醫(yī)學(xué)免疫學(xué)課件：Th17 Cells in Multiple Sclerosis

1、Th17 Cells in Multiple SclerosisMultiple SclerosisDemyelinating diseaseDisrupting the ability to communicateLeading to physical, mental and psychiatric problemsIncluding relapsing forms and progressive formsAutoimmune disorder affecting the central nervous systemhttp:/diseases-conditions/multiple-sc

2、lerosis/home/ovc-20131882 accessed on Dec 14th, 2015 Fig.1 Multiple sclerosisExperimental Autoimmune Encephalomyelitis(EAE)Animal ModelFig.2 Induction of EAE http:/research-resources/animal-models/584-animal-arsenal-overview-animal-models-mimic-key-aspects-ms accessed on Dec 14th, 2015 HistoryGenera

3、lly, IL-12-induced CD4+ Th1 cells are regarded to play a critical role in the pathogenesis of MS/EAEIL-12-deficiency mice are still susceptible to EAEknocking out either IL-17 or IL-23 in mice with EAE abrogated the disease and In MS patients, the proportion of Th17 cells in peripheral blood was fou

4、nd to be increased during acute relapseCD4+ Th1 and Th17 cells are associated with the pathogenesis of MS/EAEFig.3 IL-12p35/ are susceptible to EAE, while IL-12p40/ mice are resistantBruno Gran et al. J Immunol 2002;169:7104-7110Induction of Th17 cells TGF-1 + IL-6Nonpathogenic Th17 cells TGF-1 + IL

5、-6 +IL-23Pathogenic Th17 cells IL-1 + IL-6 +IL-23Pathogenic Th17 cells TGF-3 + IL-6Pathogenic Th17 cells Role of mucosal tissueLung mucosaHome to autoimmune effector and memory T cellsActivated T cells moving to bronchus-associated lymphoid tissues(BALT) and draining lymph nodesEnter the blood circu

6、lationReach the CNS Mode switch(from activation to migration)F Odoardi et al. Nature 000, 1-5 (2012) doi:10.1038/nature11337Fig.4 Switch of Tblast cells into a migratory modeGut mucosaMicrobiota and nutritional factors can modulate Th17 responses and CNS autoimmunitya substantial alleviation of EAE

7、symptoms was observed in germ-free mice and EAE susceptibility could be restored by re-colonization with SFB elevated sodium chloride concentration enhanced the generation of Th17 cellsAryl-hydrocarbon receptor (AhR)Control elements for integrating these environmental signalsExpressed on both Th17 a

8、nd Treg cellsDifferent AhR-ligand can either enhance or suppress Th17 inductionTrafficking to CNSTh17 cells initially enter CNS at the site of choroid plexus mediated by CCR6 binding to CCL20 Fig.5 Molecular mechanisms involved in T cell migration across the epithelial bloodcerebrospinal fluid barri

9、er (BCSFB)B Engelhardt et al. Trends Immuno, 2012;33:579589 Veit Rothhammer et al. J Exp Med 2011;208:2465-2476Fig.6 4-/-mice develop atypical EAE Veit Rothhammer et al. J Exp Med 2011;208:2465-2476Fig.7 Atypical EAE in 4-/- mice and predominant cerebral T cell infiltration are inhibited by administ

10、ration of blocking antibodies to CD11a (L integrin) Integrin LFA-1 facilitates Th17 cells to infiltrate into the CNSTh17 Effector Function cytokinesDirect pro-inflammatory cytokinesIL-17A, IL-17FGM-CSF(granulocyte-macrophage colony-stimulating factor)IL-6, IL-23IL-9, IL-21, IL-22, IL-26, TNF-IL-17A

11、promoted cytokinesIL-1, IL-6, GM-CSF, TNF-MMPs(matrix metalloproteinases)CXCL8(CX chemokines CX chemokine ligand 8)6 members in total, from IL-17A to IL-17FTh17 cells can produce IL-17A and IL-17Fimmune cells including CD8+ T cell, T cells, NK cells, lymphoid tissue inducer-like cells and neutrophil

12、s can also produce IL-17IL-17Rexpressed on various cells including astrocytes and microgliaIL-17Blood Brain Barrier(BBB) disruptionGeneration of reactive oxygen species(ROS) in BBB endothelial cellsActivation of contractile machineryDown-regulation and disorganization of tight junctionsOverexpressio

13、n of endothelial adhesion molecules, facilitating transmigration of other inflammatory cells including Th1 cellsProduction of MMPsDegradation of the tight junction proteinsDemyelinating processTogether with TNF-, promoting oxidative stress in oligodendrocyte, leading to apoptosis of these myelin-for

14、ming cellsExhibiting strong inhibitory effects on the maturation of oligodendrocyte lineage cells and reducing their survivalGM-CSFFig.8 GM-CSF production by Th1 and Th17 cells is required for their encephalitogenicity M. El-Behi et al. Nat Immunol 2011;12:568-75GM-CSF is proven to be indispensable

15、for EAE onset.IL-23-GM-CSF amplification loopGM-CSF induces IL-23 in APCsIL-23 upregulates GM-CSF in Th17 cellsRole of GM-CSFEnhancing Th17 differentiation and maintenance of Th17 phenotypesPromoting the production of IL-6 and IL-23 by dendritic cells and macrophagesTargeting at myeloid origin cells

16、Activation of resident microgliaRecruitment of peripheral macrophages and expansion of encephalitogenic T cellsPlasticity of Th17 cellsFig.9 Plasticity of Th17 cellsC. Sie et al. Exp Neurol 2014;262:18-27GM-CSF co-expression with IFN- and T-bet, which is important for Th1 cellsDisconnection between

17、GM-CSF and IL-17 IL-23 is important for the reprogramming of Th17 cells into T cells producing IFN-Regulation of Th17 responsesTreg cells contribute to the preservation of immune homeostasis, producing immunosuppressive cytokines, including IL-10, IL-35, and TGF-.IL-35 proliferation and development

18、of Treg cells suppress Th17 cell differentiation.IL-10 inhibits the expression of pro-inflammatory cytokines Treg cells need to sense IL-10 to control Th17 mediated inflammation and IL-10R on Tregs can lead to Stat3-dependent expression of further IL-10Nave T cellsTGF-TF: RORtTh17 cellsTGF-TF: Foxp3

19、 Treg cellsTGF-TF: T-bet Stat4Th1 cellsTGF-Balance!Vitamin A: Re-establish the balance of the Th17/Treg cell axis in individuals with MS IL-6Summary & OutlookSummaryTh17 cellsModulated by microbiota and environmental factorsCytokinesIL-17IL-23-Th17-GM-CSF axis Balance of Th17/Treg OutlookTherapyGM-C

20、SFBalance of Th17/Treg ReferenceSie, Christopher, Thomas Korn, and Meike Mitsdoerffer. Th17 cells in central nervous system autoimmunity. Experimental neurology 262 (2014): 18-27.Kostic, Milos, et al. Deleterious versus protective autoimmunity in multiple sclerosis. Cellular immunology (2015).Odoardi, Francesca, et al. T cells become licensed in the lung to enter the central nervous system. Nature 488.7413 (2012): 675-679.Gran, Bruno