunoregulation in inflammatory bowel diseases. Falk sympos. 153 / Eds. Dignass A. et al. – 2006:30–5.

Cario E, Podolsky DK. Toll-like receptor signaling and its relevans to intestinal inflammation. In: Inflammatory bowel disease / Eds. Domschke WW. et al. Ann NY Acad Sci. 2006; 1072:332–8.

Caron G, Duluc D, Freumaux I, et al. Direct stimulation of human T cells via TLR5 and TLR 7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J Immunol. 2005; 175 (3):1551–7.

Elson ChO, Casey TW. In vivo models of inflammatory bowel diseases. In: Inflammatory bowel disease / Eds. Targan SR. et al. – 2010:25–51.

Fava F, Danese S. Intestinal microbiota in inflammatory bowel disease: Friend or foe? World J Gastroenterol.2011; 17 (5):557–66.

Fuss IJ. The adaptive immune responses in inflammatory bowel disease. In: Inflammatory bowel diseases. Falk sympos. 153 / Eds. Dignoss A. et al. – 2006:12–20.

Gardet A, Xavier RJ. Common alleles that influence autophagy and the risk for inflammatory bowel disease. Curr Opin Immunol. 2012; 24:522–9.

Giarardin SE, Boneca IG, Viala J, et al. NOD2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003; 278:8869–72.

Gorelik L, Flavell RA. Abrogation of TGF-beta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000; 12:171–81.

Hart AL, Al-Hassi HO, Rigby RJ, et al. Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology. 2005; 129 (1):50–65.

Hausmann M, Kiessling S, Mestermann S, et al. Tolllike receptors 2 and 4 are up-regulated during intestinal inflammation. Gastroenterology. 2002; 122 (7):1987–2000.

Hawinkels LJ, Ten Dijke P. Exploring anti-TGF- therapies in cancer and fibrosis. Growth Factors. 2011; 29:140–52.

Hisamatsu T, Suzuki M, Reinecker HC, et al. CARD15/ NOD2 functions as an antibacterial factor in human intestinal epithelial cells. Gastroenterology. 2003; 124:993–1000.

Hortner M, Nielsch U, Mayr LM, et al. Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony stimulating factor receptor and modulates its signal transduction. J Immunol. 2002; 169:1219–27.

Hugot J-P. CARD 15/NOD2 Mutations in Crohn’s disease. Ann NY Acad Sci. 2006; 1072:9–18.

Hwang S, Maloney NS, Bruinsma MW, et al. Nondegradative role of Atg5-Atg12/Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. Cell Host Microbe. 2012; 11:397–409.

Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Chron’s disease. J Biol Chem. – 2003; 278:5509–12.

Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev. 2006; 212:256–71.

Janeway CA, Medzhidov R. Innate immune recognition. Annu Rev Immunol. 2002; 20:197–216.

Kaser A, Blumberg RS. Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease. Gastroenterology. 2011; 140 (6):1738–47.

Kawamura T, Kanai T, Dohi T, et al. Ectopic CD40 ligand expression on B cells triggers intestinal inflammation. J Immunol. 2004; 172:6388–97.

Kufer TA, Banks DJ, Philpott DJ. Innate immune sensing of microbes by NOD proteins. Ann NY Acad Sci. 2006; 1072:19–27.

Kuhn R, LohlerJ, Rennick D, et al. Interleukin-10 –deficient mice develop chronic enterocolitis. Cell. 1993;75:263–74.

Lee J, Mo JH, Katakura K, et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signaling in intestinal epithelial cells. Nat Cell Biol. 2006; 8 (12):1327–36.

Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011; 469:323–35.

Li Y, de Haar C, Peppelenbosch MP, van der Woude CJ. SOCS3 in immune regulation of inflammatory bowel disease and inflammatory bowel disease-related cancer. Cytokine Growth Factor Rev. 2012; 23:127–38.

MacDonald TT, Monteleone G. Adaptive immunity: Effector and inhibitory cytokine pathways in gut inflammation. In: Inflammatory bowel disease / Eds. Targan SR. et al. – 2010:82–91.

Maillard MH, Snapper SB. Cytokines and chemokines in mucosal homeostasis. In Inflammatory bowel disease / Eds. Targan SR. et al. – 2010:119–56.

Matsumura Y, Kobayashi T, Ichiyama K, et al. Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells. J Immunol. 2007;179:2170–9.

Obermeier F, Dunger N, Deml L, et al. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur J Immunol. 2002; 32 (7):2084–92.

Piessevaux J, Lavens D, Peelman F, et al. The many faces of the SOCS box. Cytokine Growth Factor Rev. 2008; 19:371–81.

Rumio C, Besusso D, Palazzo M. Degranulation of paneth cells via toll-like receptor 9. Am J Pathol. 2004; 165 (2):373–81.

Takedatsu H, Taylor KD, Mei L, et al. Linkage of CD-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBirl and ASCA and show reduced NF-B activation. Gut. 2009; 58:60–7.

Totsuka T, Kanai T, Nemoto Y, et al. IL-7 is essential for the development and the persistence of chronic colitis. J Immunol. 2007;178:4737–48.

Vijay-Kumar M, Sanders CJ, Taylor RT, et al. Detection of TLR5 results in spontaneous colitis in mice. J Clin Invest. 2007; 117 (12):3909–21.

Vijay-Kumar M, Wu H, Aitken J, et al. Activation of toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm Bowel Dis. 2007; 13 (7):856–64.

Wehkamp J, Schmid M. Defensin deficiency, intestinal microbes and clinical phenotypes of Crohn’s disease. J Leukocyte Biol. 2005; 77:460–5.

Welte T, Zhang SS, Wang T, et al. STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci USA. 2003; 100:1879–84.

White GE, Cotterill A, Addley MR, et al. Suppressor of cytokine signalling protein SOCS3 expression is increased at sites of acute and chronic inflammation. J Mol Histol. 2010; 42:137–51.

Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007; 2:541–6.

Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006; 116:1310–6.

Zeissig S, Bűrgel N, Gűnzel D, et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut. 2007; 56 (1):61–72.

The authors declare that there are no conflicts of interest present.