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Pathogenesis of ankylosing spondylitis — recent advances and future directions

Key Points

  • More than 100 genetic loci have been associated with ankylosing spondylitis (AS), but together they explain less than 30% of AS heritability

  • Multiple genes involved in antigen processing and presentation are associated with AS

  • Investigation into the cellular sources and regulation of IL-17 production is crucial to understanding the pathogenesis of AS

  • Cells involved in type 3 immunity produce IL-17 and include innate lymphoid cells and γδ T cells

  • Given the efficacy of the anti-IL-17 monoclonal antibody secukinumab in the treatment of AS, other therapies targeting type 3 immunity could also be effective

Abstract

Over the past 5 years, advances in high-throughput techniques and studies involving large cohorts of patients have led to considerable advances in the identification of novel genetic associations and immune pathways involved in ankylosing spondylitis (AS). These discoveries include genes encoding cytokine receptors, transcription factors, signalling molecules and transport proteins. Although progress has been made in understanding the functions and potential pathogenic roles of some of these molecules, much work remains to be done to comprehend their complex interactions and therapeutic potential in AS. In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.

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Figure 1: Antigen processing and presentation: potential link to AS.
Figure 2: Type 3 immunity and AS.

References

  1. Van Praet, L., Jacques, P., Van Den Bosch, F., & Elewaut, D. The transition of acute to chronic bowel inflammation in spondyloarthritis. Nat. Rev. Rheumatol. 8, 288–295 (2012).

    CAS  PubMed  Google Scholar 

  2. Marroquin Belaunzaran, O. et al. HLA-B27-homodimer-specific antibody modulates the expansion of pro-inflammatory T-cells in HLA-B27 transgenic rats. PLoS ONE 10, e0130811 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. Baeten, D. et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–1713 (2013).

    CAS  PubMed  Google Scholar 

  4. Brewerton, D. A. et al. Ankylosing spondylitis and HL-A 27. Lancet 1, 904–907 (1973).

    CAS  PubMed  Google Scholar 

  5. The Australo-Anglo-American Spondyloarthritis Consortium et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat. Genet. 43, 761–767 (2011).

  6. Wellcome Trust Case Control Consortium et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

  7. International Genetics of Ankylosing Spondylitis Consortium et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat. Genet. 45, 730–738 (2013).

  8. Australo-Anglo-American Spondyloarthritis Consortium et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

  9. Ellinghaus, D. et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat. Genet. 48, 510–518 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Brown, M. A., Kenna, T. & Wordsworth, B. P. Genetics of ankylosing spondylitis — insights into pathogenesis. Nat. Rev. Rheumatol. 12, 81–91 (2016).

    CAS  PubMed  Google Scholar 

  11. Cortes, A. et al. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat. Commun. 6, 7146 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. Robinson, W. P. et al. HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients. Arthritis Rheum. 32, 1135–1141 (1989).

    CAS  PubMed  Google Scholar 

  13. Brown, M. A. et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann. Rheum. Dis. 55, 268–270 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kim, K. et al. An HLA-C amino-acid variant in addition to HLA-B*27 confers risk for ankylosing spondylitis in the Korean population. Arthritis Res. Ther. 17, 342 (2015).

    PubMed  PubMed Central  Google Scholar 

  15. Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2 et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

  16. Kirino, Y. et al. Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1. Nat. Genet. 45, 202–207 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kuiper, J. J. et al. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy. Hum. Mol. Genet. 23, 6081–6087 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Alvarez-Navarro, C., Martin-Esteban, A., Barnea, E., Admon, A. & Lopez de Castro, J. A. Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphism relevant to inflammatory disease shapes the peptidome of the birdshot chorioretinopathy-associated HLA-A*29:02 antigen. Mol. Cell. Proteomics 14, 1770–1780 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Rausch, P. et al. Colonic mucosa-associated microbiota is influenced by an interaction of crohn disease and FUT2 (Secretor) genotype. Proc. Natl Acad. Sci. USA 108, 19030–19035 (2011).

    CAS  PubMed  Google Scholar 

  20. Costello, M. E. et al. Intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 67, 686–691 (2014).

    Google Scholar 

  21. O'Rielly, D. D. et al. Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis. Ann. Rheum. Dis. 75, 772–779 (2015).

    PubMed  PubMed Central  Google Scholar 

  22. Bowness, P. Hla-B27. Annu. Rev. Immunol. 33, 29–48 (2015).

    CAS  PubMed  Google Scholar 

  23. Khan, M. A. Polymorphism of HLA-B27: 105 subtypes currently known. Curr. Rheumatol. Rep. 15, 362 (2013).

    PubMed  Google Scholar 

  24. Garcia-Medel, N. et al. Peptide handling by HLA-B27 subtypes influences their biological behavior, association with ankylosing spondylitis and susceptibility to endoplasmic reticulum aminopeptidase 1 (ERAP1). Mol. Cell. Proteomics 13, 3367–3380 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Schittenhelm, R. B., Sian, T. C., Wilmann, P. G., Dudek, N. L. & Purcell, A. W. Revisiting the arthritogenic peptide theory: quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes. Arthritis Rheumatol. 67, 702–713 (2015).

    CAS  PubMed  Google Scholar 

  26. Schittenhelm, R. B., Sivaneswaran, S., Lim Kam Sian, T. C., Croft, N. P. & Purcell, A. W. Human leukocyte antigen (HLA) B27 allotype-specific binding and candidate arthritogenic peptides revealed through heuristic clustering of data-independent acquisition mass spectrometry (DIA-MS) data. Mol. Cell. Proteomics 15, 1867–1876 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hulsmeyer, M. et al. Dual, HLA-B27 subtype-dependent conformation of a self-peptide. J. Exp. Med. 199, 271–281 (2004).

    PubMed  PubMed Central  Google Scholar 

  28. Rysnik, O. et al. Non-conventional forms of HLA-B27 are expressed in spondyloarthritis joints and gut tissue. J. Autoimmun. 70, 12–21 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kenna, T. J., Robinson, P. C. & Haroon, N. Endoplasmic reticulum aminopeptidases in the pathogenesis of ankylosing spondylitis. Rheumatology (Oxford) 54, 1549–1556 (2015).

    CAS  Google Scholar 

  30. Allen, R. L., O'Callaghan, C. A., McMichael, A. J. & Bowness, P. Cutting edge: HLA-B27 can form a novel β2-microglobulin-free heavy chain homodimer structure. J. Immunol. 162, 5045–5048 (1999).

    CAS  PubMed  Google Scholar 

  31. Colbert, R. A., DeLay, M. L., Klenk, E. I. & Layh-Schmitt, G. From HLA-B27 to spondyloarthritis: a journey through the ER. Immunol. Rev. 233, 181–202 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ciccia, F. et al. Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation. Ann. Rheum. Dis. 73, 1566–1574 (2013).

    PubMed  PubMed Central  Google Scholar 

  33. Neerinckx, B., Carter, S. & Lories, R. J. No evidence for a critical role of the unfolded protein response in synovium and blood of patients with ankylosing spondylitis. Ann. Rheum. Dis. 73, 629–630 (2014).

    PubMed  Google Scholar 

  34. Ciccia, F. & Haroon, N. Autophagy in the pathogenesis of ankylosing spondylitis. Clin. Rheumatol. 35, 1433–1436 (2016).

    PubMed  Google Scholar 

  35. Neerinckx, B., Carter, S. & Lories, R. IL-23 expression and activation of autophagy in synovium and PBMCs of HLA-B27 positive patients with ankylosing spondylitis. Response to: 'Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation' by Ciccia et al. Ann. Rheum. Dis. 73, e68 (2014).

    CAS  PubMed  Google Scholar 

  36. Guiliano, D. B. et al. Endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 1 targets misfolded HLA-B27 dimers for endoplasmic reticulum-associated degradation. Arthritis Rheumatol. 66, 2976–2988 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bowness, P. et al. Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J. Immunol. 186, 2672–2680 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Abdullah, H., Zhang, Z., Yee, K. & Haroon, N. KIR3DL1 interaction with HLA-B27 is altered by ankylosing spondylitis associated ERAP1 and enhanced by MHC class I cross-linking. Discov. Med. 20, 79–89 (2015).

    PubMed  Google Scholar 

  39. Ridley, A. et al. Activation-induced killer cell immunoglobulin-like receptor 3DL2 binding to HLA-B27 licenses pathogenic T cell differentiation in spondyloarthritis. Arthritis Rheumatol. 68, 901–914 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Saveanu, L. et al. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat. Immunol. 6, 689–697 (2005).

    CAS  PubMed  Google Scholar 

  41. Chang, S. C., Momburg, F., Bhutani, N. & Goldberg, A. L. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc. Natl Acad. Sci. USA 102, 17107–17112 (2005).

    CAS  PubMed  Google Scholar 

  42. Saric, T. et al. An IFN-γ-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat. Immunol. 3, 1169–1176 (2002).

    CAS  PubMed  Google Scholar 

  43. Kochan, G. et al. Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proc. Natl Acad. Sci. USA 108, 7745–7750 (2011).

    CAS  PubMed  Google Scholar 

  44. Chen, L. et al. Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis. Ann. Rheum. Dis. 75, 916–923 (2016).

    CAS  PubMed  Google Scholar 

  45. Evnouchidou, I. et al. Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme. J. Immunol. 186, 1909–1913 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Reeves, E., Colebatch-Bourn, A., Elliott, T., Edwards, C. J. & James, E. Functionally distinct ERAP1 allotype combinations distinguish individuals with ankylosing spondylitis. Proc. Natl Acad. Sci. USA 111, 17594–17599 (2014).

    CAS  PubMed  Google Scholar 

  47. Haroon, N., Tsui, F. W., Uchanska-Ziegler, B., Ziegler, A. & Inman, R. D. Endoplasmic reticulum aminopeptidase 1 (ERAP1) exhibits functionally significant interaction with HLA-B27 and relates to subtype specificity in ankylosing spondylitis. Ann. Rheum. Dis. 71, 589–595 (2012).

    CAS  PubMed  Google Scholar 

  48. Garcia-Medel, N. et al. Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo. Mol. Cell. Proteomics 11, 1416–1429 (2012).

    PubMed  PubMed Central  Google Scholar 

  49. Akram, A., Lin, A., Gracey, E., Streutker, C. J. & Inman, R. D. HLA-B27, but not HLA-B7, immunodominance to influenza is ERAP dependent. J. Immunol. 192, 5520–5528 (2014).

    CAS  PubMed  Google Scholar 

  50. Tran, T. M., Hong, S., Edwan, J. H. & Colbert, R. A. ERAP1 reduces accumulation of aberrant and disulfide-linked forms of HLA-B27 on the cell surface. Mol. Immunol. 74, 10–17 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Kenna, T. J. et al. Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis. Genes Immun. 16, 35–42 (2014).

    PubMed  Google Scholar 

  52. Tsui, F. W. et al. Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Ann. Rheum. Dis. 69, 733–736 (2010).

    CAS  PubMed  Google Scholar 

  53. Evnouchidou, I., Weimershaus, M., Saveanu, L. & van Endert, P. ERAP1–ERAP2 dimerization increases peptide-trimming efficiency. J. Immunol. 193, 901–908 (2014).

    CAS  PubMed  Google Scholar 

  54. Robinson, P. C. et al. ERAP2 functional knockout in humans does not alter surface heavy chains or HLA-B27, inflammatory cytokines or endoplasmic reticulum stress markers. Ann. Rheum. Dis. 74, 2092–2095 (2015).

    CAS  PubMed  Google Scholar 

  55. Martin-Esteban, A., Guasp, P., Barnea, E., Admon, A. & Lopez de Castro, J. A. Functional interaction of the ankylosing spondylitis associated endoplasmic reticulum aminopeptidase 2 with the HLA-B*27 peptidome in human cells. Arthritis Rheumatol. 68, 2466–2475 (2016).

    CAS  PubMed  Google Scholar 

  56. Wendling, D., Cedoz, J. P., Racadot, E. & Dumoulin, G. Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis. Joint Bone Spine 74, 304–305 (2007).

    CAS  PubMed  Google Scholar 

  57. Mei, Y. et al. Increased serum IL-17 and IL-23 in the patient with ankylosing spondylitis. Clin. Rheumatol. 30, 269–273 (2011).

    PubMed  Google Scholar 

  58. Shen, H., Goodall, J. C. & Hill Gaston, J. S. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 60, 1647–1656 (2009).

    CAS  PubMed  Google Scholar 

  59. Glatigny, S. et al. Proinflammatory Th17 cells are expanded and induced by dendritic cells in spondylarthritis-prone HLA-B27-transgenic rats. Arthritis Rheum. 64, 110–120 (2012).

    CAS  PubMed  Google Scholar 

  60. Benham, H. et al. Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol. 66, 1755–1767 (2014).

    CAS  PubMed  Google Scholar 

  61. Gracey, E. et al. Sexual dimorphism in the Th17 signature of ankylosing spondylitis. Arthritis Rheumatol. 68, 679–689 (2016).

    CAS  PubMed  Google Scholar 

  62. Smith, J. A. & Colbert, R. A. Review: the interleukin-23/interleukin-17 axis in spondyloarthritis pathogenesis: Th17 and beyond. Arthritis Rheumatol. 66, 231–241 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Lau, M. C. et al. Genetic association of ankylosing spondylitis with TBX21 influences T-bet and pro-inflammatory cytokine expression in humans and SKG mice as a model of spondyloarthritis. Ann. Rheum. Dis. 76, 261–269 (2016).

    PubMed  Google Scholar 

  64. Krausgruber, T. et al. T-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine. Nat. Commun. 7, 11627 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sujino, T. et al. Tissue adaptation of regulatory and intraepithelial CD4+ T cells controls gut inflammation. Science 352, 1581–1586 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gracey, E. et al. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann. Rheum. Dis. 75, 2124–2132 (2016).

    CAS  PubMed  Google Scholar 

  67. Hayashi, E. et al. Involvement of mucosal-associated invariant T cells in ankylosing spondylitis. J. Rheumatol. 43, 1695–1703 (2016).

    PubMed  Google Scholar 

  68. Ciccia, F. et al. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann. Rheum. Dis. 74, 1739–1747 (2015).

    CAS  PubMed  Google Scholar 

  69. Rihl, M. et al. Identification of interleukin-7 as a candidate disease mediator in spondylarthritis. Arthritis Rheum. 58, 3430–3435 (2008).

    CAS  PubMed  Google Scholar 

  70. Kenna, T. J. et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive γ/δ T cells in patients with active ankylosing spondylitis. Arthritis Rheum. 64, 1420–1429 (2012).

    CAS  PubMed  Google Scholar 

  71. Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4CD8 entheseal resident T cells. Nat. Med. 18, 1069–1076 (2012).

    CAS  PubMed  Google Scholar 

  72. Reinhardt, A. et al. IL-23-dependent γ/δ T cells produce IL-17 and accumulate in enthesis, aortic valve, and ciliary body. Arthritis Rheumatol. 68, 2476–2486 (2016).

    CAS  PubMed  Google Scholar 

  73. Ono, T. et al. IL-17-producing γδ T cells enhance bone regeneration. Nat. Commun. 7, 10928 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Benjamin, M. & McGonagle, D. The enthesis organ concept and its relevance to the spondyloarthropathies. Adv. Exp. Med. Biol. 649, 57–70 (2009).

    PubMed  Google Scholar 

  75. McGonagle, D., Lories, R. J., Tan, A. L. & Benjamin, M. The concept of a “synovio–entheseal complex” and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis Rheum. 56, 2482–2491 (2007).

    PubMed  Google Scholar 

  76. Jacques, P. et al. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann. Rheum. Dis. 73, 437–445 (2014).

    PubMed  Google Scholar 

  77. Ciccia, F. et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 64, 1869–1878 (2012).

    CAS  PubMed  Google Scholar 

  78. Hepworth, M. R. et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 348, 1031–1035 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lee, J. S. et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43, 727–738 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee, Y. et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991–999 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Zuniga, L. A., Jain, R., Haines, C. & Cua, D. J. Th17 cell development: from the cradle to the grave. Immunol. Rev. 252, 78–88 (2013).

    PubMed  Google Scholar 

  82. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Google Scholar 

  83. Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    CAS  PubMed  Google Scholar 

  84. Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Gagliani, N. et al. TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221–225 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Sefik, E. et al. Mucosal immunology. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 349, 993–997 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ohnmacht, C. et al. Mucosal immunology. The microbiota regulates type 2 immunity through RORγ+ T cells. Science 349, 989–993 (2015).

    CAS  PubMed  Google Scholar 

  88. Maxwell, J. R. et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity 43, 739–750 (2015).

    CAS  PubMed  Google Scholar 

  89. Jain, R. et al. Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells. Immunity 44, 131–142 (2016).

    CAS  PubMed  Google Scholar 

  90. Ellinghaus, D. et al. Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies. Gastroenterology 145, 339–347 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Baeten, D. et al. Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on synovium in spondylarthropathy: histologic findings in eight patients from an open-label pilot study. Arthritis Rheum. 44, 186–195 (2001).

    CAS  PubMed  Google Scholar 

  92. Haroon, N. et al. From gene expression to serum proteins: biomarker discovery in ankylosing spondylitis. Ann. Rheum. Dis. 69, 297–300 (2008).

    Google Scholar 

  93. Milanez, F. M. et al. IL-23/Th17 axis is not influenced by TNF-blocking agents in ankylosing spondylitis patients. Arthritis Res. Ther. 18, 52 (2016).

    PubMed  PubMed Central  Google Scholar 

  94. Evans, H. G. et al. TNF-alpha blockade induces IL-10 expression in human CD4+ T cells. Nat. Commun. 5, 3199 (2014).

    PubMed  PubMed Central  Google Scholar 

  95. Sieper, J., Porter-Brown, B., Thompson, L., Harari, O. & Dougados, M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann. Rheum. Dis. 73, 95–100 (2014).

    CAS  PubMed  Google Scholar 

  96. Sieper, J. et al. Sarilumab for the treatment of ankylosing spondylitis: results of a phase II, randomized, double-blind, placebo-controlled, international study (ALIGN). Ann. Rheum. Dis. 74, 1051–1057 (2015).

    CAS  PubMed  Google Scholar 

  97. Wilson, N. J. et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat. Immunol. 8, 950–957 (2007).

    CAS  PubMed  Google Scholar 

  98. Poddubnyy, D., Hermann, K. G., Callhoff, J., Listing, J. & Sieper, J. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann. Rheum. Dis. 73, 817–823 (2014).

    CAS  PubMed  Google Scholar 

  99. Yao, C. et al. Prostaglandin E2–EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion. Nat. Med. 15, 633–640 (2009).

    CAS  PubMed  Google Scholar 

  100. Withers, D. R. et al. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat. Med. 22, 319–323 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. de Wit, J. et al. RORγt inhibitors suppress TH17 responses in inflammatory arthritis and inflammatory bowel disease. J. Allergy Clin. Immunol. 137, 960–963 (2016).

    CAS  PubMed  Google Scholar 

  102. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Schreiber, S. et al. OP0113 No increased incidence of inflammatory bowel disease among secukinumab-treated patients with moderate to severe psoriasis, psoriatic arthritis, or ankylosing spondylitis: data from 14 phase 2 and phase 3 clinical studies [abstract]. Ann. Rheum. Dis. 75 (Suppl.), 97–98 (2016).

    Google Scholar 

  104. Asquith, M. & Rosenbaum, J. T. The interaction between host genetics and the microbiome in the pathogenesis of spondyloarthropathies. Curr. Opin. Rheumatol. 28, 405–412 (2016).

    CAS  PubMed  Google Scholar 

  105. Van de Wiele, T., Van Praet, J. T., Marzorati, M., Drennan, M. B. & Elewaut, D. How the microbiota shapes rheumatic diseases. Nat. Rev. Rheumatol. 12, 398–411 (2016).

    CAS  PubMed  Google Scholar 

  106. Tito, R. Y. et al. Dialister as microbial marker of disease activity in spondyloarthritis. Arthritis Rheumatol. 69, 114–121 (2016).

    PubMed  Google Scholar 

  107. Lin, P. et al. HLA-B27 and human β2-microglobulin affect the gut microbiota of transgenic rats. PLoS ONE 9, e105684 (2014).

    PubMed  PubMed Central  Google Scholar 

  108. Rehaume, L. M. et al. ZAP-70 genotype disrupts the relationship between microbiota and host, leading to spondyloarthritis and ileitis in SKG mice. Arthritis Rheumatol. 66, 2780–2792 (2014).

    CAS  PubMed  Google Scholar 

  109. Taurog, J. D. et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180, 2359–2364 (1994).

    CAS  PubMed  Google Scholar 

  110. Baillet, A. C. et al. High chlamydia burden promotes tumor necrosis factor-dependent reactive arthritis in SKG mice. Arthritis Rheumatol. 67, 1535–1547 (2015).

    CAS  PubMed  Google Scholar 

  111. Ruutu, M. et al. β-glucan triggers spondylarthritis and Crohn's disease-like ileitis in SKG mice. Arthritis Rheum. 64, 2211–2222 (2012).

    CAS  PubMed  Google Scholar 

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All the authors researched the data for the article, made substantial contributions to discussion of content, wrote the article, and edited/reviewed the manuscript before submission. V.R. and E.G. contributed equally to this work.

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Correspondence to Nigil Haroon.

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The authors declare no competing financial interests.

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Glossary

Genome-wide significance

In most genome-wide association studies, the threshold that an association must reach to be considered statistically significant is a high P value (≥5 × 10−8) owing to the multiple tests conducted in such studies.

Seronegative diseases

Diseases not associated with serum autoantibodies.

M1 family of zinc metallopeptidases

Aminopeptidases that cleave polypeptides from the N-terminus and are dependent on a single zinc ion for activity.

Immunochip platform

A microarray chip containing probes that recognize approximately195,000 single nucleotide polymorphisms and 700 small insertion and/or deletions; the main aim of this platform is to fine-map |genetic associations identified in 11 autoimmune and inflammatory diseases.

Data-independent acquisition mass spectrometry

Mass spectrometry technique in which all ions generated are fragmented and analysed without pre-selection.

Autophagy

A process that involves the orderly degradation of dysfunctional intracellular components through their delivery to lysosomes in structures called autophagosomes.

Endoplasmic reticulum-associated degradation

(ERAD). A process that facilitates the degradation of misfolded proteins in the endoplasmic reticulum by transporting them to the cytoplasm, where ubiquitylation followed by proteasome-mediated degradation occurs.

Coat protein complex II

Vesicle coat protein that aids anterograde transport of proteins from the endoplasmic reticulum to the Golgi apparatus.

SKG mice

Mice carrying a hypomorphic single nucleotide polymorphism in ZAP70 (a T cell receptor signalling molecule), which predisposes T cells to a T helper 17 cell phenotype. Under specific pathogen-free conditions, SKG mice are disease-free; however, a single dose of curdlan, an IL-23-inducing molecule, induces progressive spondyloathropathy characterized by axial and peripheral arthritis, dermatitis and colitis.

Innate-like lymphocytes

Cells of the lymphocyte lineage that express T cell receptors of limited diversity and are restricted by non-classical MHC molecules such as CD1 or MR1. These cells typically recognize non-peptide antigens and are activated faster than regular peptide-restricted adaptive immune cells.

Mucosal-associated invariant T (MAIT) cells

A population of innate-like lymphocytes that recognize bacterially derived vitamin B metabolites presented on the non-classical MHC molecule MR1.

Synovio-enthesal complex

Anatomical unit comprising the fibrous insertion of tendon or ligament enthesis and the adjacent synovial membrane of the bursa.

Fate-mapping studies

Studies that investigate the origin of cell populations through labelling and tracking of cells of interest. Immunological studies typically use membrane-incorporated dyes, or genetic switches that result in constitutive fluorochrome expression if a cell marker is expressed.

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Ranganathan, V., Gracey, E., Brown, M. et al. Pathogenesis of ankylosing spondylitis — recent advances and future directions. Nat Rev Rheumatol 13, 359–367 (2017). https://doi.org/10.1038/nrrheum.2017.56

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