医学免疫学课件：Th17细胞与系统性红斑狼疮

1、Th17 Cells & Systemic Lupus ErythematosusContentSystemic lupus erythematosus （SLE）1.1 Brief introduction1.2 Clinical menifestations & complications1.3 Pathophysiology & Conventional treatment1.4 EtiologyTh17 cells2.1 History & Discovery2.2 Properties2.3 mechanisms of Th17 cell differentiation & IL-1

2、7A expressionTh17 cells pathway in SLE3.1 Hypothesis：Th17 cells in other human autoimmune diseases 3.2 Phenomena：Incresed IL-17 level and Th17 cells in SLE3.3 Proofs：Induction of SLE by Th17 cells and IL-173.4 Mechanisms：How does IL-17 promote SLE?Clinical application4.1 Therapeutic potential of tar

3、geting Th17 pathway in SLE4.2 Diagnostic potentialProspects5.1 Fundamental research of Th17 cells5.2 Clinical application1. Systemic lupus erythematosus （SLE）1.1 Brief introduction1.2 Clinical menifestations & complications1.3 Pathophysiology1.4 Etiology1.1 brief introductionSystemic Lupus Erythemat

4、osus （SLE）Autoimmune diseaseConnective tissueskin, kidney, CNS, joint, heart, vessels et alMost complexIncurable, unpredictableEpidemiologyWomen, especially pregnant women, more susceptible (:=9:1)Incidence: 53/100,000 in US, 40/100,000 in Northern Europe1.2 Clinical menifestations & ComplicationsDe

5、rmatological symptoms(30%)Skin injuryTypical “butterfly rash” (30%-50%)discoid lupus（in some patients）Lupus nephritis (LN，50%-70%)Strongest predictor of poor prognosisSyptoms in joints (65%)CNS lupusNeuropsychiatric involvement（NPSLE）Images derived from： /wiki/Systemic_lupus_erythematosus1.3 Pathoph

6、ysiology & Conventional treatmentPathophysiology: Emerging of multiple autoantibodiesAnti dsNA, histone, SM, Ro, RNP antibodies help in diagnosisConventional treatmentCorticosteroidsImmunosuppressantsHydroxychloroquine a kind of anti-malarial drugs1 Li D, Guo B, Wu H, et al. Interleukin-17 in system

7、ic lupus erythematosus: A comprehensive reviewJ. Autoimmunity, 2015, 48(6).1.4 Etiology Mutifactorial disease Genetic susceptibilityHLA class, , IRF5, PTPN22, IRF5, PTPN22, STAT4, CDKN1A, ITGAM, BLK, TNFSF4 et alEnvironmental effectsUltraviolet (UV) skin lesionInfection by viruses & bacteriaEstrogen

8、Disturbances in both innate & adaptive immunityApoptotic cell clearanceCytokinesB-cell immunityT-cell signalling2. Th17 cells2.1 History & Discovery2.2 Properties2.3 mechanisms of Th17 cell differentiation & IL-17A expression2.1 History & DiscoveryInterleukin-17 （IL-17）Hallmark cytokine of Th17 cell

9、sIL-17A: discovered in 1993 named as CTLA86 family members: IL-17A to IL-17F based on aa sequence homologyIL-17Ealso known as IL-25Potentiates type 2 allergic responsesIL-17Acommonly known as IL-17Also produced by T cells, lymphoid tissue inducer cells (LTi), innate lymphoid cells (ILCs), and natura

10、l killer (NK) cellsIL-17Fmost closely related to IL-17AIL-17E IL-17A IL-17F IL-17C IL-17B IL-17D1 Gu C, Wu L, Li X. IL-17 family: cytokines, receptors and signaling.J. Cytokine, 2013, 64(2):477-485.2.1 History & DiscoveryIL-17RIdentified soon after the discovery of IL-175 family members: IL-17RA, IL

11、-17RB, IL-17RC, IL-17RD, IL-17REIL-17RA: ubiquitously expressed on many cellsIL-17ABinds to IL-17RA/IL-17RCIL-17FAlso signals through IL-RA/IL-17RCWith 1%-10% affinity 1 Gu C, Wu L, Li X. IL-17 family: cytokines, receptors and signaling.J. Cytokine, 2013, 64(2):477-485.2.1 History & DiscoveryTh17 ce

12、llsIndirectly discoveried by functional analysis of IL-23 & IL-12 (Murphy et al., 2003)Induction of Collagen-induced arthritis (CIA) in p19-/- and p35-/-IL-12 IL-231 Patel D, Kuchroo V. Th17 Cell Pathway in Human Immunity: Lessons from Genetics and Therapeutic InterventionsJ. Immunity, 2015, 43(6):1

13、040-1051.1 Murphy C A, Langrish C L, Chen Y, et al. Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune InflammationJ. Journal of Experimental Medicine, 2003, 198(12):1951-7.2.2 Properties of Th17 cellsA subset of CD4+ T helper (Th) cellsMainly produce IL-17A, IL-17F, I

14、L-22, IL-21IL-17 stimulates IL-6, IL-1, TNF, GM-CSF & chemokinesImportant role in host defense against infectionBy recruiting neutrophils & macrophages to infected tissuesCandida albicansStaphylococcus aureus1 Dong C. TH17 cells in development: an updated view of their molecular identity and genetic

15、 programming.J. Nature Reviews Immunology, 2008, 8(5):337-348.2.3 mechanisms of Th17 cell differentiation & IL-17A expression2.3.1 Th17 cell differentiation: Cytokine-mediated regulationAn emerging model includes 3 overlapping stepsDifferentiation: TGF- + IL-6Inducing the expression of ROR-t (retino

16、ic acidrelated orphan receptor t)ROR-t: a master transcription factor in Th17 cellsAmplification: IL-21 produced by developing Th17 cellsStabilization: IL-23IL-1: augments the differentiation1 Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming.J. N

17、ature Reviews Immunology, 2008, 8(5):337-348.2.3 mechanisms of Th17 cell differentiation & IL-17A expression2.3.2 Th17 cell differentiationIntracellular signaling pathwaysComplex transcription factor networkEpigenetic modificationsOther TFs: Runx1, RORa, IRF-4, BATF, NF-AT and AhR1 Li D, Guo B, Wu H

18、, et al. Interleukin-17 in systemic lupus erythematosus: A comprehensive reviewJ. Autoimmunity, 2015, 48(6).1 Li D, Guo B, Wu H, et al. Interleukin-17 in systemic lupus erythematosus: A comprehensive reviewJ. Autoimmunity, 2015, 48(6).3. Th17 cells pathway in SLE3.1 Hypothesis：Th17 cells in other hu

19、man autoimmune diseases 3.2 Phenomena：Incresed IL-17 level and Th17 cells in SLE3.3 Proofs：Induction of SLE by Th17 cells and IL-173.4 Mechanisms：How does IL-17 promote SLE?3.1 Hypothesis：Th17 in other human autoimmune diseases Mice loss of IL-17A, IL-17F, or their receptors resistant toEAECIAIL-17

20、has been identified in human in lesions ofMultiple sclerosis (MS)PsoriasisSjogrens syndromeInflammatory bowel disease (IBD)Whole-genome transcriptomic analysis of the CNS of the MS patients3.1 Hypothesis：Th17 in other human autoimmune diseasesThe role of IL-23/Th17 axis in autoimmune diseaseInitiati

21、onProgressionMaintenace1 Fragoulis G E, Siebert S, Mcinnes I B. Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases.J. Medicine, 2016, 67(67).3.2 Phenomena：Incresed IL-17 level & Th17 in SLEIn lupus animal modelsIncreased serum levels of IL-17A & IL-21Patients with SLEIL-1

22、7A is higherNew-onset SLEPediatric SLEJuvenile SLEPregnant women affected by SLEFrequency of Th17, IL-17A mRNA in activated PBMCs: also increased significantlySystemic Lupus Erythematosus Disease Activity Index (SLEDAI)Correlates positively with Th17 or IL-17AIL-17F: similar results with IL-17AResul

23、ts not always consistent3.3 Proofs：Induction of SLE by Th17 & IL-17The role of IL-17 & Th17Can promote SLE?Or merely associate with SLE?Direct evidenceAmarilyo et al., 2014Wild-type (WT): C57BL/6 (B6) miceIL-17 deficient (IL-17-/-) miceTreated with pristane: a lupus-inducing agent1 Amarilyo G, Loure

24、no E V, Shi F D, et al. IL-17 promotes murine lupus.J. Journal of Immunology, 2014, 193(2):540-3.Result 1: IL-17 deficiency protects mice from serologic manifestations of SLE1 Amarilyo G, Loureno E V, Shi F D, et al. IL-17 promotes murine lupus.J. Journal of Immunology, 2014, 193(2):540-3.Result 2:

25、IL-17 deficiency prevents lupus nephritis（LN）1 Amarilyo G, Loureno E V, Shi F D, et al. IL-17 promotes murine lupus.J. Journal of Immunology, 2014, 193(2):540-3.3.4 Mechanisms：How does IL-17 promote SLE?1 Li D, Guo B, Wu H, et al. Interleukin-17 in systemic lupus erythematosus: A comprehensive revie

26、wJ. Autoimmunity, 2015, 48(6).1 Konya C, Paz Z, Tsokos G C. The role of T cells in systemic lupus erythematosus: an update.J. Current Opinion in Rheumatology, 2014, 26(5):493-501.1 Konya C, Paz Z, Tsokos G C. The role of T cells in systemic lupus erythematosus: an update.J. Current Opinion in Rheuma

27、tology, 2014, 26(5):493-501.4. Clinical application4.1 Therapeutic potential of targeting Th17 pathway in SLE4.2 Diagnostic potential4.1 Therapeutic potential of targeting Th17 pathway in SLEThe strategies for anti-IL-17 therapySpecific antibodies directed against IL-17Blocking of the IL-17 receptor

28、IL-17 vaccineSmall-molecule inhibitors of IL-17Several IL-17A pathway blockers into clinical trialsAnti-IL-17A monoclonal antibodySecukinumab (Trade name Cosentyx, Novartis)Ixekizumab (Trade name Taltz, Eli Lilly)Anti-17RA monoclonal antibodybrodalumabImage derived from: /0b0e17dc-c4a4-fc77-7f19-ac1

29、b74511b70/Ishtml1 Patel D, Kuchroo V. Th17 Cell Pathway in Human Immunity: Lessons from Genetics and Therapeutic InterventionsJ. Immunity, 2015, 43(6):1040-1051.SLE？1 Patel D, Kuchroo V. Th17 Cell Pathway in Human Immunity: Lessons from Genetics and Therapeutic InterventionsJ. Immunity,

30、 2015, 43(6):1040-1051.4.2 Diagnostic potential1 Cheng F, Guo Z, Xu H, et al. Decreased plasma IL22 levels, but not increased IL17 and IL23 levels, correlate with disease activity in patients with systemic lupus erythematosus.J. Annals of the Rheumatic Diseases, 2009, 68(4):604-6.5. Prospects5.1 Fun

31、damental research of Th17 cells5.2 Clinical application5.1 Fundamental research of Th17 cellsThe precise role of Th17 in SLE in humansMany other cells in SLEDouble-negative T cellsT regulatory cellsT cellsExtrafollicular T cellsB cells1 Suarez-Fueyo A, Bradley SJ & Tsokos GC. T cells in Systemic Lup

32、us Erythematosus.J.Current Opinion In Immunology, 2016, 43:32-38.5.2 Clinical applicationSeveral ongoing issues for IL-17-related therapyClinical trials in SLELong-term safety & efficacyHigh heterogeneity for SLEReferences1 Li D, Guo B, Wu H, et al. Interleukin-17 in systemic lupus erythematosus: A

33、comprehensive reviewJ. Autoimmunity, 2015, 48(6).2 Gu C, Wu L, Li X. IL-17 family: cytokines, receptors and signaling.J. Cytokine, 2013, 64(2):477-485.3 Patel D, Kuchroo V. Th17 Cell Pathway in Human Immunity: Lessons from Genetics and Therapeutic InterventionsJ. Immunity, 2015, 43(6):1040-1051.4 Mu

34、rphy C A, Langrish C L, Chen Y, et al. Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune InflammationJ. Journal of Experimental Medicine, 2003, 198(12):1951-7.5 Cua D J, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for

35、autoimmune inflammation of the brain.J. Nature, 2003, 421(6924):744-8.6 Park H, Li Z, Yang X O, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.J. Nature Immunology, 2005, 6(11):1133-41.7 Dong C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells.J. Na