醫(yī)學免疫學課件：The ambivalent role of Th17 cells in IBD

1、The ambivalent role of Th17 cells in IBDContentsBrief Introduction A brief introduction to Crohns Disease (CD) and Ulcerative Colitis (UC) A brief introduction to mucosal immune systemRole of Th17 cells in IBD Local induction/expansion or migration of Th17 cells Pro-inflammatory or Anti-inflammatory

2、 Th17 cells Th17 cells and Treg cellsThe cytokines produced by Th17 cells IL-17 IL-21A brief introduction to Crohns disease (CD)1 Baumgart D C, Sandborn W J. Crohns diseaseJ. The Lancet, 2012,380(9853):1590-1605.2 Torres J, Mehandru S, Colombel J, et al. Crohns diseaseJ. The Lancet, 2016A brief intr

3、oduction to Ulcerative colitis (UC)1 Ungaro R, Mehandru S, Allen P B, et al. Ulcerative colitisJ. The Lancet, 2016.Mucosal immune system involved in defenseFigure from: Abraham C, Cho J H. Mechanisms of Disease: Inflammatory Bowel DiseaseJ. NEJM, 2009.Three aspects:Physical and chemical epithelium b

4、arrier 1. Tightly arranged epithelium 2. Chemical barrier 3. Microbial barrierInnate immune defense 1. PRR 2. Antigen presentation by DCAdaptive immune system Adaptive immune system involved in IBDFigure from: Torres J, Mehandru S, Colombel J, et al. Crohns diseaseJ. The Lancet, 2016.Induction/expan

5、sion of Th17 cellsAntigenTCRNFAT/NF-B/AP-1Cytokine (TGF-, IL-6)Cytokine receptorSTAT3Master TF (RORt)IL-17, IL-23, IL-22, IL-21Yosef N, Shalek A K, Gaublomme J T, et al. Dynamic regulatory network controlling Th17 cell differentiationJ. Nature, 2013Migration of Th17 cell to the gut maintaining homeo

6、stasis1 Esplugues, E., et al., Control of TH17 cells occurs in the Small Intestine. Nature. 2011Th17 cells, by up-regulating CCL20 expression in small intestine via IL-17 signaling, develop an elegant mechanisms to limit pathogenicity in order to avoid severe immune response. Pro-inflammatory Th17 c

7、ells, beneficial in clearing infection, but immunopathogenic in excess, can be controlled by acquisition of immune-suppressive phenotype or elimination into the intestinal lumen. Phenotype of Th17 cells : pro-inflammatory v.s anti-inflammatory1 Ghoreschi, K., et al., Generation of pathogenic TH17 ce

8、lls in the absence of TGF- signalling. Nature, 2010. Induction of Th17 cell without TGF-; while in the present of IL-1, IL-6, IL-23;IL-1 and IL-6 can promote the expression of IL-23;Th17 induced by IL-23 Th17 (23) express T-bet gene thus production of IFN-Injection of Th17 (23) cell into EAE mice, w

9、hich shows severe symptoms with more IL-17+ and IFN-+ CD4+ T cells.Phenotype of Th17 cells : pro-inflammatory v.s anti-inflammatory1 Lee, Y., et al., Induction and molecular signature of pathogenic TH17 cells. Nature Immunology, 2012.Pro-inflammatory and anti-inflammatory are not synonymous with pat

10、hogenic and protective. Pro-inflammatory will be protective during infection, but pathogenic during autoimmunity.Differences between pro-inflammatory and anti-inflammatory Th17 cells:Pro-inflammatory Th17 cells: produce IFN- and IL-17AAnti-inflammatory Th17 cells: produce IL-17A and IL-10Pathogenic

11、cell produce more IL-23R than non-pathogenic cellsPhenotype of Th17 cells : pro-inflammatory v.s anti-inflammatory1 CE, Z., et al., Pathogen-induced human TH17 cells produce IFN- or IL-10 and are regulated by IL-1. Nature, 2012. Candida albicans-specific Th17 cells pathogenic produce IFN- Staphyloco

12、ccus aureusspecific Th17 cells non-pathogenic produce IL-10Th17 and TregThe existence of TGF-The existence of IL-23The relationship between Treg and Th17 relies on characteristics of inflammatory microenvironment.1 Zhou, L., et al., TGF-induced Foxp3 inhibits Th17 cell differentiation by antagonizin

13、g RORt function. Nature, 2008. 2 Hovhannisyan, Z., et al., Characterization of Interleukin-17Producing Regulatory T Cells in Inflamed Intestinal Mucosa From Patients With Inflammatory Bowel Diseases. Gastroenterology, 2011. 140(3): p. 957-965.Th17 and Treg1 Harrison, O.J., et al., Epithelial-derived

14、 IL-18 regulates Th17 cell differentiation and Foxp3(+) Treg cell function in the intestine. Mucosal immunology, 2015. 8(6): p. 1226-36.2 Sara, O. and T.T. Pizarro, The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome. Frontiers in Immunology, 2016. Metabolic control: Normoxic and h

15、ypoxic condition promote Th17 differentiation, prevent Treg commitment Commensal flora control:SFB (segmented filamentous bacteria)Bacteroides fragilis IL-17IL-17 family: IL-17A (IL-17) , IL-17B, IL-17C, IL-17D, IL-17E(IL-25), IL-17F；IL-17A & IL-17F use common receptor: IL-17RA1.Korn, T., et al., IL

16、-17 and Th17 Cells. Annu. Rev. Immunol., 2009. 27(1): p. 485-517.2 Fujino, S., et al., Increased expression of interleukin 17 in inflammatory bowel disease. Gut, 2003. 52(1): p. 65-70.3. PhD, Z.Z.M., et al., Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflammatory Bowel

17、Diseases, 2006. 12(5): p. 382388.4 Seiderer, J., et al., Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohns disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflammatory Bowel Diseases, 2008. 14(4): p.

18、437-45.Controversial role of IL-171 Chang, S.H., et al., 112 Regulation of inflammatory responses by IL-17R. Journal of Experimental Medicine, 2008. 205(5): p.: 10631075.2 William OConnor, J., et al., A protective function for interleukin 17A in T cellmediated intestinal inflammation. Nature Immunol

19、ogy, 2009. 10(6): p. 603-9.3 Coccia, M., et al., IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells. The Journal of experimental medicine, 2012. 209(9): p. 1595-609.IL-17 and the barrier function of epitheli

20、um1 Song X, Dai D, He X, et al. Growth Factor FGF2 Cooperates with Interleukin-17 to Repair Intestinal Epithelial Damage.J. Immunity, 2015.2 Yang Y, Torchinsky M B, Gobert M, et al. Focused Specificity of Intestinal Th17 Cells towards Commensal Bacterial AntigensJ. Nature, 2014.3 Sano, T., et al., A

21、n IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses. Cell, 2015.Secukinumab, a human IL-17A monoclonal antibody1 Hueber W. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohns disease: unexpected results of a randomised,

22、 double-blind placebo-controlled trial.J. Gut, 2012,61(12):1693-1700.2 Mcinnes, I.B., Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II

23、 proof-of-concept trial. Annals of the Rheumatic Diseases, 2014. 73(2): p. 349-56.IL-21proinflammatory function in IBDIL-21, belong to IL-2 cytokine family, mainly secreted by Th17 cells IL-21 itself can promote Th17 cell differentiation, thus act as a positive feedback mechanismIL-21R positive cell

24、s are significantly increased in inflamed mucosa of IBD patients, mainly in peripheral blood and lamina propria CD4+, CD8+ T, B and NK cells. 1 Yang L, Anderson D E, Baecher-Allan C, et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.J. Nature, 20082 Liu Z, Yang L, Cui

25、Y, et al. Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease.J. Inflammatory Bowel Diseases, 2009IL-21proinflammatory function in IBDFina D, Sarra M, Fantini M C, et al. Regulation of gut inflammation and th17 cell response by

26、 interleukin-21.J. Gastroenterology, 2008.Wild typeCompare Wild type and IL-21-KOCompare wild type and IL-21R/Fc treated Compare health and CD patientsHigher IL-21 and IL-17 in CD patients than health controlIL-21protective function1 Salzer E, Kansu A, Sic H, et al. Early-onset inflammatory bowel di

27、sease and common variable immunodeficiency-like disease caused by IL-21 deficiency.J. Journal of Allergy & Clinical Immunology, 2014, 133(6):1651-1659.2 Yeste A, Mascanfroni I D, Nadeau M, et al. IL-21 induces IL-22 production in CD4+ T-cellsJ. Nature Communications, 2014, 5(6183):3753-3753.IL-21pro

28、tective function1 Yeste A, Mascanfroni I D, Nadeau M, et al. IL-21 induces IL-22 production in CD4+ T-cellsJ. Nature Communications, 2014, 5(6183):3753-3753.2 Wang Y, Jiang X, Zhu J, et al. IL-21/IL-21R signaling suppresses intestinal inflammation induced by DSS through regulation of Th responses in

29、 lamina propria in mice.J. Scientific reports, 2016,6:31881.Reference1 Baumgart D C, Sandborn W J. Crohns diseaseJ. The Lancet, 2012,380(9853):1590-1605.2 Torres J, Mehandru S, Colombel J, et al. Crohns diseaseJ. The Lancet, 20163 Ungaro R, Mehandru S, Allen P B, et al. Ulcerative colitisJ. The Lanc

30、et, 20164 Abraham C, Cho J H. Mechanisms of Disease: Inflammatory Bowel DiseaseJ. NEJM, 2009.5 Yosef N, Shalek A K, Gaublomme J T, et al. Dynamic regulatory network controlling Th17 cell differentiationJ. Nature, 20136 Esplugues, E., et al., Control of TH17 cells occurs in the Small Intestine. Natur

31、e. 20117 Ghoreschi, K., et al., Generation of pathogenic TH17 cells in the absence of TGF- signalling. Nature, 2010. 8 Lee, Y., et al., Induction and molecular signature of pathogenic TH17 cells. Nature Immunology, 20129 CE, Z., et al., Pathogen-induced human TH17 cells produce IFN- or IL-10 and are

32、 regulated by IL-1. Nature, 2012. 10 Zhou, L., et al., TGF-induced Foxp3 inhibits Th17 cell differentiation by antagonizing RORt function. Nature, 2008. 11 Hovhannisyan, Z., et al., Characterization of Interleukin-17Producing Regulatory T Cells in Inflamed Intestinal Mucosa From Patients With Inflam

33、matory Bowel Diseases. Gastroenterology, 2011. 140(3): p. 957-965.12 Harrison, O.J., et al., Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3(+) Treg cell function in the intestine. Mucosal immunology, 2015. 8(6): p. 1226-36.13 Sara, O. and T.T. Pizarro, The Treg/Th17 Axis: A D

34、ynamic Balance Regulated by the Gut Microbiome. Frontiers in Immunology, 2016. 14.Korn, T., et al., IL-17 and Th17 Cells. Annu. Rev. Immunol., 2009. 27(1): p. 485-517.15 Fujino, S., et al., Increased expression of interleukin 17 in inflammatory bowel disease. Gut, 2003. 52(1): p. 65-70.16. PhD, Z.Z.

35、M., et al., Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflammatory Bowel Diseases, 2006. 12(5): p. 382388.17 Seiderer, J., et al., Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohns disease

36、 and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflammatory Bowel Diseases, 2008. 14(4): p. 437-45.18 Chang, S.H., et al., 112 Regulation of inflammatory responses by IL-17R. Journal of Experimental Medicine, 2008. 205(5): p.: 10631075.19 William OConnor, J., et al., A protective functi

37、on for interleukin 17A in T cellmediated intestinal inflammation. Nature Immunology, 2009. 10(6): p. 603-9.20 Coccia, M., et al., IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells. The Journal of experiment

38、al medicine, 2012. 209(9): p. 1595-609.21 Song X, Dai D, He X, et al. Growth Factor FGF2 Cooperates with Interleukin-17 to Repair Intestinal Epithelial Damage.J. Immunity, 2015.22 Yang Y, Torchinsky M B, Gobert M, et al. Focused Specificity of Intestinal Th17 Cells towards Commensal Bacterial Antige

39、nsJ. Nature, 2014.23 Sano, T., et al., An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses. Cell, 2015.24 Hueber W. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohns disease: unexpected results of a randomised, double-blind placebo-controlled trial.J. Gut, 2012,61(12):1693-1700.25 Mcinnes, I.B., Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised,