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Ankylosing spondylitis: an autoimmune or autoinflammatory disease?


Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.

Key points

  • The pathogenesis of ankylosing spondylitis (AS) is not fully understood, despite advances in understanding some of the underlying mechanisms.

  • Genetic studies and the effects of local tissue factors, such as biomechanical stress and bacterial products, support the importance of a chronic innate immune response in AS.

  • Innate and innate-like immune cells can be found at sites of disease and probably represent the major source of IL-17 production in AS.

  • Immune pathways such as inflammasome activation, autophagy and ubiquitination are involved in both innate and adaptive immunity in AS.

  • The presence of an autoimmune response accompanied by the production of specific autoantibodies is a growing concept in AS.

  • Both autoinflammatory and autoimmune factors participate in the pathogenesis of AS in a probable continuum.

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Fig. 1: Contribution of biomechanical stress to the onset of axial disease in ankylosing spondylitis.
Fig. 2: Immune mechanisms linking intestinal dysbiosis to disease in ankylosing spondylitis.
Fig. 3: Autoimmunity versus autoinflammation in the pathogenesis of ankylosing spondylitis.


  1. 1.

    Sieper, J., Braun, J., Dougados, M. & Baeten, D. Axial spondyloarthritis. Nat. Rev. Dis. Prim. 1, 15013 (2015).

    PubMed  Google Scholar 

  2. 2.

    Taams, L. S., Steel, K. J. A., Srenathan, U., Burns, L. A. & Kirkham, B. W. IL-17 in the immunopathogenesis of spondyloarthritis. Nat. Rev. Rheumatol. 14, 453–466 (2018).

    CAS  PubMed  Google Scholar 

  3. 3.

    Krainer, J., Siebenhandl, S. & Weinhäusel, A. Systemic autoinflammatory diseases. J. Autoimmun. 109, 102421 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    McGonagle, D. & McDermott, M. F. A proposed classification of the immunological diseases. PLoS Med. 3, e297 (2006).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Wang, L., Wang, F.-S. & Gershwin, M. E. Human autoimmune diseases: a comprehensive update. J. Intern. Med. 278, 369–395 (2015).

    CAS  PubMed  Google Scholar 

  6. 6.

    Ambarus, C., Yeremenko, N., Tak, P. P. & Baeten, D. Pathogenesis of spondyloarthritis. Curr. Opin. Rheumatol. 24, 351–358 (2012).

    CAS  PubMed  Google Scholar 

  7. 7.

    Generali, E., Bose, T., Selmi, C., Voncken, J. W. & Damoiseaux, J. G. M. C. Nature versus nurture in the spectrum of rheumatic diseases: classification of spondyloarthritis as autoimmune or autoinflammatory. Autoimmun. Rev. 17, 935–941 (2018).

    CAS  PubMed  Google Scholar 

  8. 8.

    Brown, M. A. & Wordsworth, B. P. Genetics in ankylosing spondylitis – current state of the art and translation into clinical outcomes. Best Pract. Res. Clin. Rheumatol. 31, 763–776 (2017).

    PubMed  Google Scholar 

  9. 9.

    Braun, J. & Sieper, J. Ankylosing spondylitis. Lancet 369, 1379–1390 (2007).

    Google Scholar 

  10. 10.

    Kenna, T. J., Hanson, A., Costello, M.-E. & Brown, M. A. Functional genomics and its bench-to-bedside translation pertaining to the identified susceptibility alleles and loci in ankylosing spondylitis. Curr. Rheumatol. Rep. 18, 63 (2016).

    PubMed  Google Scholar 

  11. 11.

    Rahman, P. et al. Association of interleukin-23 receptor variants with ankylosing spondylitis. Arthritis Rheum. 58, 1020–1025 (2008).

    CAS  PubMed  Google Scholar 

  12. 12.

    Galozzi, P. et al. Altered cytokine pattern and inflammatory pathways in monogenic and complex autoinflammatory diseases [abstract]. Pediatr. Rheumatol. 13, O48 (2015).

    Google Scholar 

  13. 13.

    Pfeifle, R. et al. Regulation of autoantibody activity by the IL-23–TH17 axis determines the onset of autoimmune disease. Nat. Immunol. 18, 104–113 (2017).

    CAS  PubMed  Google Scholar 

  14. 14.

    Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

    CAS  PubMed  Google Scholar 

  15. 15.

    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 

  16. 16.

    McInnes, I. B. et al. 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 proof-of-concept trial. Ann. Rheum. Dis. 73, 349–356 (2014).

    CAS  PubMed  Google Scholar 

  17. 17.

    Højgaard, P. et al. Pain mechanisms and ultrasonic inflammatory activity as prognostic factors in patients with psoriatic arthritis: protocol for a prospective, exploratory cohort study. BMJ Open 6, e010650 (2016).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Mease, P. J. et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann. Rheum. Dis. 76, 79–87 (2017).

    CAS  PubMed  Google Scholar 

  19. 19.

    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  Google Scholar 

  20. 20.

    Feagan, B. G. et al. Risankizumab in patients with moderate to severe Crohn’s disease: an open-label extension study. Lancet Gastroenterol. Hepatol. 3, 671–680 (2018).

    PubMed  Google Scholar 

  21. 21.

    Baeten, D. et al. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: Results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann. Rheum. Dis. 77, 1295–1302 (2018).

    CAS  PubMed  Google Scholar 

  22. 22.

    Evans, D. M. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Vecellio, M., Cohen, C. J., Roberts, A. R., Wordsworth, P. B. & Kenna, T. J. RUNX3 and T-bet in immunopathogenesis of ankylosing spondylitis — novel targets for therapy? Front. Immunol. 9, 3132 (2019).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    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 

  25. 25.

    Gracey, E. et al. TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis. J. Clin. Invest. 130, 1863–1878 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Dendrou, C. A. et al. Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci. Transl. Med. 8, 363ra149 (2016).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Snelgrove, T. et al. Association of Toll-like receptor 4 variants and ankylosing spondylitis: a case-control study. J. Rheumatol. 34, 368–370 (2007).

    CAS  PubMed  Google Scholar 

  28. 28.

    Assassi, S. et al. Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of Toll-like receptor 4 and 5. J. Rheumatol. 38, 87–98 (2011).

    CAS  PubMed  Google Scholar 

  29. 29.

    Ciccia, F. et al. Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis. Ann. Rheum. Dis. 76, 1123–1132 (2017).

    CAS  PubMed  Google Scholar 

  30. 30.

    Li, Z. et al. Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis. PLoS Genet. 15, e1008038 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Akar, S. et al. High prevalence of spondyloarthritis and ankylosing spondylitis among familial Mediterranean fever patients and their first-degree relatives: further evidence for the connection. Arthritis Res. Ther. 15, R21 (2013).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kaşifoğlu, T., Çalişir, C., Cansu, D. Ü. & Korkmaz, C. The frequency of sacroiliitis in familial Mediterranean fever and the role of HLA-B27 and MEFV mutations in the development of sacroiliitis. Clin. Rheumatol. 28, 41–46 (2009).

    PubMed  Google Scholar 

  33. 33.

    Cosan, F. et al. Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis. Arthritis Rheum. 62, 3232–3236 (2010).

    PubMed  Google Scholar 

  34. 34.

    Varan, O., Kucuk, H. & Tufan, A. Anakinra for the treatment of familial Mediterranean fever-associated spondyloarthritis. Scand. J. Rheumatol. 45, 252–253 (2016).

    CAS  PubMed  Google Scholar 

  35. 35.

    Georgin-Lavialle, S. et al. Spondyloarthritis associated with familial Mediterranean fever: successful treatment with anakinra. Rheumatology 56, 167–169 (2017).

    PubMed  Google Scholar 

  36. 36.

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

    Google Scholar 

  37. 37.

    Chen, H. et al. ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing. Sci. Rep. 6, 28902 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Vande Walle, L. et al. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature 512, 69–73 (2014).

    PubMed  Google Scholar 

  39. 39.

    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  Google Scholar 

  40. 40.

    Stawczyk-Macieja, M. et al. ERAP1 and HLA-C*06 are strongly associated with the risk of psoriasis in the population of northern Poland. Adv. Dermatol. Allergol. 35, 286–292 (2018).

    Google Scholar 

  41. 41.

    Burillo-Sanz, S. et al. Behçet’s disease and genetic interactions between HLA-B*51 and variants in genes of autoinflammatory syndromes. Sci. Rep. 9, 2777 (2019).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Kuiper, J. J. W. 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 

  43. 43.

    López de Castro, J. A. et al. Molecular and pathogenic effects of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in MHC-I-associated inflammatory disorders: towards a unifying view. Mol. Immunol. 77, 193–204 (2016).

    PubMed  Google Scholar 

  44. 44.

    Seregin, S. S. et al. Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens. Autoimmunity 46, 497–508 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Kuiper, J. J. W. et al. Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(birdshot) uveitis. Hum. Mol. Genet. 27, 4333–4343 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Costantino, F., Breban, M. & Garchon, H.-J. Genetics and functional genomics of spondyloarthritis. Front. Immunol. 9, 2933 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Farh, K. K.-H. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).

    CAS  PubMed  Google Scholar 

  48. 48.

    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 (2017).

    CAS  PubMed  Google Scholar 

  49. 49.

    Bombardieri, M., Lewis, M. & Pitzalis, C. Ectopic lymphoid neogenesis in rheumatic autoimmune diseases. Nat. Rev. Rheumatol. 13, 141–154 (2017).

    CAS  PubMed  Google Scholar 

  50. 50.

    Demetter, P. et al. Increase in lymphoid follicles and leukocyte adhesion molecules emphasizes a role for the gut in spondyloarthropathy pathogenesis. J. Pathol. 198, 517–522 (2002).

    CAS  PubMed  Google Scholar 

  51. 51.

    Masi, A. T. Might axial myofascial properties and biomechanical mechanisms be relevant to ankylosing spondylitis and axial spondyloarthritis? Arthritis Res. Ther. 16, 107 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Watad, A. et al. The early phases of ankylosing spondylitis: emerging insights from clinical and basic science. Front. Immunol. 9, 2668 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Debusschere, K., Cambré, I., Gracey, E. & Elewaut, D. Born to run: The paradox of biomechanical force in spondyloarthritis from an evolutionary perspective. Best Pract. Res. Clin. Rheumatol. 31, 887–894 (2017).

    PubMed  Google Scholar 

  54. 54.

    Watad, A., Cuthbert, R. J., Amital, H. & McGonagle, D. Enthesitis: Much more than focal insertion point inflammation. Curr. Rheumatol. Rep. 20, 41 (2018).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    François, R. J., Braun, J. & Khan, M. A. Entheses and enthesitis: a histopathologic review and relevance to spondyloarthritides. Curr. Opin. Rheumatol. 13, 255–264 (2001).

    PubMed  Google Scholar 

  56. 56.

    Schett, G. et al. Enthesitis: from pathophysiology to treatment. Nat. Rev. Rheumatol. 13, 731–741 (2017).

    CAS  PubMed  Google Scholar 

  57. 57.

    Weber, U. et al. Frequency and anatomic distribution of magnetic resonance imaging features in the sacroiliac joints of young athletes: Exploring “background noise” toward a data-driven definition of sacroiliitis in early spondyloarthritis. Arthritis Rheumatol. 70, 736–745 (2018).

    PubMed  Google Scholar 

  58. 58.

    Varkas, G. et al. Effect of mechanical stress on magnetic resonance imaging of the sacroiliac joints: assessment of military recruits by magnetic resonance imaging study. Rheumatology 57, 508–513 (2018).

    PubMed  Google Scholar 

  59. 59.

    Renson, T. et al. High prevalence of spondyloarthritis-like MRI lesions in postpartum women: a prospective analysis in relation to maternal, child and birth characteristics. Ann. Rheum. Dis. 79, 929–934 (2020).

    PubMed  Google Scholar 

  60. 60.

    Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+CD3+CD4−CD8− entheseal resident T cells. Nat. Med. 18, 1069–1076 (2012).

    CAS  PubMed  Google Scholar 

  61. 61.

    Cuthbert, R. J. et al. Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 69, 1816–1822 (2017).

    CAS  PubMed  Google Scholar 

  62. 62.

    Bridgewood, C. et al. Identification of myeloid cells in the human enthesis as the main source of local IL-23 production. Ann. Rheum. Dis. 78, 929–933 (2019).

    CAS  PubMed  Google Scholar 

  63. 63.

    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 

  64. 64.

    Ward, M. M., Reveille, J. D., Learch, T. J., Davis, J. C. & Weisman, M. H. Occupational physical activities and long-term functional and radiographic outcomes in patients with ankylosing spondylitis. Arthritis Rheum. 59, 822–832 (2008).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Ramiro, S. et al. Lifestyle factors may modify the effect of disease activity on radiographic progression in patients with ankylosing spondylitis: a longitudinal analysis. RMD Open 1, e000153 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Baum, R. & Gravallese, E. M. Impact of inflammation on the osteoblast in rheumatic diseases. Curr. Osteoporos. Rep. 12, 9–16 (2014).

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    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 

  68. 68.

    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 

  69. 69.

    Rehaume, L. M. et al. IL-23 favours outgrowth of spondyloarthritis-associated pathobionts and suppresses host support for homeostatic microbiota. Ann. Rheum. Dis. 78, 494–503 (2019).

    CAS  PubMed  Google Scholar 

  70. 70.

    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 

  71. 71.

    Tanaka, S. et al. Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. J. Immunol. 185, 2295–2305 (2010).

    CAS  PubMed  Google Scholar 

  72. 72.

    Costello, M.-E. et al. Brief report: intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 67, 686–691 (2015).

    PubMed  Google Scholar 

  73. 73.

    Tito, R. Y. et al. Brief report: dialister as a microbial marker of disease activity in spondyloarthritis. Arthritis Rheumatol. 69, 114–121 (2017).

    CAS  PubMed  Google Scholar 

  74. 74.

    Breban, M. et al. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis. Ann. Rheum. Dis. 76, 1614–1622 (2017).

    CAS  PubMed  Google Scholar 

  75. 75.

    Wen, C. et al. Quantitative metagenomics reveals unique gut microbiome biomarkers in ankylosing spondylitis. Genome Biol. 18, 142 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Zhang, L. et al. Fecal microbiota in patients with ankylosing spondylitis: correlation with dietary factors and disease activity. Clin. Chim. Acta 497, 189–196 (2019).

    CAS  PubMed  Google Scholar 

  77. 77.

    Yin, J. et al. Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy and the host’s genotype upon microbiome composition. Ann. Rheum. Dis. 79, 132–140 (2020).

    CAS  PubMed  Google Scholar 

  78. 78.

    Manasson, J. et al. Interleukin-17 inhibition in spondyloarthritis is associated with subclinical gut microbiome perturbations and a distinctive interleukin-25-driven intestinal inflammation. Arthritis Rheumatol. 72, 645–657 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Zhou, C. et al. Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis. J. Autoimmun. 107, 102360 (2019).

    PubMed  Google Scholar 

  80. 80.

    Asquith, M. et al. HLA alleles associated with risk of ankylosing spondylitis and rheumatoid arthritis influence the gut microbiome. Arthritis Rheumatol. 71, 1642–1650 (2019).

    CAS  PubMed  Google Scholar 

  81. 81.

    Viladomiu, M. et al. IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent inflammation. Sci. Transl. Med. 9, eaaf9655 (2017).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Stoll, M. L. et al. Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis. Arthritis Res. Ther. 16, 486 (2014).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Salas-Cuestas, F. et al. Higher levels of secretory IgA are associated with low disease activity index in patients with reactive arthritis and undifferentiated spondyloarthritis. Front. Immunol. 8, 476 (2017).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Franssen, M. J., van de Putte, L. B. & Gribnau, F. W. IgA serum levels and disease activity in ankylosing spondylitis: a prospective study. Ann. Rheum. Dis. 44, 766–771 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Asquith, M. J. et al. Perturbed mucosal immunity and dysbiosis accompany clinical disease in a rat model of spondyloarthritis. Arthritis Rheumatol. 68, 2151–2162 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Zhao, Q. & Elson, C. O. Adaptive immune education by gut microbiota antigens. Immunology 154, 28–37 (2018).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    Silverman, G. J. The microbiome in SLE pathogenesis. Nat. Rev. Rheumatol. 15, 72–74 (2019).

    PubMed  Google Scholar 

  88. 88.

    Paun, A., Yau, C. & Danska, J. S. The influence of the microbiome on type 1 diabetes. J. Immunol. 198, 590–595 (2017).

    CAS  PubMed  Google Scholar 

  89. 89.

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

    CAS  PubMed  Google Scholar 

  90. 90.

    Noordenbos, T. et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum. 64, 99–109 (2012).

    CAS  PubMed  Google Scholar 

  91. 91.

    Rivellese, F. et al. Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production. Ann. Rheum. Dis. 77, 1773–1781 (2018).

    CAS  PubMed  Google Scholar 

  92. 92.

    Appel, H. et al. Analysis of IL-17+ cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res. Ther. 13, R95 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Price, A. E., Reinhardt, R. L., Liang, H.-E. & Locksley, R. M. Marking and quantifying IL-17A-producing cells in vivo. PLoS ONE 7, e39750 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Noordenbos, T. et al. Human mast cells capture, store, and release bioactive, exogenous IL-17A. J. Leukoc. Biol. 100, 453–462 (2016).

    CAS  PubMed  Google Scholar 

  95. 95.

    Kenna, T. J. & Brown, M. A. The role of IL-17-secreting mast cells in inflammatory joint disease. Nat. Rev. Rheumatol. 9, 375–379 (2013).

    CAS  PubMed  Google Scholar 

  96. 96.

    McGonagle, D. G., McInnes, I. B., Kirkham, B. W., Sherlock, J. & Moots, R. The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies. Ann. Rheum. Dis. 78, 1167–1178 (2019).

    CAS  PubMed  Google Scholar 

  97. 97.

    Tamassia, N. et al. A reappraisal on the potential ability of human neutrophils to express and produce IL-17 family members in vitro: failure to reproducibly detect it. Front. Immunol. 9, 795 (2018).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Chen, S. et al. Histologic evidence that mast cells contribute to local tissue inflammation in peripheral spondyloarthritis by regulating interleukin-17A content. Rheumatology 58, 617–627 (2019).

    CAS  PubMed  Google Scholar 

  99. 99.

    Paramarta, J. E. et al. A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis. J. Transl. Med. 14, 308 (2016).

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    McGonagle, D. et al. Histological assessment of the early enthesitis lesion in spondyloarthropathy. Ann. Rheum. Dis. 61, 534–537 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Bollow, M. et al. Quantitative analyses of sacroiliac biopsies in spondyloarthropathies: T cells and macrophages predominate in early and active sacroiliitis — cellularity correlates with the degree of enhancement detected by magnetic resonance imaging. Ann. Rheum. Dis. 59, 135–140 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Braun, J. et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum. 38, 499–505 (1995).

    CAS  PubMed  Google Scholar 

  103. 103.

    Smith, J. A. et al. Gene expression analysis of macrophages derived from ankylosing spondylitis patients reveals interferon-γ dysregulation. Arthritis Rheum. 58, 1640–1649 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Baeten, D. et al. Association of CD163+macrophages and local production of soluble CD163 with decreased lymphocyte activation in spondylarthropathy synovitis. Arthritis Rheum. 50, 1611–1623 (2004).

    PubMed  Google Scholar 

  105. 105.

    Ciccia, F. et al. Macrophage phenotype in the subclinical gut inflammation of patients with ankylosing spondylitis. Rheumatology 53, 104–113 (2014).

    CAS  PubMed  Google Scholar 

  106. 106.

    Longman, R. S. et al. CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J. Exp. Med. 211, 1571–1583 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Diehl, G. E. et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 494, 116–120 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Ciccia, F. et al. Proinflammatory CX3CR1+CD59+Tumor Necrosis Factor–Like Molecule 1 A+Interleukin-23+monocytes are expanded in patients with ankylosing spondylitis and modulate innate lymphoid cell 3 immune functions. Arthritis Rheumatol. 70, 2003–2013 (2018).

    CAS  PubMed  Google Scholar 

  109. 109.

    Yaddanapudi, K. et al. Control of tumor-associated macrophage alternative activation by macrophage migration inhibitory factor. J. Immunol. 190, 2984–2993 (2013).

    CAS  PubMed  Google Scholar 

  110. 110.

    Nishihira, J. Macrophage migration inhibitory factor (MIF): its essential role in the immune system and cell growth. J. Interf. Cytokine Res. 20, 751–762 (2000).

    CAS  Google Scholar 

  111. 111.

    Ranganathan, V. et al. Macrophage migration inhibitory factor induces inflammation and predicts spinal progression in ankylosing spondylitis. Arthritis Rheumatol. 69, 1796–1806 (2017).

    CAS  PubMed  Google Scholar 

  112. 112.

    Bloom, J., Sun, S. & Al-Abed, Y. MIF, a controversial cytokine: a review of structural features, challenges, and opportunities for drug development. Expert Opin. Ther. Targets 20, 1463–1475 (2016).

    CAS  PubMed  Google Scholar 

  113. 113.

    Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    CAS  PubMed  Google Scholar 

  114. 114.

    Mauro, D., Macaluso, F., Fasano, S., Alessandro, R. & Ciccia, F. ILC3 in axial spondyloarthritis: the gut angle. Curr. Rheumatol. Rep. 21, 37 (2019).

    PubMed  Google Scholar 

  115. 115.

    Hoorweg, K. et al. Functional differences between human NKp44 and NKp44+ RORC+ innate lymphoid cells. Front. Immunol. 3, 72 (2012).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    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 

  117. 117.

    Ciccia, F. et al. Clinical efficacy of α4 integrin block with natalizumab in ankylosing spondylitis. Ann. Rheum. Dis. 75, 2053–2054 (2016).

    PubMed  Google Scholar 

  118. 118.

    Mortier, C., Govindarajan, S., Venken, K. & Elewaut, D. It takes ‘guts’ to cause joint inflammation: Role of innate-like T cells. Front. Immunol. 9, 1498 (2018).

    Google Scholar 

  119. 119.

    Venken, K. et al. RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in spondyloarthritis patients. Nat. Commun. 10, 9 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    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  Google Scholar 

  121. 121.

    Gherardin, N. A. et al. Human blood MAIT cell subsets defined using MR1 tetramers. Immunol. Cell Biol. 96, 507–525 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Toussirot, E. & Saas, P. MAIT cells: potent major cellular players in the IL-17 pathway of spondyloarthritis? RMD Open 4, e000821 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).

    CAS  Google Scholar 

  124. 124.

    Al-Mossawi, H. et al. Context-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele. Nat. Commun. 10, 4575 (2019).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Toussirot, É., Laheurte, C., Gaugler, B., Gabriel, D. & Saas, P. Increased IL-22-and IL-17A-producing mucosal-associated invariant T cells in the peripheral blood of patients with ankylosing spondylitis. Front. Immunol. 9, 1610 (2018).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

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

    PubMed  Google Scholar 

  127. 127.

    Rosine, N. et al. FRI0361 Innate versusadaptive IL-17A producing cells in axial spondyloarthritis. [abstract]. Ann. Rheum. Dis. 78 (Suppl. 2), 862–863 (2019).

    Google Scholar 

  128. 128.

    Martin, B., Hirota, K., Cua, D. J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).

    CAS  PubMed  Google Scholar 

  129. 129.

    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 

  130. 130.

    Ito, Y. et al. Gamma/delta T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis. Arthritis Rheum. 60, 2294–2303 (2009).

    CAS  PubMed  Google Scholar 

  131. 131.

    Chowdhury, A. C., Chaurasia, S., Mishra, S. K., Aggarwal, A. & Misra, R. IL-17 and IFN-γ producing NK and γδ-T cells are preferentially expanded in synovial fluid of patients with reactive arthritis and undifferentiated spondyloarthritis. Clin. Immunol. 183, 207–212 (2017).

    CAS  PubMed  Google Scholar 

  132. 132.

    Cuthbert, R. J. et al. Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression. Ann. Rheum. Dis. 78, 1559–1565 (2019).

    CAS  PubMed  Google Scholar 

  133. 133.

    Jacques, P. et al. Invariant natural killer T cells are natural regulators of murine spondylarthritis. Arthritis Rheum. 62, 988–999 (2010).

    CAS  PubMed  Google Scholar 

  134. 134.

    Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. Inflammasomes in health and disease. Nature 481, 278–286 (2012).

    CAS  PubMed  Google Scholar 

  135. 135.

    Mills, K. H. G., Dungan, L. S., Jones, S. A. & Harris, J. The role of inflammasome-derived IL-1 in driving IL-17 responses. J. Leukoc. Biol. 93, 489–497 (2013).

    CAS  PubMed  Google Scholar 

  136. 136.

    Mailer, R. K. W. et al. IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3. Sci. Rep. 5, 14674 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Iwai, Y. et al. An IFN-gamma-IL-18 signaling loop accelerates memory CD8+ T cell proliferation. PLoS ONE 3, e2404 (2008).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    Zhong, L., Song, H., Wang, W., Li, J. & Ma, M. MEFV M694V mutation has a role in susceptibility to ankylosing spondylitis: a meta-analysis. PLoS ONE 12, e0182967 (2017).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Xia, Q. et al. Autophagy-related IRGM genes confer susceptibility to ankylosing spondylitis in a Chinese female population: a case–control study. Genes. Immun. 18, 42–47 (2017).

    CAS  PubMed  Google Scholar 

  140. 140.

    Laukens, D. CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn’s disease. Ann. Rheum. Dis. 64, 930–935 (2005).

    CAS  PubMed  Google Scholar 

  141. 141.

    Guggino, G. et al. Inflammasome activation in ankylosing spondylitis is associated to gut dysbiosis. Arthritis Rheumatol. (2021).

    Article  PubMed  Google Scholar 

  142. 142.

    Tan, A. L. et al. Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann. Rheum. Dis. 63, 1041–1045 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Haibel, H., Rudwaleit, M., Listing, J. & Sieper, J. Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann. Rheum. Dis. 64, 296–298 (2005).

    CAS  PubMed  Google Scholar 

  144. 144.

    Verfaillie, T., Salazar, M., Velasco, G. & Agostinis, P. Linking ER stress to autophagy: potential implications for cancer therapy. Int. J. Cell Biol. 2010, 930509 (2010).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Navid, F. & Colbert, R. A. Causes and consequences of endoplasmic reticulum stress in rheumatic disease. Nat. Rev. Rheumatol. 13, 25–40 (2017).

    CAS  PubMed  Google Scholar 

  146. 146.

    Wu, D. J. & Adamopoulos, I. E. Autophagy and autoimmunity. Clin. Immunol. 176, 55–62 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Saiga, H. et al. The recombinant BCG ΔureC::hly vaccine targets the AIM2 inflammasome to induce autophagy and inflammation. J. Infect. Dis. 211, 1831–1841 (2015).

    CAS  PubMed  Google Scholar 

  148. 148.

    Yao, Y. et al. Antigen-specific CD8+ T cell feedback activates NLRP3 inflammasome in antigen-presenting cells through perforin. Nat. Commun. 8, 15402 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Clarke, A. J. et al. Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann. Rheum. Dis. 74, 912–920 (2015).

    PubMed  Google Scholar 

  150. 150.

    Kemp, K. & Poe, C. Stressed: the unfolded protein response in T cell development, activation, and function. Int. J. Mol. Sci. 20, 1792 (2019).

    CAS  PubMed Central  Google Scholar 

  151. 151.

    Gaudette, B. T., Jones, D. D., Bortnick, A., Argon, Y. & Allman, D. mTORC1 coordinates an immediate unfolded protein response-related transcriptome in activated B cells preceding antibody secretion. Nat. Commun. 11, 723 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Colbert, R. A., Tran, T. M. & Layh-Schmitt, G. HLA-B27 misfolding and ankylosing spondylitis. Mol. Immunol. 57, 44–51 (2014).

    CAS  PubMed  Google Scholar 

  153. 153.

    DeLay, M. L. et al. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum. 60, 2633–2643 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    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 

  155. 155.

    Navid, F., Layh-Schmitt, G., Sikora, K. A., Cougnoux, A. & Colbert, R. A. The role of autophagy in the degradation of misfolded HLA-B27 heavy chains. Arthritis Rheumatol. 70, 746–755 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    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 (2014).

    CAS  PubMed  Google Scholar 

  157. 157.

    Goodall, J. C. et al. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc. Natl Acad. Sci. USA 107, 17698–17703 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Jiao, Y. & Sun, J. Bacterial manipulation of autophagic responses in infection and inflammation. Front. Immunol. 10, 2821 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    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 

  160. 160.

    Duong, B. H. et al. A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity. Immunity 42, 55–67 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Wertz, I. E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430, 694–699 (2004).

    CAS  PubMed  Google Scholar 

  162. 162.

    Catrysse, L., Vereecke, L., Beyaert, R. & van Loo, G. A20 in inflammation and autoimmunity. Trends Immunol. 35, 22–31 (2014).

    CAS  PubMed  Google Scholar 

  163. 163.

    Malynn, B. A. & Ma, A. A20: a multifunctional tool for regulating immunity and preventing disease. Cell. Immunol. 340, 103914 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Lee, E. G. et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289, 2350–2354 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Verhelst, K. et al. A20 inhibits LUBAC-mediated NF-κB activation by binding linear polyubiquitin chains via its zinc finger 7. EMBO J. 31, 3845–3855 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Onizawa, M. et al. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat. Immunol. 16, 618–627 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Xuan, N. T. et al. A20 expression in dendritic cells protects mice from LPS-induced mortality. Eur. J. Immunol. 45, 818–828 (2015).

    PubMed  Google Scholar 

  168. 168.

    Hammer, G. E. et al. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat. Immunol. 12, 1184–1193 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Kool, M. et al. The ubiquitin-editing protein a20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 35, 82–96 (2011).

    CAS  PubMed  Google Scholar 

  170. 170.

    De Wilde, K. et al. A20 inhibition of STAT1 expression in myeloid cells: A novel endogenous regulatory mechanism preventing development of enthesitis. Ann. Rheum. Dis. 76, 585–592 (2017).

    PubMed  Google Scholar 

  171. 171.

    Matmati, M. et al. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat. Genet. 43, 908–912 (2011).

    CAS  PubMed  Google Scholar 

  172. 172.

    Das, T., Chen, Z., Hendriks, R. W. & Kool, M. A20/tumor necrosis factor α-induced protein 3 in immune cells controls development of autoinflammation and autoimmunity: Lessons from mouse models. Front. Immunol. 9, 104 (2018).

    PubMed  PubMed Central  Google Scholar 

  173. 173.

    De, A., Dainichi, T., Rathinam, C. V. & Ghosh, S. The deubiquitinase activity of A20 is dispensable for NF-κB signaling. EMBO Rep. 15, 775–783 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Wertz, I. E. et al. Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation. Nature 528, 370–375 (2015).

    CAS  PubMed  Google Scholar 

  175. 175.

    Martens, A. et al. Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities. Nat. Immunol. 21, 381–387 (2020).

    CAS  PubMed  Google Scholar 

  176. 176.

    Razani, B. et al. Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis-like disease and inflammation. Nat. Immunol. 21, 422–433 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Priem, D., van Loo, G. & Bertrand, M. J. M. A20 and cell death-driven inflammation. Trends Immunol. 41, 421–435 (2020).

    CAS  PubMed  Google Scholar 

  178. 178.

    Berger, S. B. et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192, 5476–5480 (2014).

    CAS  PubMed  Google Scholar 

  179. 179.

    Peltzer, N. et al. LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis. Nature 557, 112–117 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Damgaard, R. B. et al. OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death. EMBO Mol. Med. 11, e9324 (2019).

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13, 1178–1186 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Boisson, B. et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J. Exp. Med. 212, 939–951 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Zhou, Q. et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat. Genet. 48, 67–73 (2015).

    PubMed  PubMed Central  Google Scholar 

  184. 184.

    Rajamäki, K. et al. Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation. RMD Open 4, e000740 (2018).

    PubMed  PubMed Central  Google Scholar 

  185. 185.

    Franco-Jarava, C. et al. TNFAIP3 haploinsufficiency is the cause of autoinflammatory manifestations in a patient with a deletion of 13 Mb on chromosome 6. Clin. Immunol. 191, 44–51 (2018).

    CAS  PubMed  Google Scholar 

  186. 186.

    Liu, Y. et al. Genetic and functional associations with decreased anti-inflammatory tumor necrosis factor alpha induced protein 3 in macrophages from subjects with axial spondyloarthritis. Front. Immunol. 8, 860 (2017).

    PubMed  PubMed Central  Google Scholar 

  187. 187.

    Lewis, M. J. et al. UBE2L3 polymorphism amplifies NF-κB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases. Am. J. Hum. Genet. 96, 221–234 (2015).

    CAS  Google Scholar 

  188. 188.

    Hövelmeyer, N. et al. A20 deficiency in B cells enhances B-cell proliferation and results in the development of autoantibodies. Eur. J. Immunol. 41, 595–601 (2011).

    PubMed  Google Scholar 

  189. 189.

    Blanco-Gelaz, M. A. et al. The amino acid at position 97 is involved in folding and surface expression of HLA-B27. Int. Immunol. 18, 211–220 (2006).

    CAS  PubMed  Google Scholar 

  190. 190.

    Schwimmbeck, P. L. & Oldstone, M. B. A. Molecular mimicry between human leukocyte antigen B27 and klebsiella. Consequences for spondyloarthropathies. Am. J. Med. 85, 51–53 (1988).

    CAS  PubMed  Google Scholar 

  191. 191.

    Taurog, J. D. et al. Spondylarthritis in HLA-B27/human beta2-microglobulin-transgenic rats is not prevented by lack of CD8. Arthritis Rheum. 60, 1977–1984 (2009).

    CAS  PubMed  Google Scholar 

  192. 192.

    Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).

    CAS  PubMed  Google Scholar 

  193. 193.

    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 

  194. 194.

    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 

  195. 195.

    Appel, H. et al. Use of HLA-B27 tetramers to identify low-frequency antigen-specific T cells in Chlamydia-triggered reactive arthritis. Arthritis Res. Ther. 6, R521–R534 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Hermann, E., Yu, D. T., Meyer zum Büschenfelde, K. H. & Fleischer, B. HLA-B27-restricted CD8 T cells derived from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet 342, 646–650 (1993).

    CAS  PubMed  Google Scholar 

  197. 197.

    Atagunduz, P. et al. HLA-B27-restricted CD8+ T cell response to cartilage-derived self peptides in ankylosing spondylitis. Arthritis Rheum. 52, 892–901 (2005).

    CAS  PubMed  Google Scholar 

  198. 198.

    Kuon, W. et al. Identification of HLA-B27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases. J. Immunol. 167, 4738–4746 (2001).

    CAS  PubMed  Google Scholar 

  199. 199.

    Fiorillo, M. T., Maragno, M., Butler, R., Dupuis, M. L. & Sorrentino, R. CD8+ T-cell autoreactivity to an HLA-B27-restricted self-epitope correlates with ankylosing spondylitis. J. Clin. Invest. 106, 47–53 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200.

    Fiorillo, M. T. & Sorrentino, R. T-cell responses against viral and self-epitopes and HLA-B27 subtypes differentially associated with ankylosing spondylitis. Adv. Exp. Med. Biol. 649, 255–262 (2009).

    CAS  PubMed  Google Scholar 

  201. 201.

    Gracey, E. et al. Altered cytotoxicity profile of CD8+ T cells in ankylosing spondylitis. Arthritis Rheumatol. 72, 428–434 (2019).

    Google Scholar 

  202. 202.

    Zhang, L., Jarvis, L. B. & Baek, H.-J. & Hill Gaston, J. S. Regulatory IL4+CD8+ T cells in patients with ankylosing spondylitis and healthy controls. Ann. Rheum. Dis. 68, 1345–1351 (2009).

    CAS  PubMed  Google Scholar 

  203. 203.

    Hanson, A. L. et al. T-cell receptor immunosequencing reveals altered repertoire diversity and disease-associated clonal expansions in ankylosing spondylitis patients. Arthritis Rheumatol. 72, 1289–1302 (2020).

    CAS  PubMed  Google Scholar 

  204. 204.

    Qaiyum, Z., Gracey, E., Yao, Y. C. & Inman, R. D. Integrin and transcriptomic profiles identify a distinctive synovial CD8+ T cell subpopulation in spondyloarthritis. Ann. Rheum. Dis. 78, 1566–1575 (2019).

    CAS  PubMed  Google Scholar 

  205. 205.

    Guggino, G., Rizzo, A., Mauro, D., Macaluso, F. & Ciccia, F. Gut-derived CD8+ tissue-resident memory T cells are expanded in the peripheral blood and synovia of SpA patients. Ann. Rheum. Dis. (2019).

    Article  PubMed  Google Scholar 

  206. 206.

    Zhu, W. et al. Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res. 7, 22 (2019).

    PubMed  PubMed Central  Google Scholar 

  207. 207.

    Limón-Camacho, L. et al. In vivo peripheral blood proinflammatory T cells in patients with ankylosing spondylitis. J. Rheumatol. 39, 830–835 (2012).

    PubMed  Google Scholar 

  208. 208.

    Reinhardt, A. & Prinz, I. Whodunit? The contribution of interleukin (IL)-17/IL-22-producing γδ T cells, αβ T cells, and innate lymphoid cells to the pathogenesis of spondyloarthritis. Front. Immunol. 9, 885 (2018).

    PubMed  PubMed Central  Google Scholar 

  209. 209.

    Niu, X.-Y. et al. Peripheral B-cell activation and exhaustion markers in patients with ankylosing spondylitis. Life Sci. 93, 687–692 (2013).

    CAS  PubMed  Google Scholar 

  210. 210.

    Chen, M. et al. Defective function of CD24(+)CD38(+) regulatory B cells in ankylosing spondylitis. DNA Cell Biol. 35, 88–95 (2016).

    CAS  PubMed  Google Scholar 

  211. 211.

    Bautista-Caro, M. B. et al. Increased frequency of circulating CD19+CD24hiCD38hi B cells with regulatory capacity in patients with ankylosing spondylitis (AS) naïve for biological agents. PLoS ONE 12, e0180726 (2017).

    PubMed  PubMed Central  Google Scholar 

  212. 212.

    Song, I. H. et al. Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial. Arthritis Rheum. 62, 1290–1297 (2010).

    CAS  PubMed  Google Scholar 

  213. 213.

    Feng, X., Xu, X., Wang, Y., Zheng, Z. & Lin, G. Ectopic germinal centers and IgG4-producing plasmacytes observed in synovia of HLA-B27+ ankylosing spondylitis patients with advanced hip involvement. Int. J. Rheumatol. 2015, 316421 (2015).

    PubMed  PubMed Central  Google Scholar 

  214. 214.

    Voswinkel, J., Weisgerber, K., Pfreundschuh, M. & Gause, A. B lymphocyte involvement in ankylosing spondylitis: the heavy chain variable segment gene repertoire of B lymphocytes from germinal center-like foci in the synovial membrane indicates antigen selection. Arthritis Res. 3, 189–195 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215.

    Wright, C. et al. Detection of multiple autoantibodies in patients with ankylosing spondylitis using nucleic acid programmable protein arrays. Mol. Cell. Proteom. 11, M9.00384 (2012).

    Google Scholar 

  216. 216.

    Baerlecken, N. T. et al. Autoantibodies against CD74 in spondyloarthritis. Ann. Rheum. Dis. 73, 1211–1214 (2014).

    CAS  PubMed  Google Scholar 

  217. 217.

    Baraliakos, X., Baerlecken, N., Witte, T., Heldmann, F. & Braun, J. High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis. Ann. Rheum. Dis. 73, 1079–1082 (2014).

    CAS  PubMed  Google Scholar 

  218. 218.

    de Winter, J. J. et al. Anti-CD74 antibodies have no diagnostic value in early axial spondyloarthritis: data from the spondyloarthritis caught early (SPACE) cohort. Arthritis Res. Ther. 20, 38 (2018).

    PubMed  PubMed Central  Google Scholar 

  219. 219.

    Tsui, F. W. L., Tsui, H. W., Las Heras, F., Pritzker, K. P. H. & Inman, R. D. Serum levels of novel noggin and sclerostin-immune complexes are elevated in ankylosing spondylitis. Ann. Rheum. Dis. 73, 1873–1879 (2013).

    PubMed  Google Scholar 

  220. 220.

    Appel, H. et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum. 60, 3257–3262 (2009).

    PubMed  Google Scholar 

  221. 221.

    Lories, R. J. U., Derese, I. & Luyten, F. P. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J. Clin. Invest. 115, 1571–1579 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Luchetti, M. M. et al. Sclerostin and antisclerostin antibody serum levels predict the presence of axial spondyloarthritis in patients with inflammatory bowel disease. J. Rheumatol. 45, 630–637 (2018).

    CAS  PubMed  Google Scholar 

  223. 223.

    Klingberg, E. et al. A distinct gut microbiota composition in patients with ankylosing spondylitis is associated with increased levels of fecal calprotectin. Arthritis Res. Ther. 21, 248 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 224.

    Ma, X., Aoki, T. & Narumiya, S. Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways. Cell. Mol. Immunol. 13, 240–250 (2016).

    CAS  PubMed  Google Scholar 

  225. 225.

    Zhang, J. & Wang, J. H.-C. Production of PGE(2) increases in tendons subjected to repetitive mechanical loading and induces differentiation of tendon stem cells into non-tenocytes. J. Orthop. Res. 28, 198–203 (2010).

    PubMed  Google Scholar 

  226. 226.

    Cortes, A. et al. Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Ann. Rheum. Dis. 74, 1387–1393 (2015).

    CAS  PubMed  Google Scholar 

  227. 227.

    Maas, F. et al. Reduction in spinal radiographic progression in ankylosing spondylitis patients receiving prolonged treatment with tumor necrosis factor inhibitors. Arthritis Care Res. 69, 1011–1019 (2017).

    CAS  Google Scholar 

  228. 228.

    van der Heijde, D. et al. Limited radiographic progression and sustained reductions in MRI inflammation in patients with axial spondyloarthritis: 4-year imaging outcomes from the RAPID-axSpA phase III randomised trial. Ann. Rheum. Dis. 77, 699–705 (2018).

    PubMed  Google Scholar 

  229. 229.

    Jung, J.-Y., Kim, M.-Y., Hong, Y. S., Park, S.-H. & Kang, K. Y. Trabecular bone loss contributes to radiographic spinal progression in patients with axial spondyloarthritis. Semin. Arthritis Rheum. 50, 827–833 (2020).

    PubMed  Google Scholar 

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All authors researched data for the article. D.M., R.T., M.A.B. and F.C. provided substantial contributions to discussions of content. All authors wrote the article. D.M., R.T., R.L., M.A.B. and F.C. reviewed and/or edited the manuscript before submission.

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Correspondence to Francesco Ciccia.

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Nature Reviews Rheumatology thanks R. Inman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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The sites at which ligaments and tendons attach to the bones.

Epistatic interaction

Interaction among gene alleles at multiple locations that influence the phenotype.

Ectopic lymphoid neogenesis

The formation of lymphoid structures in the target tissues of chronic inflammation.

SKG mice

Mice with attenuated T cell receptor signalling that develop spontaneous inflammatory arthritis with extra-articular manifestations, including inflammatory bowel disease, under conventional conditions.


A cellular and molecular system that senses the mechanical strain exerted on bones.

Paneth cells

Specialized epithelial cells located at the bottom of intestinal crypts that contribute to the maintenance of sterility in the crypts.


A molecule that modulates the permeability of tight junctions between intestinal epithelial cells.

Minicircle technology

The use of small circular DNA elements to induce the expression of genes in vivo or in vitro.


Mice with a deletion of the AU-rich element (ARE) from the TNF gene; ARE controls the stability of the TNF mRNA; therefore these mice have increased production of TNF.


An inflammatory form of lytic programmed cell death that occurs following inflammasome activation.


A form of inflammatory cell death similar to necrosis that is regulated in a caspase-dependent manner and that can be induced by extracellular stimuli such as TNF.

TNF receptor complex I

A receptor complex of TNF that contains a death domain that mediates the induction of apoptosis and necroptosis.

Linear ubiquitin assembly complex

A three-protein complex with ubiquitin ligase activity that forms ubiquitin chains linked to the first lysine and is involved in intracellular signalling.


Forced classification into an arbitrary standard, deriving from the Procrustean bed ancient Greek myth.

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Mauro, D., Thomas, R., Guggino, G. et al. Ankylosing spondylitis: an autoimmune or autoinflammatory disease?. Nat Rev Rheumatol 17, 387–404 (2021).

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