New insights toward the pathogenesis of ankylosing spondylitis; genetic variations and epigenetic modifications

References

• Schett G. Bone formation versus bone resorption in ankylosing spondylitis. In: Molecular Mechanisms of Spondyloarthropathies. Vol. 649 of the series Advances in Experimental Medicine and Biology. Springer; 2009:114–21.
   Google Scholar
• Brown MA, Kennedy LG, Macgregor AJ, Darke C, Duncan E, Shatford JL, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum. 1997;40(10):1823–8.
   PubMed Web of Science ®Google Scholar
• Hamersma J, Cardon L, Bradbury L, Brophy S, Der Horst-Bruinsma V, Calin A, et al. Is disease severity in ankylosing spondylitis genetically determined? Arthritis Rheum. 2001;44(6):1396–400.
   PubMed Web of Science ®Google Scholar
• Brophy S, Hickey S, Menon A, Taylor G, Bradbury L, Hamersma J, et al. Concordance of disease severity among family members with ankylosing spondylitis? J Rheumatol. 2004;31(9):1775–8.
   PubMed Web of Science ®Google Scholar
• Fallahi S, Mahmoudi M, Nicknam MH, Gharibdoost F, Farhadi E, Saei A, et al. Effect of HLA-B*27 and its subtypes on clinical manifestations and severity of ankylosing spondylitis in Iranian patients . Iran J Allergy Asthma Immunol. 2013;12(4):321–30.
   PubMed Web of Science ®Google Scholar
• Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genetics. 2007;39(11):1329–37.
   PubMed Web of Science ®Google Scholar
• Brionez TF, Reveille JD. The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis. Curr Opin Rheumatol. 2008;20(4):384–91.
   PubMed Web of Science ®Google Scholar
• Greer JM, McCombe PA. The role of epigenetic mechanisms and processes in autoimmune disorders. Biologics. 2012;6:307
   PubMedGoogle Scholar
• Fernández-Morera J, Calvanese V, Rodríguez-Rodero S, Menéndez-Torre E, Fraga M. Epigenetic regulation of the immune system in health and disease. Tissue Antigens. 2010;76(6):431–9.
   PubMedGoogle Scholar
• Sawalha AH. Epigenetics and T-cell immunity. Autoimmunity. 2008;41(4):245–52.
   PubMed Web of Science ®Google Scholar
• Brown M, Laval S, Brophy S, Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis. 2000;59(11):883–6.
   PubMed Web of Science ®Google Scholar
• Brewerton D, Hart F, Nicholls A, Caffrey M, James D, Sturrock R. Ankylosing spondylitis and HL-A 27. Lancet. 1973;1(7809):904–7.
   PubMed Web of Science ®Google Scholar
• Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med. 1973;288(14):704–6.
   PubMed Web of Science ®Google Scholar
• MacLean I, Iqball S, Woo P, Keat A, Hughes R, Kingsley JG, et al. HLA-B27 subtypes in the spondarthropathies Clin Exp Immunol. 1993;91(2):214–19.
   PubMed Web of Science ®Google Scholar
• Nicknam MH, Mahmoudi M, Amirzargar AA, Hakemi MG, Khosravi F, Jamshidi AR, et al. Determination of HLA-B27 subtypes in Iranian patients with ankylosing spondylitis. Iran J Allergy Asthma Immunol. 2008;7(1):19–24.
   PubMed Web of Science ®Google Scholar
• Reveille J, Inman R, Khan M, Yu D, Jin L. Family studies in ankylosing spondylitis: microsatellite analysis of 55 concordant sib pairs. J Rheumatol. 2000; 27(Suppl 59):5.
   Google Scholar
• Lopez-Larrea C, Sujirachato K, Mehra N, Chiewsilp P, Isarangkura D, Kanga U, et al. HLA‐B27 subtypes in Asian patients with ankylosing spondylitis Evidence for new associations. Tissue Antigens. 1995;45(3):169–76.
   PubMedGoogle Scholar
• Gonzalez-Roces S, Alvarez M, Gonzalez S, Dieye A, Makni H, Woodfield D, et al. HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis. Tissue Antigens. 1997;49(2):116–23.
   PubMedGoogle Scholar
• Armas JB, Gonzalez S, Martinez-Borra J, Laranjeira F, Ribeiro E, Correia J, et al. Susceptibility to ankylosing spondylitis is independent of the Bw4 and Bw6 epitopes of HLA-B27 alleles. Tissue Antigens. 1999;53(3):237–43.
   PubMedGoogle Scholar
• García R, Rognan D, Lamas J, Marina A, Castro J. An HLA-B27 polymorphism (B*2710) that is critical for T-cell recognition has limited effects on peptide specificity. Tissue Antigens. 1998;51(1):1–9.
   PubMedGoogle Scholar
• García-Fernández S, Gonzalez S, Mina Blanco A, Martinez-Borra J, Blanco-Gelaz M, López-Vazquez A, et al. New insights regarding HLA‐B27 diversity in the Asian population. Tissue Antigens. 2001;58(4):259–62.
   PubMedGoogle Scholar
• Djouadi K, Nedelec B, Tamouza R, Genin E, Ramasawmy R, Charron D, et al. Interleukin 1 gene cluster polymorphisms in multiplex families with spondylarthropathies. Cytokine. 2001;13(2):98–103.
   PubMed Web of Science ®Google Scholar
• Cortes A, Brown MA. Promise and pitfalls of the Immunochip. Arthritis Res Ther. 2011;13(1):101.
   PubMed Web of Science ®Google Scholar
• Robinson WP, Van Der Linden SM, Khan MA, Rentsch HU, Cats A, Russell A, et al. HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients. Arthritis Rheum. 1989;32(9):1135–41.
   PubMed Web of Science ®Google Scholar
• Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J, et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheumc Dis. 1996;55(4):268–70.
   PubMed Web of Science ®Google Scholar
• Wei J, Tsai W, Lin H, Tsai C, Chou C. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients. Rheumatology. 2004;43(7):839–42.
   PubMed Web of Science ®Google Scholar
• Caffrey MF, James D. Human lymphocyte antigen association in ankylosing spondylitis. Nature. 1973;242:121. doi: 10.1038/242121a0.
   Google Scholar
• Consortium IGoAS. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nature Genetics. 2013;45(7):730–8.
   PubMed Web of Science ®Google Scholar
• Lin Z, Bei J-X, Shen M, Li Q, Liao Z, Zhang Y, et al. A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nature Genetics. 2012;44(1):73–7.
   Web of Science ®Google Scholar
• Yamaguchi A, Tsuchiya N, Mitsui H, Shiota M, Ogawa A, Tokunaga K, et al. Association of HLA-B39 with HLA-B27-negative ankylosing spondylitis and pauciarticular juvenile rheumatoid arthritis in Japanese patients. Evidence for a role of the peptide-anchoring B pocket. Arthritis Rheum. 1995;38(11):1672–7.
   PubMed Web of Science ®Google Scholar
• Cortes A, Pulit SL, Leo PJ, Pointon JJ, Robinson PC, Weisman MH, et al. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nature Commun. 2015;6. doi: 10.1038/ncomms8146.
   Web of Science ®Google Scholar
• Calin A, Marder A, Becks E, Burns T. Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls. Arthritis Rheum. 1983;26(12):1460–4.
   PubMed Web of Science ®Google Scholar
• van der Linden S, Valkenburg H, Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study. Rheumatology. 1983;22(suppl 2):18–19.
   Google Scholar
• Pedersen O, Svendsen AJ, Ejstrup L, Skytthe A, Harris J, Junker P. Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation. Scand J Rheumatol. 2008;37(2):120–6.
   PubMed Web of Science ®Google Scholar
• Pickart CM. Mechanisms underlying ubiquitination. Annual Rev Biochem. 2001;70(1):503–33.
   PubMed Web of Science ®Google Scholar
• Wang S, Adrianto I, Wiley GB, Lessard CJ, Kelly JA, Adler AJ, et al. A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes Immunity. 2012;13(5):380–7.
   PubMed Web of Science ®Google Scholar
• Genetic Analysis of Psoriasis Consortium and the Wellcome Trust Case Control Consortium 2. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nature Genetics. 2010;42(11):985–90.
   PubMed Web of Science ®Google Scholar
• Chapman JA, Kirkness EF, Simakov O, Hampson SE, Mitros T, Weinmaier T, et al. The dynamic genome of Hydra. Nature. 2010;464(7288):592–6.
   PubMed Web of Science ®Google Scholar
• Dendrou CA, Fung E, Esposito L, Todd JA, Wicker LS, Plagnol V. Fluorescence intensity normalisation: correcting for time effects in large-scale flow cytometric analysis. Adv Bioinformatics. 2009;2009. doi: 10.1155/2009/476106.
   PubMedGoogle Scholar
• Mehta AM, Jordanova ES, van Wezel T, Uh HW, Corver WE, Kwappenberg K, et al. Genetic variation of antigen processing machinery components and association with cervical carcinoma. Genes Chromosomes Cancer. 2007;46(6):577–86.
   PubMed Web of Science ®Google Scholar
• Chang S-C, Momburg F, Bhutani N, Goldberg AL. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc Natl Acad Sci USA. 2005;102(47):17107–12.
   PubMed Web of Science ®Google Scholar
• York IA, Chang S-C, Saric T, Keys JA, Favreau JM, Goldberg AL, et al. The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues. Nature Immunol. 2002;3(12):1177–84.
   PubMed Web of Science ®Google Scholar
• Choi C-B, Kim T-H, Jun J-B, Lee H-S, Shim SC, Lee B, et al. ARTS1 polymorphisms are associated with ankylosing pondylitis in Koreans. Ann Rheum Dis. 2010;69(3):582–4.
   PubMed Web of Science ®Google Scholar
• Davidson SI, Wu X, Liu Y, Wei M, Danoy PA, Thomas G, et al. Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum. 2009;60(11):3263–8.
   PubMed Web of Science ®Google Scholar
• Harvey D, Pointon JJ, Karaderi T, Appleton LH, Farrar C, Wordsworth BP. A common functional variant of endoplasmic reticulum aminopeptidase 2 (ERAP2) that reduces major histocompatibility complex class I expression is not associated with ankylosing spondylitis. Rheumatology. 2011;50(9):1720–1.
   PubMed Web of Science ®Google Scholar
• Li C, Lin Z, Xie Y, Guo Z, Huang J, Wei Q, et al. ERAP1 is associated with ankylosing spondylitis in Han Chinese. J Rheumatol. 2011;38(2):317–21.
   PubMed Web of Science ®Google Scholar
• Maksymowych W, Inman R, Gladman D, Reeve J, Pope A, Rahman P. Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitis. Arthritis Rheum. 2009;60(5):1317–23.
   PubMed Web of Science ®Google Scholar
• Pimentel-Santos F, Ligeiro D, Matos M, Mourao A, Sousa E, Pinto P, et al. Association of IL23R and ERAP1 genes with ankylosing spondylitis in a Portuguese population. Clin Exp Rheumatol. 2009;27:800–6.
   Google Scholar
• Mahmoudi M, Jamshidi AR, Amirzargar AA, Farhadi E, Nourijelyani K, Fallahi S, et al. Association between endoplasmic reticulum aminopeptidase-1 (ERAP-1) and susceptibility to ankylosing spondylitis in Iran. Iran J Allergy Asthma Immunol. 2012;11(4):294.
   PubMed Web of Science ®Google Scholar
• Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature Genetics. 2011;43(8):761–7.
   PubMed Web of Science ®Google Scholar
• Evnouchidou I, Momburg F, Papakyriakou A, Chroni A, Leondiadis L, Chang S-C, et al. The internal sequence of the peptide-substrate determines its N-terminus trimming by ERAP1. PLoS One. 2008;3(11):e3658.
   PubMed Web of Science ®Google Scholar
• Kochan G, Krojer T, Harvey D, Fischer R, Chen L, Vollmar M, et al. Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming. Proc Natl Acad Sci. 2011;108(19):7745–50.
   PubMed Web of Science ®Google Scholar
• Nguyen TT, Chang S-C, Evnouchidou I, York IA, Zikos C, Rock KL, et al. Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nature Struct Mol Biol. 2011;18(5):604–13.
   PubMed Web of Science ®Google Scholar
• Hammer GE, Gonzalez F, Champsaur M, Cado D, Shastri N. The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules. Nature Immunol. 2006;7(1):103–12.
   PubMed Web of Science ®Google Scholar
• García-Medel N, Sanz-Bravo A, Van Nguyen D, Galocha B, Gómez-Molina P, Martín-Esteban A, et al. Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo. Mol Cell Proteom. 2012;11(11):1416–29.
   PubMed Web of Science ®Google Scholar
• Ombrello MJ, Kastner DL, Remmers EF. Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics. Curr Opin Rheumatol. 2015;27(4):349–56.
   PubMed Web of Science ®Google Scholar
• Kadi A, Izac B, Said-Nahal R, Leboime A, Van Praet L, de Vlam K, et al. Investigating the genetic association between ERAP1 and spondyloarthritis. Ann Rheum Dis. 2013;72(4):608–13.
   PubMed Web of Science ®Google Scholar
• Bettencourt BF, Rocha FL, Alves H, Amorim R, Caetano-Lopes J, Vieira-Sousa E, et al. Protective effect of an ERAP1 haplotype in ankylosing spondylitis: investigating non-MHC genes in HLA-B27-positive individuals. Rheumatology (Oxford). 2013;52(12):2168–76.
   PubMed Web of Science ®Google Scholar
• Tsui FW, Haroon N, Reveille JD, Rahman P, Chiu B, Tsui HW, et al. Association of an ERAP1 ERAP2 haplotype with familial ankylosing spondylitis. Ann Rheum Dis. 2010;69(4):733–6.
   PubMed Web of Science ®Google Scholar
• Birtley JR, Saridakis E, Stratikos E, Mavridis IM. The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing. Biochemistry. 2011;51(1):286–95.
   PubMed Web of Science ®Google Scholar
• Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, et al. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nature Immunol. 2005;6(7):689–97.
   PubMed Web of Science ®Google Scholar
• Hinks A, Cobb J, Marion MC, Prahalad S, Sudman M, Bowes J, et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nature Genetics. 2013;45(6):664–9.
   PubMed Web of Science ®Google Scholar
• Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nature Genetics. 2012;44(12):1341–8.
   PubMed Web of Science ®Google Scholar
• Andrés AM, Dennis MY, Kretzschmar WW, Cannons JL, Lee-Lin S-Q, Hurle B, et al. Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. PLoS Genet. 2010;6(10):e1001157.
   PubMed Web of Science ®Google Scholar
• Evnouchidou I, Birtley J, Seregin S, Papakyriakou A, Zervoudi E, Samiotaki M, et al. A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing. J Immunol. 2012;189(5):2383–92.
   PubMed Web of Science ®Google Scholar
• Saveanu L, Carroll O, Weimershaus M, Guermonprez P, Firat E, Lindo V, et al. IRAP identifies an endosomal compartment required for MHC class I cross-presentation. Science. 2009;325(5937):213–17.
   PubMed Web of Science ®Google Scholar
• Menzies FM, Hourez R, Imarisio S, Raspe M, Sadiq O, Chandraratna D, et al. Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. Hum Mol Genetics. 2010;19:4573–86.
   PubMed Web of Science ®Google Scholar
• Kudo LC, Parfenova L, Ren G, Vi N, Hui M, Ma Z, et al. Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAUP301L double-transgenic mice. Hum Mol Genetics. 2011;20:1820–33.
   PubMed Web of Science ®Google Scholar
• Ciccia F, Accardo-Palumbo A, Rizzo A, Guggino G, Raimondo S, Giardina A, 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. Anne Rheum Dis. 2014;73(8):1566–74.
   PubMed Web of Science ®Google Scholar
• Danoy P, Pryce K, Hadler J, Bradbury LA, Farrar C, Pointon J, et al. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease. PLoS Genet. 2010;6(12):e1001195.
   PubMed Web of Science ®Google Scholar
• Di Meglio P, Di Cesare A, Laggner U, Chu C-C, Napolitano L, Villanova F, et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PloS One. 2011;6(2):e17160.
   PubMed Web of Science ®Google Scholar
• Sarin R, Wu X, Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc Natl Acad Sci. 2011;108(23):9560–5.
   PubMed Web of Science ®Google Scholar
• Davidson S, Jiang L, Cortes A, Wu X, Glazov E, Donskoi M, et al. Brief report: high-throughput sequencing of IL23R reveals a low-frequency, nonsynonymous single-nucleotide polymorphism that is associated with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum. 2013;65(7):1747–52.
   PubMed Web of Science ®Google Scholar
• Daryabor G, Mahmoudi M, Jamshidi A, Nourijelyani K, Amirzargar A, Ahmadzadeh N, et al. Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Network. 2014;25(1):24–9.
   PubMed Web of Science ®Google Scholar
• Adamopoulos IE, Tessmer M, Chao C-C, Adda S, Gorman D, Petro M, et al. IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. J. Immunol. 2011;187(2):951–9.
   PubMed Web of Science ®Google Scholar
• Ciccia F, Bombardieri M, Principato A, Giardina A, Tripodo C, Porcasi R, et al. Overexpression of interleukin‐23, but not interleukin‐17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2009;60(4):955–65.
   PubMed Web of Science ®Google Scholar
• Sherlock JP, Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt + CD3 + CD4-CD8- entheseal resident T cells. Nature Med. 2012;18(7):1069–76.
   PubMed Web of Science ®Google Scholar
• Boldizsar F, Tarjanyi O, Nemeth P, Mikecz K, Glant TT. Th1/Th17 polarization and acquisition of an arthritogenic phenotype in arthritis-susceptible BALB/c, but not in MHC-matched, arthritis-resistant DBA/2 mice. Int Immunol. 2009;21(5):511–22.
   PubMed Web of Science ®Google Scholar
• DeLay ML, Turner MJ, Klenk EI, Smith JA, Sowders DP, Colbert RA.. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum. 2009;60(9):2633–43.
   PubMed Web of Science ®Google Scholar
• Kontoyiannis D, Boulougouris G, Manoloukos M, Armaka M, Apostolaki M, Pizarro T, et al. Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease. J Exp Med. 2002;196(12):1563–74.
   PubMed Web of Science ®Google Scholar
• Ruutu M, Yadav B, Thomas G, Steck R, Strutton G, Tran A, et al. Fungal beta-glucan triggers spondyloarthropathy and Crohn’s disease in SKG mice. Arthritis Rheum. 2010;62(Suppl 10):1446.
   Google Scholar
• D'Elios MM, Del Prete G, Amedei A. Targeting IL-23 in human diseases. Expert Opin Therap Targets. 2010;14(7):759–74.
   PubMed Web of Science ®Google Scholar
• Lubberts E. The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol. 2015;11(7):415–29.
   PubMed Web of Science ®Google Scholar
• Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med. 2006;203(11):2485–94.
   PubMed Web of Science ®Google Scholar
• Kopp T, Lenz P, Bello-Fernandez C, Kastelein RA, Kupper TS, Stingl G. IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity. J Immunol. 2003;170(11):5438–44.
   PubMed Web of Science ®Google Scholar
• Crawford MP, Yan SX, Ortega SB, Mehta RS, Hewitt RE, Price DA, et al. High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay. Blood. 2004;103(11):4222–31.
   PubMed Web of Science ®Google Scholar
• Sanchez E, Rueda B, Callejas J, Sabio J, Ortego-Centeno N, Jimenez-Alonso J, et al. Analysis of interleukin‐23 receptor (IL23R) gene polymorphisms in systemic lupus erythematosus. Tissue Antigens. 2007;70(3):233–7.
   PubMedGoogle Scholar
• Zhu K-J, Zhu C-Y, Shi G, Fan Y-M. Meta-analysis of IL12B polymorphisms (rs3212227, rs6887695) with psoriasis and psoriatic arthritis. Rheumatol Int. 2013;33(7):1785–90.
   PubMed Web of Science ®Google Scholar
• Coffre M, Roumier M, Rybczynska M, Sechet E, Law HK, Gossec L, et al. Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin‐23 signaling pathway in spondyloarthritis. Arthritis Rheum. 2013;65(6):1510–21.
   PubMed Web of Science ®Google Scholar
• Sims A-M, Timms AE, Bruges-Armas J, Burgos-Vargas R, Chou C-T, Doan T, et al. Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis. Ann Rheum Dis. 2008;67(9):1305–9.
   PubMed Web of Science ®Google Scholar
• Van der Paardt M, Crusius J, García-González M, Baudoin P, Kostense P, Alizadeh B, et al. Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis. Rheumatology (Oxford). 2002;41(12):1419–23.
   PubMed Web of Science ®Google Scholar
• Consortium A-A-AS. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nature Genetics. 2010;42(2):123–7.
   PubMed Web of Science ®Google Scholar
• Haibel H, Rudwaleit M, Listing J, Sieper J. Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis. 2005;64(2):296–8.
   PubMed Web of Science ®Google Scholar
• Tan AL, Marzo-Ortega H, O’Connor P, Fraser A, Emery P, McGonagle D. Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann Rheum Dis. 2004;63(9):1041–5.
   PubMed Web of Science ®Google Scholar
• Mahmoudi M, Amirzargar A, Jamshidi A, Farhadi E, Noori S, Avraee M, et al. Association of IL1R polymorphism with HLA-B27 positive in Iranian patients with ankylosing spondylitis. Eur Cytokine Network. 2011;22(4):175–80.
   PubMed Web of Science ®Google Scholar
• Momenzadeh P, Mahmoudi M, Beigy M, Garshasbi M, Vodjdanian M, Farazmand A, et al. Determination of IL1 R2, ANTXR2, CARD9, and SNAPC4 single nucleotide polymorphisms in Iranian patients with ankylosing spondylitis. Rheumatol Int. 2016;36:429–35.
   PubMed Web of Science ®Google Scholar
• Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, et al. Meta-analysis of genome-wide association studies in 80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation. 2011;123(7):731–8.
   PubMed Web of Science ®Google Scholar
• Wilk JB, Walter RE, Laramie JM, Gottlieb DJ, T O'Connor G. Framingham Heart Study genome-wide association: results for pulmonary function measures. BMC Med Genetics. 2007;8(Suppl 1):S8.
   PubMedGoogle Scholar
• Nicknam MH, Mahmoudi M, Amirzargar AA, Jamshidi AR, Rezaei N, Nikbin B. HLA-B27 subtypes and tumor necrosis factor α promoter region polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Network. 2009;20(1):17–20.
   PubMed Web of Science ®Google Scholar
• Park J-H, Adoro S, Guinter T, Erman B, Alag AS, Catalfamo M, et al. Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nature Immunol. 2010;11(3):257–64.
   PubMed Web of Science ®Google Scholar
• Brenner O, Levanon D, Negreanu V, Golubkov O, Fainaru O, Woolf E, et al. Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proc Natl Acad Sci USA. 2004;101(45):16016–21.
   PubMed Web of Science ®Google Scholar
• Cruz-Guilloty F, Pipkin ME, Djuretic IM, Levanon D, Lotem J, Lichtenheld MG, et al. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med. 2009;206(1):51–9.
   PubMed Web of Science ®Google Scholar
• Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003;302(5647):1041–3.
   PubMed Web of Science ®Google Scholar
• Yagi R, Junttila IS, Wei G, Urban JF, Zhao K, Paul WE, et al. The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma. Immunity. 2010;32(4):507–17.
   PubMed Web of Science ®Google Scholar
• Intlekofer AM, Banerjee A, Takemoto N, Gordon SM, DeJong CS, Shin H, et al. Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science. 2008;321(5887):408–11.
   PubMed Web of Science ®Google Scholar
• Candeias S, Peschon J, Muegge K, Durum S. Defective T-cell receptor γ gene rearrangement in interleukin-7 receptor knockout mice. Immunol Lett. 1997;57(1):9–14.
   PubMed Web of Science ®Google Scholar
• Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genetics. 2010;42(12):1118–25.
   PubMed Web of Science ®Google Scholar
• Rakowski LA, Garagiola DD, Li CM, Decker M, Caruso S, Jones M, et al. Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias. Cancer Res. 2013;73(2):930–41.
   PubMed Web of Science ®Google Scholar
• Klose CS, Kiss EA, Schwierzeck V, Ebert K, Hoyler T, d’Hargues Y, et al. A T-bet gradient controls the fate and function of CCR6-RORγt + innate lymphoid cells. Nature. 2013;494(7436):261–5.
   PubMed Web of Science ®Google Scholar
• Sciumé G, Hirahara K, Takahashi H, Laurence A, Villarino AV, Singleton KL, et al. Distinct requirements for T-bet in gut innate lymphoid cells. J Exp Med. 2012;209(13):2331–8.
   PubMed Web of Science ®Google Scholar
• Kenna TJ, Brown MA. The role of IL-17-secreting mast cells in inflammatory joint disease. Nature Reviews Rheumatology 2013;9(6):375–9.
   PubMed Web of Science ®Google Scholar
• Ciccia F, Accardo-Palumbo A, Alessandro R, Rizzo A, Principe S, Peralta S, et al. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 2012;64(6):1869–78.
   PubMed Web of Science ®Google Scholar
• Baerlecken N, Nothdorft S, Stummvoll G, Sieper J, Rudwaleit M, Reuter S, et al. Autoantibodies against CD74 in spondyloarthritis. Ann Rheum Dis. 2014;73(6):1211–14.
   PubMed Web of Science ®Google Scholar
• 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. 2014;73(6):1079–82.
   PubMed Web of Science ®Google Scholar
• Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E, et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature. 2004;429(6991):566–71.
   PubMed Web of Science ®Google Scholar
• Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19(7):813–24.
   PubMed Web of Science ®Google Scholar
• Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity. Curr Opin Immunol. 2007;19(3):309–14.
   PubMed Web of Science ®Google Scholar
• Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8(3):239–45.
   PubMed Web of Science ®Google Scholar
• Lee S, Lee Y, Woo D, Song R, Park E, Ryu M, et al. Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population. Arthritis Res Ther. 2006;8(6):R163.
   PubMedGoogle Scholar
• Soleimanifar N, Amirzargar AA, Mahmoudi M, Pourfathollah AA, Azizi E, Jamshidi AR, et al. Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis. Inflammation. 2011;34(6):707–12.
   PubMed Web of Science ®Google Scholar
• Harper K, Balzano C, Rouvier E, Mattûi M-G, Luciani M, Golstein P. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol. 1991;147(3):1037–44.
   PubMed Web of Science ®Google Scholar
• Vaidya B, Imrie H, Perros P, Young ET, Kelly WF, Carr D, et al. The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus. Hum Mol Genetics. 1999;8(7):1195–9.
   PubMed Web of Science ®Google Scholar
• Azizi E, Massoud A, Amirzargar AA, Mahmoudi M, Soleimanifar N, Rezaei N, et al. Association of CTLA4 gene polymorphism in Iranian patients with ankylosing spondylitis. J Clin Immunol. 2010;30(2):268–71.
   PubMed Web of Science ®Google Scholar
• Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G-protein-coupled receptors. Nature. 2009;459(7245):356–63.
   PubMed Web of Science ®Google Scholar
• Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem. 2006;281(31):22021–8.
   PubMed Web of Science ®Google Scholar
• Ren G, Su J, Zhang L, Zhao X, Ling W, L'Huillie A, et al. Species variation in the mechanisms of mesenchymal Stem cell-mediated immunosuppression. Stem Cells. 2009;27(8):1954–62.
   PubMed Web of Science ®Google Scholar
• Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nature Immunol. 2011;12(9):870–8.
   PubMed Web of Science ®Google Scholar
• Marazziti D, Di Pietro C, Golini E, Mandillo S, Matteoni R, Tocchini-Valentini GP. Induction of macroautophagy by overexpression of the Parkinson's disease-associated GPR37 receptor. FASEB J. 2009;23(6):1978–87.
   PubMed Web of Science ®Google Scholar
• Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307–17.
   PubMed Web of Science ®Google Scholar
• Tosa N, Murakami M, Jia WY, Yokoyama M, Masunaga T, Iwabuchi C, et al. Critical function of T cell death‐associated gene 8 in glucocorticoid‐induced thymocyte apoptosis. Int Immunol. 2003;15(6):741–9.
   PubMed Web of Science ®Google Scholar
• Mahmoudi M, Nicknam MH, Ahmadzadeh N, Jamshidi AR. rs6759298 polymorphism and its interaction with Human Leukocyte Antigene-B27 in Iranian Patients with Ankylosing Spondylitis. Unpublished Data, 2016.
   Google Scholar
• McGonagle D, Aydin SZ, Gul A, Mahr A, Direskeneli H. 'MHC-I-opathy'-unified concept for spondyloarthritis and Behçet disease. Nat Rev Rheumatol. 2015;11(12):731–40.
   PubMed Web of Science ®Google Scholar
• Hayday AC. γδ Gammadelta T cells and the lymphoid stress-surveillance response. Immunity. 2009;31(2):184–96.
   PubMed Web of Science ®Google Scholar
• Tran TM, Colbert RA. Endoplasmic reticulum aminopeptidase 1 and rheumatic disease: functional variation. Curr Opin Rheumatol. 2015;27(4):357–63.
   PubMed Web of Science ®Google Scholar
• Robinson PC, Costello M-E, Leo P, Bradbury LA, Hollis K, Cortes A, et al. ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients. Ann Rheum Dis. 2015;74:1627–9.
   PubMed Web of Science ®Google Scholar
• Guasp P, Alvarez-Navarro C, Gomez-Molina P, Martín-Esteban A, Marcilla M, Barnea E, et al. The peptidome of the Behçet's disease‐associated HLA‐B* 51: 01 includes two sub‐peptidomes differentially shaped by ERAP1. Arthritis Rheumatol. 2016;68:505–15.
   PubMed Web of Science ®Google Scholar
• Costantino F, Talpin A, Evnouchidou I, Kadi A, Leboime A, Said-Nahal R, et al. ERAP1 gene expression is influenced by nonsynonymous polymorphisms associated with predisposition to spondyloarthritis. Arthritis Rheumatol. 2015;67(6):1525–34.
   PubMed Web of Science ®Google Scholar
• Chen L, Fischer R, Peng Y, Reeves E, McHugh K, Ternette N, et al. Critical role of endoplasmic reticulum aminopeptidase 1 in determining the length and sequence of peptides bound and presented by HLA–B27. Arthritis Rheumatol. 2014;66(2):284–94.
   PubMed Web of Science ®Google Scholar
• Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease. Nature Genetics. 2010;42(8):698–702.
   PubMed Web of Science ®Google Scholar
• Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nature Genetics. 2010;42(8):703–6.
   PubMed Web of Science ®Google Scholar
• Chi W, Zhu X, Yang P, Liu X, Lin X, Zhou H, et al. Upregulated IL-23 and IL-17 in Behçet patients with active uveitis. Invest Ophthalmol Vis Sci. 2008;49(7):3058–64.
   PubMed Web of Science ®Google Scholar
• Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, et al. Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nature Genetics. 2013;45(2):202–7.
   PubMed Web of Science ®Google Scholar
• Selmi C, Lu Q, Humble MC. Heritability versus the role of the environment in autoimmunity. J Autoimmun. 2012;39(4):249–52.
   PubMed Web of Science ®Google Scholar
• Aslani S, Mahmoudi M, Karami J, Jamshidi AR, Malekshahi Z, Nicknam MH. Epigenetic alterations underlying autoimmune diseases. Autoimmunity. 2016;49:69–83.
   PubMed Web of Science ®Google Scholar
• Germolec D, Kono DH, Pfau JC, Pollard KM. Animal models used to examine the role of the environment in the development of autoimmune disease: findings from an NIEHS Expert Panel Workshop. J Autoimmun. 2012;39(4):285–93.
   PubMed Web of Science ®Google Scholar
• Miller FW, Pollard KM, Parks CG, Germolec DR, Leung PS, Selmi C, et al. Criteria for environmentally associated autoimmune diseases. J Autoimmun. 2012;39(4):253–8.
   PubMed Web of Science ®Google Scholar
• Ngalamika O, Zhang Y, Yin H, Zhao M, Gershwin ME, Lu Q. Epigenetics, autoimmunity and hematologic malignancies: a comprehensive review. J Autoimmun. 2012;39(4):451–65.
   PubMed Web of Science ®Google Scholar
• Selmi C, Leung PS, Sherr DH, Diaz M, Nyland JF, Monestier M, et al. Mechanisms of environmental influence on human autoimmunity: a national institute of environmental health sciences expert panel workshop. J Autoimmun. 2012;39(4):272–84.
   PubMed Web of Science ®Google Scholar
• Waddington CH. Canalization of development and the inheritance of acquired characters. Nature. 1942;150(3811):563–5.
   Google Scholar
• McCarrey JR. Epigenetic mechanisms regulating gene expression. In: Krawetz SA, Womble DD editors. Introduction to bioinformatics. Springer; 2003:123–39.
   Google Scholar
• Quintero-Ronderos P, Montoya-Ortiz G. Epigenetics and autoimmune diseases. Autoimmune Dis. 2012;2012. doi: 10.1155/2012/593720.
   PubMedGoogle Scholar
• Huang K, Fan G. DNA methylation in cell differentiation and reprogramming: an emerging systematic view. Regenerative Med. 2010;5(4):531–44.
   PubMed Web of Science ®Google Scholar
• Fan S, Zhang X. CpG island methylation pattern in different human tissues and its correlation with gene expression. Biochem Biophys Res Commun. 2009;383(4):421–5.
   PubMed Web of Science ®Google Scholar
• Yun M, Wu J, Workman JL, Li B.. Readers of histone modifications. Cell Res. 2011;21(4):564–78.
   PubMed Web of Science ®Google Scholar
• Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–95.
   PubMed Web of Science ®Google Scholar
• De Ruijter A, Van Gennip A, Caron H, Kemp S, van Kuilenburg A. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370:737–49.
   PubMed Web of Science ®Google Scholar
• Scaria V, Hariharan M, Maiti S, Pillai B, Brahmachari SK. Host-virus interaction: a new role for microRNAs. Retrovirology. 2006;3(1):68
   PubMed Web of Science ®Google Scholar
• Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.
   PubMed Web of Science ®Google Scholar
• Lai N-S, Chou J-L, Chen GC, Liu S-Q, Lu M-C, Chan MW. Association between cytokines and methylation of SOCS-1 in serum of patients with ankylosing spondylitis. Mol Biol Rep. 2014;41(6):3773–80.
   PubMed Web of Science ®Google Scholar
• Aslani S, Mahmoudi M, Karami J, Jamshidi A, Nicknam MH. Evaluation of DNMT1 gene expression profile and methylation of its promoter region in patients with ankylosing spondylitis. Unpublished Data, 2016.
   Google Scholar
• Karami J, Mahmoudi M, Aslani S, Jamshidi AR, Nicknam MH. Expression and methylation of BCL11B in PBMCs from patients with ankylosing spondylitis. Unpublished Data, 2016.
   Google Scholar
• Liu C-C, Fang T-J, Ou T-T, Wu C-C, Li R-N, Lin Y-C, et al. Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol Lett. 2011;135(1-2):96–9.
   PubMed Web of Science ®Google Scholar
• Jiang Y, Wang L. Role of histone deacetylase 3 in ankylosing spondylitis via negative feedback loop with microRNA-130a and enhancement of tumor necrosis factor-1α expression in peripheral blood mononuclear cells. Mol Med Rep. 2016;13(1):35–40.
   PubMed Web of Science ®Google Scholar
• Lai NS, Yu HC, Chen HC, Yu CL, Huang HB, Lu MC. Aberrant expression of microRNAs in T cells from patients with ankylosing spondylitis contributes to the immunopathogenesis. Clin Exp Immunol. 2013;173(1):47–57.
   PubMed Web of Science ®Google Scholar
• Daoussis D, Andonopoulos AP. The emerging role of Dickkopf-1 in bone biology: is it the main switch controlling bone and joint remodeling? Sem Arthritis Rheumatism. 2011;41:170–7.
   Google Scholar
• Huang J, Song G, Yin Z, Luo X, Ye Z. Elevated miR-29a expression is not correlated with disease activity index in PBMCs of patients with ankylosing spondylitis. Modern Rheumatol. 2014;24(2):331–4.
   PubMed Web of Science ®Google Scholar
• Sugatani T, Vacher J, Hruska KA. A microRNA expression signature of osteoclastogenesis. Blood. 2011;117(13):3648–57.
   PubMed Web of Science ®Google Scholar
• Huang C-H, Wei JC-C, Chang W-C, Chiou S-Y, Chou C-H, Lin Y-J, et al. Higher expression of whole blood microRNA-21 in patients with ankylosing spondylitis associated with programmed cell death 4 mRNA expression and collagen cross-linked C-telopeptide concentration. J. Rheumatol. 2014;41(6):1104–11.
   PubMed Web of Science ®Google Scholar
• Stanczyk J, Pedrioli DML, Brentano F, Sanchez-Pernaute O, Kolling C, Gay RE, et al. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 2008;58(4):1001–9.
   PubMed Web of Science ®Google Scholar
• Dai Y, Huang Y-S, Tang M, Lv T-Y, Hu C-X, Tan Y-H, et al. Microarray analysis of microRNA expression in peripheral blood cells of systemic lupus erythematosus patients. Lupus. 2007;16(12):939–46.
   PubMed Web of Science ®Google Scholar
• Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression Proc Natl Acad Sci. USA. 2008;105(17):6415–20.
   PubMed Web of Science ®Google Scholar
• Robinson PC, Brown MA. Genetics of ankylosing spondylitis. Mol Immunol. 2014;57(1):2–11.
   PubMed Web of Science ®Google Scholar