医学免疫学课件：HLA-B27与强直性脊柱炎

1、HLA-B27 and Ankylosing SpondylitisOutlineIntroduction of AS and HLAHLA-B27: structure and functionsPathogenic MechanismsTheoriesLatest resultsonstudyprogressProblems to be solvedFuture IssuesAnkylosing Spondylitis(AS)A chronic inflammatory rheumatic diseasesPrevalence: 0.1 - 0.2% Affects joints in t

2、he spine and the sacroiliac jointNo cure Genetic predisposition90% patients express theHLA-B27 genotype1-2% individuals with the HLA-B27 contract the diseaseHuman Leukocyte antigen (HLA)polymorphismHLA-B27B pocketP45 glutamic acid P67 cysteineOther Functions of HLA-B27Thymic selection of the T cell

3、repertoireNeurodevelopment and mate selection Interactions with gut microbiotaHLA-B27-associated spondyloarthritidesBowness, P., HLA-B27. Annual Review of Immunology, 2015. 33(1): p. 29-48.Pathogenic MechanismsPresentation of Arthritogenic PeptidesUnfolded Protein Response and ER Stress ResponseCell

4、 Surface Expression of Free Heavy Chain Forms of HLA-B27Presentation of Arthritogenic PeptidesMolecular mimicryHLA-B27binding a peptide （from a microorganism）eliciting cross-reactive: CD8 T cell with a B27/self-peptide combinationSupportive evidenceHLA-B27-restricted CD8 immune responses to bacteria

5、 trigger ReACross-reactive CD8 T cell responses recognized both an epitope from EBV and a self-peptide derived from VIPR（Fiorillo, 2000）T cell expansions in the joints of SpA patientsHLA-B27 subtypes differ only in peptide-binding grooveHLA-B27 Subtypes and ASBowness, P., HLA-B27. Annual Review of I

6、mmunology, 2015. 33(1): p. 29-48.HLA-B27 Subtypes and ASB*2704 and B*2705 definitely associated with ASB2706 and B*2709 weakly or not associatedPositions 114 and 116 lie at the base of the peptide-binding grooveF pocketInfluence the nature of the amino acid side chain at the C terminusSupportive evi

7、denceHLA-B27-restricted CD8 immune responses to bacteria trigger ReACross-reactive CD8 T cell responses recognized both an epitope from EBV and a self-peptide derived from VIPR（Fiorillo, 2000）T cell expansions in the joints of SpA patientsHLA-B27 subtypes differ only in peptide-binding grooveContrar

8、y evidenceCD8 T cells are not required for disease in HLA-B27 transgenic rat modelsEkkehard, J Immunol 2003: antibody-mediated depletionJoel D. Taurog, Arthritis Rheum 2009: CD8 knockout Jonathan P Sherlock, 2012: IL-23 drives murine SpA-like disease by acting on CD3+CD4CD8 ROR-t-expressing T cellsU

9、nfolded Protein Response and ER Stress ResponseMear JP, Schreiber KL, M unz C, Zhu X, Stevanovic S, et al. 1999. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J. Immunol. 163(12):666570Unfolded Protein Response a

10、nd ER Stress ResponseGenerates ER stress and activates the unfolded protein response（UPR）Enhances the production of IL-23Enhances Th17 T cells survival and stimulate IL-17 productionCD4+ T cells expressing IL-17 in the peripheral blood of AS patients（Shen Hui, 2009）Contrary evidenceTran, T. M. et al

11、. Additional human beta2-microglobulin curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA-B27-transgenic rats. Arthritis and rheumatism 54, 1317-1327, doi:10.1002/art.21740 (2006).Unanswered questionsNo evidence for UPR or ER stress in association with inflam

12、mationAutophagy, but not UPR, regulates the expression of IL-23 in the gut of patients with AS (Ciccia,2014) form disulfide bonds through its unpaired cysteine at position 67B272 and FHC bind to innate immune receptorsfollowing endosomal recycling of heterotrimersCell Surface Expression of Free Heav

13、y ChainCell Surface Expression of Free Heavy ChainForm 2m-free, Cys67-mediated disulfide-bonded homodimersFollowing endosomal recycling of heterotrimersCell surface B272 and FHC bind to innate immune receptors on T and NKcellsBowness, P., HLA-B27. Annual Review of Immunology, 2015. 33(1): p. 29-48.A

14、ntibody with specificity for B272Payeli SK, Kollnberger S, Marroquin Belaunzaran O, ThielM,McHugh K, et al. 2012. Inhibiting HLAB27 homodimer-driven immune cell inflammation in spondylarthritis. Arthritis Rheumatol. 64(10):313949HD6 inhibits binding of B272 to immunoreceptorsPayeli SK, Kollnberger S

15、, Marroquin Belaunzaran O, ThielM,McHugh K, et al. 2012. Inhibiting HLAB27 homodimer-driven immune cell inflammation in spondylarthritis. Arthritis Rheumatol. 64(10):313949Unanswered questionsCellular requirements for B272 formationB272 , disease activity and tissue specificityBlockade of B272 inter

16、action with KIR3DL2 ameliorate diseaseFuture IssuesHLA-B27-restricted T cells and specificity present in the joints of AS patientsEffects of HLA-B27 on the gut microbiomeERAP1 and HLA-B27Effects of HLA-B27 on the gut microbiomeA 2013 clinical research：“46.2% of the patients showed microscopic gut in

17、flammation”Inflammation was located in the ileum in 50% of cases, in the colon in 23.3%, and in 26.7% both affected.Van Praet, L. et al. Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model. Annals of the rheumatic diseases 72, 414-417, doi:10.1136/annrheumdis-

18、2012-202135 (2013).Effect on Gut Microbiota of Transgenic RatsLin, P. et al. HLA-B27 and human beta2-microglobulin affect the gut microbiota of transgenic rats. PloS one 9, e105684, doi:10.1371/journal.pone.0105684 (2014).ERAP1 and HLA-B27Evans, D. M. et al. Interaction between ERAP1 and HLA-B27 in

19、ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature genetics 43, 761-767, doi:10.1038/ng.873 (2011).ERAP1 and HLA-B27Similar interaction in psoriasis for HLA Cw3 (95) and for Behcet disease and HLA-B51only confirmed function is to trim pe

20、ptides for binding to HLA ISeveral questions under active investigationHLA-B27 misfolding increasesMore surface HLA-B27 FHC expressedInteracts directly with HLA-B27Inhibition of ERAP1 might be a valid therapeutic strategy for treatmentTHANK YOU!ReferenceBowness, P., HLA-B27. Annual Review of Immunol

21、ogy, 2015. 33(1): p. 29-48.Mear JP, Schreiber KL, M unz C, Zhu X, Stevanovic S, et al. 1999. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J. Immunol. 163(12):666570Tran, T. M. et al. Additional human beta2-micro

22、globulin curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA-B27-transgenic rats. Arthritis and rheumatism 54, 1317-1327, doi:10.1002/art.21740 (2006).Payeli SK, Kollnberger S, Marroquin Belaunzaran O, ThielM,McHugh K, et al. 2012. Inhibiting HLAB27 homodimer-driven immune cell inflammation in spondylarthritis. Arthritis Rheumatol. 64(10):313949Colbert, R. A., DeLay, M. L., Klenk, E. I.