Aberrant antigen processing and presentation: Key pathogenic factors leading to immune activation in Ankylosing spondylitis

Zhu W, He X, Cheng K, Zhang L, Chen D, Wang X, Qiu G, Cao X, Weng X (2019) Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res 7:22. https://doi.org/10.1038/s41413-019-0057-8 Nakamura A, Talukdar A, Nakamura S, Pathan E, Haroon N (2019) Bone formation in axial spondyloarthritis: Is disease modification possible? Best Pract Res Clin Rheumatol 33:101491. https://doi.org/10.1016/j.berh.2020.101491 Ranganathan V, Gracey E, Brown MA, Inman RD, Haroon N (2017) Pathogenesis of ankylosing spondylitis - recent advances and future directions. Nat Rev Rheumatol 13:359–367. https://doi.org/10.1038/nrrheum.2017.56 Tsui FW, Tsui HW, Akram A, Haroon N, Inman R (2014) The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis. Appl Clin Genet 7:105–115. https://doi.org/10.2147/TACG.S37325 Ellinghaus D, Jostins L, Spain SL et al (2016) Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet 48:510–518. https://doi.org/10.1038/ng.3528 Reveille JD, Sims A-M, Danoy P et al (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42:123–127. https://doi.org/10.1038/ng.513 Cortes A, Hadler J, Pointon JP et al (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45:730–738. https://doi.org/10.1038/ng.2667 Zinkernagel RM, Doherty PC (1974) Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248:701–702. https://doi.org/10.1038/248701a0 Doherty PC, Zinkernagel RM, Ramshaw IA (1974) Specificity and development of cytotoxic thymus-derived lymphocytes in lymphocytic choriomeningitis. J Immunol 112:1548–1552 Khan MA (2017) An update on the genetic polymorphism of HLA-B*27 with 213 alleles encompassing 160 subtypes (and still counting). Curr Rheumatol Rep 19:9. https://doi.org/10.1007/s11926-017-0640-1 Inman RD (2016) Oxford textbook of axial spondyloarthritis. OXFORD Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J, Wordsworth BP, Cornelis F (1996) HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis 55:268–270. https://doi.org/10.1136/ard.55.4.268 Luo F, Zhao Z, Zhang J, Leng J (2019) Comparison of HLA-B*27 subtypes between Chinese patients with ankylosing spondylitis and non-ankylosing spondylitis carriers. J Int Med Res 47:3171–3178. https://doi.org/10.1177/0300060519853929 Yang M, Xu M, Pan X, Hu Z, Li Q, Wei Y, Zhang Y, Rong J, Zhai J, He P, Hu S, Song H, Wu H, Zhan F, Liu S, Gao G, Liu Z, Li Y, Shen L, Huang A, Lin Z, Liao Z, Cao S, Wei Q, Li Q, Lv Q, Qi J, Li T, Jin O, Pan Y, Gu J (2013) Epidemiological comparison of clinical manifestations according to HLA-B*27 carrier status of Chinese ankylosing spondylitis patients. Tissue Antigens 82:338–343. https://doi.org/10.1111/tan.12186 Glatigny S, Fert I, Blaton MA, Lories RJ, Araujo LM, Chiocchia G, Breban M (2012) Proinflammatory Th17 cells are expanded and induced by dendritic cells in spondylarthritis-prone HLA-B27-transgenic rats. Arthritis Rheum 64:110–120. https://doi.org/10.1002/art.33321 DeLay ML, Turner MJ, Klenk EI et al (2009) 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. https://doi.org/10.1002/art.24763 Milia AF, Ibba-Manneschi L, Manetti M, Benelli G, Messerini L, Matucci-Cerinic M (2009) HLA-B27 transgenic rat: an animal model mimicking gut and joint involvement in human spondyloarthritides. Ann N Y Acad Sci 1173:570–574. https://doi.org/10.1111/j.1749-6632.2009.04757.x Braem K, Lories RJ (2012) Insights into the pathophysiology of ankylosing spondylitis: contributions from animal models. Jt Bone Spine 79:243–248. https://doi.org/10.1016/j.jbspin.2011.09.008 Stam NJ, Spits H, Ploegh HL (1986) Monoclonal antibodies raised against denatured HLA-B locus heavy chains permit biochemical characterization of certain HLA-C locus products. J Immunol 137:2299–2306 McMichael A, Bowness P (2002) HLA-B27: natural function and pathogenic role in spondyloarthritis. Arthritis Res 4(Suppl 3):S153–S158. https://doi.org/10.1186/ar571 Taurog JD (2010) The role of HLA-B27 in spondyloarthritis. J Rheumatol 37:2606–2616. https://doi.org/10.3899/jrheum.100889 Bowness P (2015) HLA-B27. Annu Rev Immunol 33:29–48. https://doi.org/10.1146/annurev-immunol-032414-112110 Neumann-Haefelin C, McKiernan S, Ward S, Viazov S, Spangenberg HC, Killinger T, Baumert TF, Nazarova N, Sheridan I, Pybus O, von Weizsäcker F, Roggendorf M, Kelleher D, Klenerman P, Blum HE, Thimme R (2006) Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution. Hepatology 43:563–572. https://doi.org/10.1002/hep.21049 Dazert E, Neumann-Haefelin C, Bressanelli S, Fitzmaurice K, Kort J, Timm J, McKiernan S, Kelleher D, Gruener N, Tavis JE, Rosen HR, Shaw J, Bowness P, Blum HE, Klenerman P, Bartenschlager R, Thimme R (2009) Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. J Clin Invest 119:376–386. https://doi.org/10.1172/JCI36587 Goulder PJ, Phillips RE, Colbert RA et al (1997) Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 3:212–217. https://doi.org/10.1038/nm0297-212 Appel H, Kuon W, Kuhne M, Wu P, Kuhlmann S, Kollnberger S, Thiel A, Bowness P, Sieper J (2004) Use of HLA-B27 tetramers to identify low-frequency antigen-specific T cells in Chlamydia-triggered reactive arthritis. Arthritis Res Ther 6:R521–R534. https://doi.org/10.1186/ar1221 Schittenhelm RB, Sian TCCLK, Wilmann PG et al (2015) Revisiting the arthritogenic peptide theory: quantitative not qualitative changes in the peptide repertoire of HLA-B27 allotypes. Arthritis Rheumatol (Hoboken, NJ) 67:702–713. https://doi.org/10.1002/art.38963 Schittenhelm RB, Sivaneswaran S, Lim Kam Sian TCC, Croft NP, Purcell AW (2016) 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. https://doi.org/10.1074/mcp.M115.056358 García-Medel N, Sanz-Bravo A, Alvarez-Navarro C, Gómez-Molina P, Barnea E, Marcilla M, Admon A, de Castro JAL (2014) 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. https://doi.org/10.1074/mcp.M114.039214 Faham M, Carlton V, Moorhead M et al (2017) Discovery of T cell receptor β motifs specific to HLA-B27-positive ankylosing spondylitis by deep repertoire sequence analysis. Arthritis Rheumatol (Hoboken, NJ) 69:774–784. https://doi.org/10.1002/art.40028 Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD (1990) Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell 63:1099–1112. https://doi.org/10.1016/0092-8674(90)90512-d May E, Dorris ML, Satumtira N, Iqbal I, Rehman MI, Lightfoot E, Taurog JD (2003) CD8 alpha beta T cells are not essential to the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats. J Immunol 170:1099–1105. https://doi.org/10.4049/jimmunol.170.2.1099 Taurog JD, Dorris ML, Satumtira N, Tran TM, Sharma R, Dressel R, van den Brandt J, Reichardt HM (2009) Spondylarthritis in HLA-B27/human beta2-microglobulin-transgenic rats is not prevented by lack of CD8. Arthritis Rheum 60:1977–1984. https://doi.org/10.1002/art.24599 Madden DR (1995) The three-dimensional structure of peptide-MHC complexes. Annu Rev Immunol 13:587–622. https://doi.org/10.1146/annurev.iy.13.040195.003103 Allen RL, O’Callaghan CA, McMichael AJ, Bowness P (1999) Cutting edge: HLA-B27 can form a novel β<sub>2</sub>-microglobulin-free heavy chain homodimer structure. J Immunol 162:5045 LP–5045048 Bird LA, Peh CA, Kollnberger S et al (2003) Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling. Eur J Immunol 33:748–759. https://doi.org/10.1002/eji.200323678 Rysnik O, McHugh K, van Duivenvoorde L, van Tok M, Guggino G, Taurog J, Kollnberger S, Ciccia F, Baeten D, Bowness P (2016) Non-conventional forms of HLA-B27 are expressed in spondyloarthritis joints and gut tissue. J Autoimmun 70:12–21. https://doi.org/10.1016/j.jaut.2016.03.009 Payeli SK, Kollnberger S, Marroquin Belaunzaran O, Thiel M, McHugh K, Giles J, Shaw J, Kleber S, Ridley A, Wong-Baeza I, Keidel S, Kuroki K, Maenaka K, Wadle A, Renner C, Bowness P (2012) Inhibiting HLA-B27 homodimer-driven immune cell inflammation in spondylarthritis. Arthritis Rheum 64:3139–3149. https://doi.org/10.1002/art.34538 McHugh K, Rysnik O, Kollnberger S, Shaw J, Utriainen L, al-Mossawi MH, Payeli S, Marroquin O, Milling S, Renner C, Bowness P (2014) Expression of aberrant HLA-B27 molecules is dependent on B27 dosage and peptide supply. Ann Rheum Dis 73:763–770. https://doi.org/10.1136/annrheumdis-2012-203080 Kollnberger S, Chan A, Sun M-Y, Ye Chen L, Wright C, di Gleria K, McMichael A, Bowness P (2007) Interaction of HLA-B27 homodimers with KIR3DL1 and KIR3DL2, unlike HLA-B27 heterotrimers, is independent of the sequence of bound peptide. Eur J Immunol 37:1313–1322. https://doi.org/10.1002/eji.200635997 Giles J, Shaw J, Piper C, Wong-Baeza I, McHugh K, Ridley A, Li D, Lenart I, Antoniou AN, DiGleria K, Kuroki K, Maenaka K, Bowness P, Kollnberger S (2012) HLA-B27 homodimers and free H chains are stronger ligands for leukocyte Ig-like receptor B2 than classical HLA class I. J Immunol 188:6184–6193. https://doi.org/10.4049/jimmunol.1102711 Wong-Baeza I, Ridley A, Shaw J, Hatano H, Rysnik O, McHugh K, Piper C, Brackenbridge S, Fernandes R, Chan A, Bowness P, Kollnberger S (2013) KIR3DL2 binds to HLA-B27 dimers and free H chains more strongly than other HLA class I and promotes the expansion of T cells in ankylosing spondylitis. J Immunol 190:3216–3224. https://doi.org/10.4049/jimmunol.1202926 Cauli A, Shaw J, Giles J, Hatano H, Rysnik O, Payeli S, McHugh K, Dessole G, Porru G, Desogus E, Fiedler S, Holper S, Carette A, Blanco-Gelaz MA, Vacca A, Piga M, Ibba V, Garau P, la Nasa G, Lopez-Larrea C, Mathieu A, Renner C, Bowness P, Kollnberger S (2013) The arthritis-associated HLA-B*27:05 allele forms more cell surface B27 dimer and free heavy chain ligands for KIR3DL2 than HLA-B*27:09. Rheumatology (Oxford) 52:1952–1962. https://doi.org/10.1093/rheumatology/ket219 Gaur P, Misra R, Aggarwal A (2015) Natural killer cell and gamma delta T cell alterations in enthesitis related arthritis category of juvenile idiopathic arthritis. Clin Immunol 161:163–169. https://doi.org/10.1016/j.clim.2015.07.012 Chan AT, Kollnberger SD, Wedderburn LR, Bowness P (2005) Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis. Arthritis Rheum 52:3586–3595. https://doi.org/10.1002/art.21395 Bowness P, Ridley A, Shaw J, Chan AT, Wong-Baeza I, Fleming M, Cummings F, McMichael A, Kollnberger S (2011) Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol 186:2672–2680. https://doi.org/10.4049/jimmunol.1002653 Purvis HA, Stoop JN, Mann J, Woods S, Kozijn AE, Hambleton S, Robinson JH, Isaacs JD, Anderson AE, Hilkens CMU (2010) Low-strength T-cell activation promotes Th17 responses. Blood 116:4829–4837. https://doi.org/10.1182/blood-2010-03-272153 Takeuchi Y, Hirota K, Sakaguchi S (2020) Impaired T cell receptor signaling and development of T cell-mediated autoimmune arthritis. Immunol Rev 294:164–176. https://doi.org/10.1111/imr.12841 Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, Hirota K, Tanaka S, Nomura T, Miki I, Gordon S, Akira S, Nakamura T, Sakaguchi S (2005) A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med 201:949–960. https://doi.org/10.1084/jem.20041758 Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S (2003) Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426:454–460. https://doi.org/10.1038/nature02119 Guiliano DB, North H, Panayoitou E et al (2017) Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions, and heavy-chain misfolding. Arthritis Rheumatol (Hoboken, NJ) 69:610–621. https://doi.org/10.1002/art.39948 Mear JP, Schreiber KL, Münz C 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 163:6665–6670 Dangoria NS, DeLay ML, Kingsbury DJ et al (2002) HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum. J Biol Chem 277:23459–23468. https://doi.org/10.1074/jbc.M110336200 Meusser B, Hirsch C, Jarosch E, Sommer T (2005) ERAD: the long road to destruction. Nat Cell Biol 7:766–772. https://doi.org/10.1038/ncb0805-766 Ryno LM, Wiseman RL, Kelly JW (2013) Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases. Curr Opin Chem Biol 17:346–352. https://doi.org/10.1016/j.cbpa.2013.04.009 Layh-Schmitt G, Yang EY, Kwon G, Colbert RA (2013) HLA-B27 alters the response to tumor necrosis factor α and promotes osteoclastogenesis in bone marrow monocytes from HLA-B27-transgenic rats. Arthritis Rheum 65:2123–2131. https://doi.org/10.1002/art.38001 Turner MJ, Sowders DP, DeLay ML et al (2005) HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175:2438–2448. https://doi.org/10.4049/jimmunol.175.4.2438 Antoniou AN, Lenart I, Kriston-Vizi J, Iwawaki T, Turmaine M, McHugh K, Ali S, Blake N, Bowness P, Bajaj-Elliott M, Gould K, Nesbeth D, Powis SJ (2019) Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication. Ann Rheum Dis 78:74–82. https://doi.org/10.1136/annrheumdis-2018-213532 Ciccia F, Accardo-Palumbo A, Rizzo A, Guggino G, Raimondo S, Giardina AR, Cannizzaro A, Colbert RA, Alessandro R, Triolo G (2014) 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. https://doi.org/10.1136/annrheumdis-2012-202925 Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741. https://doi.org/10.1016/j.cell.2011.10.026 Klionsky DJ (2008) Autophagy revisited: a conversation with Christian de Duve. Autophagy 4:740–743. https://doi.org/10.4161/auto.6398 Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42. https://doi.org/10.1016/j.cell.2007.12.018 Dikic I, Elazar Z (2018) Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 19:349–364. https://doi.org/10.1038/s41580-018-0003-4 Tan M, Zhang Q-B, Liu T-H et al (2020) Autophagy dysfunction may be involved in the pathogenesis of ankylosing spondylitis. Exp Ther Med 20:3578–3586. https://doi.org/10.3892/etm.2020.9116 Navid F, Layh-Schmitt G, Sikora KA et al (2018) The role of autophagy in the degradation of misfolded HLA-B27 heavy chains. Arthritis Rheumatol (Hoboken, NJ) 70:746–755. https://doi.org/10.1002/art.40414 Chen S, van Tok MN, Knaup VL, Kraal L, Pots D, Bartels L, Gravallese EM, Taurog JD, van de Sande M, van Duivenvoorde LM, Baeten DL (2019) mTOR blockade by rapamycin in spondyloarthritis: impact on inflammation and new bone formation in vitro and in vivo. Front Immunol 10:2344. https://doi.org/10.3389/fimmu.2019.02344 Kurebayashi Y, Nagai S, Ikejiri A, Ohtani M, Ichiyama K, Baba Y, Yamada T, Egami S, Hoshii T, Hirao A, Matsuda S, Koyasu S (2012) PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ. Cell Rep 1:360–373. https://doi.org/10.1016/j.celrep.2012.02.007 Ren W, Yin J, Duan J, Liu G, Tan B, Yang G, Wu G, Bazer FW, Peng Y, Yin Y (2016) mTORC1 signaling and IL-17 expression: defining pathways and possible therapeutic targets. Eur J Immunol 46:291–299. https://doi.org/10.1002/eji.201545886 Neerinckx B, Carter S, Lories R (2014) 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 pat. Ann Rheum Dis 73:e68 Burton PR, Clayton DG, Cardon LR et al (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–1337. https://doi.org/10.1038/ng.2007.17 York IA, Chang S-C, Saric T, Keys JA, Favreau JM, Goldberg AL, Rock KL (2002) The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues. Nat Immunol 3:1177–1184. https://doi.org/10.1038/ni860 Hammer GE, Shastri N (2007) Construction and destruction of MHC class I in the peptide-loading complex. Nat Immunol 8:793–794 Tsui FWL, Haroon N, Reveille JD, Rahman P, Chiu B, Tsui HW, Inman RD (2010) Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Ann Rheum Dis 69:733–736. https://doi.org/10.1136/ard.2008.103804 Londono J, Santos AM, Rueda JC, Calvo-Paramo E, Burgos-Vargas R, Vargas-Alarcon G, Martinez-Rodriguez N, Arias-Correal S, Muñoz GN, Padilla D, Cuervo F, Reyes-Martinez V, Bernal-Macías S, Villota-Eraso C, Avila-Portillo LM, Romero C, Medina JF (2020) Association of ERAP2 polymorphisms in Colombian HLA-B27+ or HLA-B15+ patients with SpA and its relationship with clinical presentation: axial or peripheral predominance. RMD Open 6:e001250. https://doi.org/10.1136/rmdopen-2020-001250 Reveille JD, Zhou X, Lee M, Weisman MH, Yi L, Gensler LS, Zou H, Ward MM, Ishimori ML, Learch TJ, He D, Rahbar MH, Wang J, Brown MA (2019) HLA class I and II alleles in susceptibility to ankylosing spondylitis. Ann Rheum Dis 78:66–73. https://doi.org/10.1136/annrheumdis-2018-213779 Haroon N, Inman RD (2010) Endoplasmic reticulum aminopeptidases: Biology and pathogenic potential. Nat Rev Rheumatol 6:461–467. https://doi.org/10.1038/nrrheum.2010.85 Cherciu M, Popa LO, Bojinca M, Dutescu MI, Bojinca V, Bara C, Popa OM (2013) Functional variants of ERAP1 gene are associated with HLA-B27 positive spondyloarthritis. Tissue Antigens 82:192–196. https://doi.org/10.1111/tan.12158 Haroon N, Tsui FW, Uchanska-Ziegler B, Ziegler A, Inman RD (2012) 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. https://doi.org/10.1136/annrheumdis-2011-200347 Haroon N (2012) Endoplasmic reticulum aminopeptidase 1 and interleukin-23 receptor in ankylosing spondylitis. Curr Rheumatol Rep 14:383–389. https://doi.org/10.1007/s11926-012-0268-0 Cortes A, Pulit SL, Leo PJ, Pointon JJ, Robinson PC, Weisman MH, Ward M, Gensler LS, Zhou X, Garchon HJ, Chiocchia G, Nossent J, Lie BA, Førre Ø, Tuomilehto J, Laiho K, Bradbury LA, Elewaut D, Burgos-Vargas R, Stebbings S, Appleton L, Farrah C, Lau J, Haroon N, Mulero J, Blanco FJ, Gonzalez-Gay MA, Lopez-Larrea C, Bowness P, Gaffney K, Gaston H, Gladman DD, Rahman P, Maksymowych WP, Crusius JBA, van der Horst-Bruinsma IE, Valle-Oñate R, Romero-Sánchez C, Hansen IM, Pimentel-Santos FM, Inman RD, Martin J, Breban M, Wordsworth BP, Reveille JD, Evans DM, de Bakker PIW, Brown MA (2015) Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat Commun 6:7146. https://doi.org/10.1038/ncomms8146 Harvey D, Pointon JJ, Evans DM, Karaderi T, Farrar C, Appleton LH, Sturrock RD, Stone MA, Oppermann U, Brown MA, Wordsworth BP (2009) Investigating the genetic association between ERAP1 and ankylosing spondylitis. Hum Mol Genet 18:4204–4212. https://doi.org/10.1093/hmg/ddp371 Kochan G, Krojer T, Harvey D, Fischer R, Chen L, Vollmar M, von Delft F, Kavanagh KL, Brown MA, Bowness P, Wordsworth P, Kessler BM, Oppermann U (2011) Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proc Natl Acad Sci U S A 108:7745–7750. https://doi.org/10.1073/pnas.1101262108 Reeves E, Colebatch-Bourn A, Elliott T, Edwards CJ, James E (2014) Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis. Proc Natl Acad Sci U S A 111:17594–17599. https://doi.org/10.1073/pnas.1408882111 Reeves E, Edwards CJ, Elliott T, James E (2013) Naturally occurring ERAP1 haplotypes encode functionally distinct alleles with fine substrate specificity. J Immunol 191:35–43. https://doi.org/10.4049/jimmunol.1300598 Roberts AR, Appleton LH, Cortes A, Vecellio M, Lau J, Watts L, Brown MA, Wordsworth P (2017) ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations. Proc Natl Acad Sci U S A 114:558–561. https://doi.org/10.1073/pnas.1618856114 Tran TM, Hong S, Edwan JH, Colbert RA (2016) ERAP1 reduces accumulation of aberrant and disulfide-linked forms of HLA-B27 on the cell surface. Mol Immunol 74:10–17. https://doi.org/10.1016/j.molimm.2016.04.002 Chen L, Ridley A, Hammitzsch A, al-Mossawi MH, Bunting H, Georgiadis D, Chan A, Kollnberger S, Bowness P (2016) 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. https://doi.org/10.1136/annrheumdis-2014-206996 Haroon N, Tsui FWL, Chiu B et al (2010) Serum cytokine receptors in ankylosing spondylitis: relationship to inflammatory markers and endoplasmic reticulum aminopeptidase polymorphisms. J Rheumatol 37:1907–1910. https://doi.org/10.3899/jrheum.100019 Zhang Z, Ciccia F, Zeng F et al (2017) Brief report: functional interaction of endoplasmic reticulum aminopeptidase 2 and HLA-B27 activates the unfolded protein response. Arthritis Rheumatol (Hoboken, NJ) 69:1009–1015. https://doi.org/10.1002/art.40033 D’Arcangelo JG, Stahmer KR, Miller EA (2013) Vesicle-mediated export from the ER: COPII coat function and regulation. Biochim Biophys Acta 1833:2464–2472. https://doi.org/10.1016/j.bbamcr.2013.02.003 Miller EA, Schekman R (2013) COPII - a flexible vesicle formation system. Curr Opin Cell Biol 25:420–427. https://doi.org/10.1016/j.ceb.2013.04.005 Sprangers J, Rabouille C (2015) SEC16 in COPII coat dynamics at ER exit sites. Biochem Soc Trans 43:97–103. https://doi.org/10.1042/BST20140283 Espenshade P, Gimeno RE, Holzmacher E, Teung P, Kaiser CA (1995) Yeast SEC16 gene encodes a multidomain vesicle coat protein that interacts with Sec23p. J Cell Biol 131:311–324. https://doi.org/10.1083/jcb.131.2.311 Watson P, Townley AK, Koka P, Palmer KJ, Stephens DJ (2006) Sec16 defines endoplasmic reticulum exit sites and is required for secretory cargo export in mammalian cells. Traffic 7:1678–1687. https://doi.org/10.1111/j.1600-0854.2006.00493.x O’Rielly DD, Uddin M, Codner D et al (2016) Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis. Ann Rheum Dis 75:772–779. https://doi.org/10.1136/annrheumdis-2014-206484 Christodoulou K, Wiskin AE, Gibson J, Tapper W, Willis C, Afzal NA, Upstill-Goddard R, Holloway JW, Simpson MA, Beattie RM, Collins A, Ennis S (2013) Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut 62:977–984. https://doi.org/10.1136/gutjnl-2011-301833