Immunologic Research

, Volume 60, Issue 2–3, pp 257–269 | Cite as

ERAP1 in the pathogenesis of ankylosing spondylitis

  • Emma Reeves
  • Tim Elliott
  • Edward James
  • Christopher J. Edwards
PATHOGENESIS AND THERAPY IN AUTOIMMUNE DISEASES

Abstract

The endoplasmic reticulum aminopeptidase 1 (ERAP1) performs a major role in antigen processing, trimming N-terminally extended peptides to the final epitope for presentation by major histocompatibility complex class I molecules. Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) within ERAP1 as being associated with disease, in particular ankylosing spondylitis (AS). AS is a polygenic chronic inflammatory disease with a strong genetic link to HLA-B27 known for over 40 years. The association of ERAP1 SNPs with AS susceptibility is only observed in HLA-B27-positive individuals, which intersect on the antigen processing pathway. Recent evidence examining the trimming activity of polymorphic ERAP1 highlights its role in generating peptides for loading onto and stabilizing HLA-B27, and the consequent alterations in the interaction of specific NK cell receptors, and the activation of the unfolded protein response as important in the mechanism of disease pathogenesis. Here, we discuss the recent genetic association findings linking ERAP1 SNPs with AS disease susceptibility and the effect of these variants on ERAP1 function, highlighting mechanisms by which AS may arise. The identification of these functional variants of ERAP1 may lead to better stratification of AS patients by providing a diagnostic tool and a potential therapeutic target.

Keywords

ERAP1 Antigen processing and presentation Major histocompatibility complex HLA-B27 Ankylosing spondylitis Autoimmunity 

References

  1. 1.
    Abe M, Sato Y. Puromycin insensitive leucyl-specific aminopeptidase (PILSAP) is required for the development of vascular as well as hematopoietic system in embryoid bodies. Genes Cells. 2006;11(7):719–29. doi:10.1111/j.1365-2443.2006.00978.x.CrossRefPubMedGoogle Scholar
  2. 2.
    Akada T, Yamazaki T, Miyashita H, Niizeki O, Abe M, Sato A, et al. Puromycin insensitive leucyl-specific aminopeptidase (PILSAP) is involved in the activation of endothelial integrins. J Cell Physiol. 2002;193(2):253–62. doi:10.1002/jcp.10169.CrossRefPubMedGoogle Scholar
  3. 3.
    Cui X, Hawari F, Alsaaty S, Lawrence M, Combs CA, Geng W, et al. Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J Clin Invest. 2002;110(4):515–26. doi:10.1172/JCI13847.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Saric T, Chang SC, Hattori A, York IA, Markant S, Rock KL, et al. An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat Immunol. 2002;3(12):1169–76. doi:10.1038/ni859.CrossRefPubMedGoogle Scholar
  5. 5.
    Suzuki T, Abe M, Miyashita H, Kobayashi T, Sato Y. Puromycin insensitive leucyl-specific aminopeptidase (PILSAP) affects RhoA activation in endothelial cells. J Cell Physiol. 2007;211(3):708–15. doi:10.1002/jcp.20980.CrossRefPubMedGoogle Scholar
  6. 6.
    Hattori A, Matsumoto H, Mizutani S, Tsujimoto M. Molecular cloning of adipocyte-derived leucine aminopeptidase highly related to placental leucine aminopeptidase/oxytocinase. J Biochem. 1999;125(5):931–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Serwold T, Gonzalez F, Kim J, Jacob R, Shastri N. ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature. 2002;419(6906):480–3. doi:10.1038/nature01074.CrossRefPubMedGoogle Scholar
  8. 8.
    Hattori A, Matsumoto K, Mizutani S, Tsujimoto M. Genomic organization of the human adipocyte-derived leucine aminopeptidase gene and its relationship to the placental leucine aminopeptidase/oxytocinase gene. J Biochem. 2001;130(2):235–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Tanioka T, Hattori A, Masuda S, Nomura Y, Nakayama H, Mizutani S, et al. Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases. J Biol Chem. 2003;278(34):32275–83. doi:10.1074/jbc.M305076200.CrossRefPubMedGoogle Scholar
  10. 10.
    Hattori A, Goto Y, Tsujimoto M. Exon 10 coding sequence is important for endoplasmic reticulum retention of endoplasmic reticulum aminopeptidase 1. Biol Pharm Bull. 2012;35(4):601–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Miyashita H, Yamazaki T, Akada T, Niizeki O, Ogawa M, Nishikawa S, et al. A mouse orthologue of puromycin-insensitive leucyl-specific aminopeptidase is expressed in endothelial cells and plays an important role in angiogenesis. Blood. 2002;99(9):3241–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Schumacher TN, Kantesaria DV, Heemels MT, Ashton-Rickardt PG, Shepherd JC, Fruh K, et al. Peptide length and sequence specificity of the mouse TAP1/TAP2 translocator. J Exp Med. 1994;179(2):533–40.CrossRefPubMedGoogle Scholar
  13. 13.
    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. Nat Immunol. 2006;7(1):103–12. doi:10.1038/ni1286.CrossRefPubMedGoogle Scholar
  14. 14.
    York IA, Chang SC, 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. Nat Immunol. 2002;3(12):1177–84. doi:10.1038/ni860.CrossRefPubMedGoogle Scholar
  15. 15.
    Van Hateren A, James E, Bailey A, Phillips A, Dalchau N, Elliott T. The cell biology of major histocompatibility complex class I assembly: towards a molecular understanding. Tissue Antigens. 2010;76(4):259–75. doi:10.1111/j.1399-0039.2010.01550.x.CrossRefPubMedGoogle Scholar
  16. 16.
    Hearn A, York IA, Rock KL. The specificity of trimming of MHC class I-presented peptides in the endoplasmic reticulum. J Immunol. 2009;183(9):5526–36. doi:10.4049/jimmunol.0803663.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Reeves E, Edwards CJ, Elliott T, James E. Naturally occurring ERAP1 haplotypes encode functionally distinct alleles with fine substrate specificity. J Immunol. 2013;191(1):35–43. doi:10.4049/jimmunol.1300598.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Serwold T, Gaw S, Shastri N. ER aminopeptidases generate a unique pool of peptides for MHC class I molecules. Nat Immunol. 2001;2(7):644–51. doi:10.1038/89800.CrossRefPubMedGoogle Scholar
  19. 19.
    Neisig A, Roelse J, Sijts AJ, Ossendorp F, Feltkamp MC, Kast WM, et al. Major differences in transporter associated with antigen presentation (TAP)-dependent translocation of MHC class I-presentable peptides and the effect of flanking sequences. J Immunol. 1995;154(3):1273–9.PubMedGoogle Scholar
  20. 20.
    Firat E, Saveanu L, Aichele P, Staeheli P, Huai J, Gaedicke S, et al. The role of endoplasmic reticulum-associated aminopeptidase 1 in immunity to infection and in cross-presentation. J Immunol. 2007;178(4):2241–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Nagarajan NA, Gonzalez F, Shastri N. Nonclassical MHC class Ib-restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum. Nat Immunol. 2012;13(6):579–86. doi:10.1038/ni.2282.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Yan J, Parekh VV, Mendez-Fernandez Y, Olivares-Villagomez D, Dragovic S, Hill T, et al. In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules. J Exp Med. 2006;203(3):647–59. doi:10.1084/jem.20052271.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Hammer GE, Gonzalez F, James E, Nolla H, Shastri N. In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. Nat Immunol. 2007;8(1):101–8. doi:10.1038/ni1409.CrossRefPubMedGoogle Scholar
  24. 24.
    Blanchard N, Kanaseki T, Escobar H, Delebecque F, Nagarajan NA, Reyes-Vargas E, et al. Endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of MHC class I peptide repertoire in normal and virus-infected cells. J Immunol. 2010;184(6):3033–42. doi:10.4049/jimmunol.0903712.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    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 USA. 2011;108(19):7745–50. doi:10.1073/pnas.1101262108.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Nguyen TT, Chang SC, Evnouchidou I, York IA, Zikos C, Rock KL, et al. Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nat Struct Mol Biol. 2011;18(5):604–13. doi:10.1038/nsmb.2021.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Chang SC, 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. doi:10.1073/pnas.0500721102.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Kanaseki T, Blanchard N, Hammer GE, Gonzalez F, Shastri N. ERAAP synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors in the endoplasmic reticulum. Immunity. 2006;25(5):795–806. doi:10.1016/j.immuni.2006.09.012.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    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. Nat Immunol. 2005;6(7):689–97. doi:10.1038/ni1208.CrossRefPubMedGoogle Scholar
  30. 30.
    Evnouchidou I, Weimershaus M, Saveanu L, van Endert P. ERAP1-ERAP2 dimerization increases peptide-trimming efficiency. J Immunol. 2014;193(2):901–8. doi:10.4049/jimmunol.1302855.CrossRefPubMedGoogle Scholar
  31. 31.
    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. Nat Genet. 2007;39(11):1329–37. doi:10.1038/ng.2007.17.CrossRefPubMedGoogle Scholar
  32. 32.
    Genetic Analysis of Psoriasis C, the Wellcome Trust Case Control C, Strange A, Capon F, Spencer CC, Knight J, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet. 2010;42(11):985–90. doi:10.1038/ng.694.CrossRefGoogle Scholar
  33. 33.
    Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, et al. Genome-wide association analysis identifies new susceptibility loci for Behcet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet. 2013;45(2):202–7. doi:10.1038/ng.2520.CrossRefPubMedGoogle Scholar
  34. 34.
    Mehta AM, Jordanova ES, Corver WE, van Wezel T, Uh HW, Kenter GG, et al. Single nucleotide polymorphisms in antigen processing machinery component ERAP1 significantly associate with clinical outcome in cervical carcinoma. Genes Chromosom Cancer. 2009;48(5):410–8. doi:10.1002/gcc.20648.CrossRefPubMedGoogle Scholar
  35. 35.
    Yewdell JW, Bennink JR. Mechanisms of viral interference with MHC class I antigen processing and presentation. Annu Rev Cell Dev Biol. 1999;15:579–606. doi:10.1146/annurev.cellbio.15.1.579.CrossRefPubMedGoogle Scholar
  36. 36.
    Blanchard N, Gonzalez F, Schaeffer M, Joncker NT, Cheng T, Shastri AJ, et al. Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum. Nat Immunol. 2008;9(8):937–44. doi:10.1038/ni.1629.CrossRefPubMedGoogle Scholar
  37. 37.
    York IA, Brehm MA, Zendzian S, Towne CF, Rock KL. Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance. Proc Natl Acad Sci USA. 2006;103(24):9202–7. doi:10.1073/pnas.0603095103.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Kim S, Lee S, Shin J, Kim Y, Evnouchidou I, Kim D, et al. Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1. Nat Immunol. 2011;12(10):984–91. doi:10.1038/ni.2097.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Mehta AM, Jordanova ES, Kenter GG, Ferrone S, Fleuren GJ. Association of antigen processing machinery and HLA class I defects with clinicopathological outcome in cervical carcinoma. Cancer Immunol Immunother. 2008;57(2):197–206. doi:10.1007/s00262-007-0362-8.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Biondi RM, Kieloch A, Currie RA, Deak M, Alessi DR. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J. 2001;20(16):4380–90. doi:10.1093/emboj/20.16.4380.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Yamazaki T, Akada T, Niizeki O, Suzuki T, Miyashita H, Sato Y. Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) binds and catalyzes PDK1, allowing VEGF-stimulated activation of S6K for endothelial cell proliferation and angiogenesis. Blood. 2004;104(8):2345–52. doi:10.1182/blood-2003-12-4260.CrossRefPubMedGoogle Scholar
  42. 42.
    Yamamoto N, Nakayama J, Yamakawa-Kobayashi K, Hamaguchi H, Miyazaki R, Arinami T. Identification of 33 polymorphisms in the adipocyte-derived leucine aminopeptidase (ALAP) gene and possible association with hypertension. Hum Mutat. 2002;19(3):251–7. doi:10.1002/humu.10047.CrossRefPubMedGoogle Scholar
  43. 43.
    Goto Y, Hattori A, Ishii Y, Tsujimoto M. Reduced activity of the hypertension-associated Lys528Arg mutant of human adipocyte-derived leucine aminopeptidase (A-LAP)/ER-aminopeptidase-1. FEBS Lett. 2006;580(7):1833–8. doi:10.1016/j.febslet.2006.02.041.CrossRefPubMedGoogle Scholar
  44. 44.
    Goto Y, Ogawa K, Hattori A, Tsujimoto M. Secretion of endoplasmic reticulum aminopeptidase 1 is involved in the activation of macrophages induced by lipopolysaccharide and interferon-gamma. J Biol Chem. 2011;286(24):21906–14. doi:10.1074/jbc.M111.239111.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Goto Y, Ogawa K, Nakamura TJ, Hattori A, Tsujimoto M. TLR-mediated secretion of endoplasmic reticulum aminopeptidase 1 from macrophages. J Immunol. 2014;192(9):4443–52. doi:10.4049/jimmunol.1300935.CrossRefPubMedGoogle Scholar
  46. 46.
    Cui X, Rouhani FN, Hawari F, Levine SJ. An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding. J Biol Chem. 2003;278(31):28677–85. doi:10.1074/jbc.M300456200.CrossRefPubMedGoogle Scholar
  47. 47.
    Cui X, Rouhani FN, Hawari F, Levine SJ. Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J Immunol. 2003;171(12):6814–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Adamik B, Islam A, Rouhani FN, Hawari FI, Zhang J, Levine SJ. An association between RBMX, a heterogeneous nuclear ribonucleoprotein, and ARTS-1 regulates extracellular TNFR1 release. Biochem Biophys Res Commun. 2008;371(3):505–9. doi:10.1016/j.bbrc.2008.04.103.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Islam A, Adamik B, Hawari FI, Ma G, Rouhani FN, Zhang J, et al. Extracellular TNFR1 release requires the calcium-dependent formation of a nucleobindin 2-ARTS-1 complex. J Biol Chem. 2006;281(10):6860–73. doi:10.1074/jbc.M509397200.CrossRefPubMedGoogle Scholar
  50. 50.
    Thomas GP, Brown MA. Genetics and genomics of ankylosing spondylitis. Immunol Rev. 2010;233(1):162–80. doi:10.1111/j.0105-2896.2009.00852.x.CrossRefPubMedGoogle Scholar
  51. 51.
    de Blecourt J, Polman A, de Blécourt-Meindersma T. Hereditary factors in rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis. 1961;20:215–20.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Caffrey MF, James DC. Human lymphocyte antigen association in ankylosing spondylitis. Nature. 1973;242(5393):121.CrossRefPubMedGoogle Scholar
  53. 53.
    Khan MA. Polymorphism of HLA-B27: 105 subtypes currently known. Curr Rheumatol Rep. 2013;15(10):362. doi:10.1007/s11926-013-0362-y.CrossRefPubMedGoogle Scholar
  54. 54.
    Galocha B, Lopez de Castro JA. Mutational analysis reveals a complex interplay of peptide binding and multiple biological features of HLA-B27. J Biol Chem. 2010;285(50):39180–90. doi:10.1074/jbc.M110.149906.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell. 1990;63(5):1099–112.CrossRefPubMedGoogle Scholar
  56. 56.
    Benjamin R, Parham P. Guilt by association: hLA-B27 and ankylosing spondylitis. Immunol Today. 1990;11(4):137–42.CrossRefPubMedGoogle Scholar
  57. 57.
    Mear JP, Schreiber KL, Munz C, Zhu X, Stevanovic S, Rammensee HG, et al. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol. 1999;163(12):6665–70.PubMedGoogle Scholar
  58. 58.
    Peh CA, Burrows SR, Barnden M, Khanna R, Cresswell P, Moss DJ, et al. HLA-B27-restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading. Immunity. 1998;8(5):531–42.CrossRefPubMedGoogle Scholar
  59. 59.
    Antoniou AN, Ford S, Taurog JD, Butcher GW, Powis SJ. Formation of HLA-B27 homodimers and their relationship to assembly kinetics. J Biol Chem. 2004;279(10):8895–902. doi:10.1074/jbc.M311757200.CrossRefPubMedGoogle Scholar
  60. 60.
    Bird LA, Peh CA, Kollnberger S, Elliott T, McMichael AJ, Bowness P. Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling. Eur J Immunol. 2003;33(3):748–59. doi:10.1002/eji.200323678.CrossRefPubMedGoogle Scholar
  61. 61.
    Allen RL, O’Callaghan CA, McMichael AJ, Bowness P. Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J Immunol. 1999;162(9):5045–8.PubMedGoogle Scholar
  62. 62.
    Brown MA, Pile KD, Kennedy LG, Campbell D, Andrew L, March R, et al. A genome-wide screen for susceptibility loci in ankylosing spondylitis. Arthritis Rheum. 1998;41(4):588–95. doi:10.1002/1529-0131(199804)41:4<588:AID-ART5>3.0.CO;2-0.CrossRefPubMedGoogle Scholar
  63. 63.
    Laval SH, Timms A, Edwards S, Bradbury L, Brophy S, Milicic A, et al. Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci. Am J Hum Genet. 2001;68(4):918–26. doi:10.1086/319509.PubMedCentralCrossRefPubMedGoogle Scholar
  64. 64.
    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. Nat Genet. 2011;43(8):761–7. doi:10.1038/ng.873.PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Maksymowych WP, Inman RD, Gladman DD, Reeve JP, Pope A, Rahman P. Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitis. Arthritis Rheum. 2009;60(5):1317–23. doi:10.1002/art.24467.CrossRefPubMedGoogle Scholar
  66. 66.
    Harvey D, Pointon JJ, Evans DM, Karaderi T, Farrar C, Appleton LH, et al. Investigating the genetic association between ERAP1 and ankylosing spondylitis. Hum Mol Genet. 2009;18(21):4204–12. doi:10.1093/hmg/ddp371.PubMedCentralCrossRefPubMedGoogle Scholar
  67. 67.
    Bang SY, Kim TH, Lee B, Kwon E, Choi SH, Lee KS, et al. Genetic studies of ankylosing spondylitis in Koreans confirm associations with ERAP1 and 2p15 reported in white patients. J Rheumatol. 2011;38(2):322–4. doi:10.3899/jrheum.100652.CrossRefPubMedGoogle Scholar
  68. 68.
    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. doi:10.1002/art.24933.CrossRefPubMedGoogle Scholar
  69. 69.
    Pimentel-Santos FM, Ligeiro D, Matos M, Mourao AF, Sousa E, Pinto P, et al. Association of IL23R and ERAP1 genes with ankylosing spondylitis in a Portuguese population. Clin Exp Rheumatol. 2009;27(5):800–6.PubMedGoogle Scholar
  70. 70.
    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. doi:10.1136/ard.2008.103804.CrossRefPubMedGoogle Scholar
  71. 71.
    Cagliani R, Riva S, Biasin M, Fumagalli M, Pozzoli U, Lo Caputo S, et al. Genetic diversity at endoplasmic reticulum aminopeptidases is maintained by balancing selection and is associated with natural resistance to HIV-1 infection. Hum Mol Genet. 2010;19(23):4705–14. doi:10.1093/hmg/ddq401.CrossRefPubMedGoogle Scholar
  72. 72.
    Hill LD, Hilliard DD, York TP, Srinivas S, Kusanovic JP, Gomez R, et al. Fetal ERAP2 variation is associated with preeclampsia in African Americans in a case-control study. BMC Med Genet. 2011;12:64. doi:10.1186/1471-2350-12-64.PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Haroon N, Tsui FW, Uchanska-Ziegler B, Ziegler A, Inman RD. Endoplasmic reticulum aminopeptidase 1 (ERAP1) exhibits functionally significant interaction with HLA-B27 and relates to subtype specificity in ankylosing spondylitis. Ann Rheum Dis. 2012;71(4):589–95. doi:10.1136/annrheumdis-2011-200347.CrossRefPubMedGoogle Scholar
  74. 74.
    Evnouchidou I, Kamal RP, Seregin SS, Goto Y, Tsujimoto M, Hattori A, et al. Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme. J Immunol. 2011;186(4):1909–13. doi:10.4049/jimmunol.1003337.PubMedCentralCrossRefPubMedGoogle Scholar
  75. 75.
    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. doi:10.1002/art.38249.CrossRefPubMedGoogle Scholar
  76. 76.
    Martin-Esteban A, Gomez-Molina P, Sanz-Bravo A, Lopez de Castro JA. Combined effects of ankylosing spondylitis-associated ERAP1 polymorphisms outside the catalytic and peptide-binding sites on the processing of natural HLA-B27 ligands. J Biol Chem. 2014;289(7):3978–90. doi:10.1074/jbc.M113.529610.PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    Garcia-Medel N, Sanz-Bravo A, Van Nguyen D, Galocha B, Gomez-Molina P, Martin-Esteban A, et al. Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo. Mol Cell Proteomics. 2012;11(11):1416–29. doi:10.1074/mcp.M112.019588.PubMedCentralCrossRefPubMedGoogle Scholar
  78. 78.
    Chakrabarti A, Chen AW, Varner JD. A review of the mammalian unfolded protein response. Biotechnol Bioeng. 2011;108(12):2777–93. doi:10.1002/bit.23282.PubMedCentralCrossRefPubMedGoogle Scholar
  79. 79.
    Turner MJ, Delay ML, Bai S, Klenk E, Colbert RA. HLA-B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: implications for the pathogenesis of spondylarthritis-like disease. Arthritis Rheum. 2007;56(1):215–23. doi:10.1002/art.22295.CrossRefPubMedGoogle Scholar
  80. 80.
    Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA, et al. HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol. 2005;175(4):2438–48.CrossRefPubMedGoogle Scholar
  81. 81.
    Kollnberger S, Bird L, Sun MY, Retiere C, Braud VM, McMichael A, et al. Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. Arthritis Rheum. 2002;46(11):2972–82. doi:10.1002/art.10605.CrossRefPubMedGoogle Scholar
  82. 82.
    Peruzzi M, Parker KC, Long EO, Malnati MS. Peptide sequence requirements for the recognition of HLA-B*2705 by specific natural killer cells. J Immunol. 1996;157(8):3350–6.PubMedGoogle Scholar
  83. 83.
    Chan AT, Kollnberger SD, Wedderburn LR, Bowness P. Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis. Arthritis Rheum. 2005;52(11):3586–95. doi:10.1002/art.21395.CrossRefPubMedGoogle Scholar
  84. 84.
    Lopez-Larrea C, Blanco-Gelaz MA, Torre-Alonso JC, Bruges Armas J, Suarez-Alvarez B, Pruneda L, et al. Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations. Arthritis Res Ther. 2006;8(4):R101. doi:10.1186/ar1988.PubMedCentralCrossRefPubMedGoogle Scholar
  85. 85.
    McCappin J, Harvey D, Wordsworth BP, Middleton D. No association of KIR3DL1 or KIR3DS1 or their alleles with ankylosing spondylitis. Tissue Antigens. 2010;75(1):68–73. doi:10.1111/j.1399-0039.2009.01392.x.CrossRefPubMedGoogle Scholar
  86. 86.
    Gudjonsson JE, Karason A, Antonsdottir AA, Runarsdottir EH, Gulcher JR, Stefansson K, et al. HLA-Cw6-positive and HLA-Cw6-negative patients with psoriasis vulgaris have distinct clinical features. J Invest Dermatol. 2002;118(2):362–5. doi:10.1046/j.0022-202x.2001.01656.x.CrossRefPubMedGoogle Scholar
  87. 87.
    Fan X, Yang S, Huang W, Wang ZM, Sun LD, Liang YH, et al. Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population. PLoS Genet. 2008;4(3):e1000038. doi:10.1371/journal.pgen.1000038.PubMedCentralCrossRefPubMedGoogle Scholar
  88. 88.
    Lysell J, Padyukov L, Kockum I, Nikamo P, Stahle M. Genetic association with ERAP1 in psoriasis is confined to disease onset after puberty and not dependent on HLA-C*06. J Invest Dermatol. 2013;133(2):411–7. doi:10.1038/jid.2012.280.PubMedCentralCrossRefPubMedGoogle Scholar
  89. 89.
    Yurdakul S, Hamuryudan V, Yazici H. Behcet syndrome. Curr Opin Rheumatol. 2004;16(1):38–42.CrossRefPubMedGoogle Scholar
  90. 90.
    Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. Epidemiology and clinical characteristics of Behcet’s disease in the US: a population-based study. Arthritis Rheum. 2009;61(5):600–4. doi:10.1002/art.24423.PubMedCentralCrossRefPubMedGoogle Scholar
  91. 91.
    Kronenberg D, Knight RR, Estorninho M, Ellis RJ, Kester MG, de Ru A, et al. Circulating preproinsulin signal peptide-specific CD8 T cells restricted by the susceptibility molecule HLA-A24 are expanded at onset of type 1 diabetes and kill beta-cells. Diabetes. 2012;61(7):1752–9. doi:10.2337/db11-1520.PubMedCentralCrossRefPubMedGoogle Scholar
  92. 92.
    Fung EY, Smyth DJ, Howson JM, Cooper JD, Walker NM, Stevens H, et al. Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun. 2009;10(2):188–91. doi:10.1038/gene.2008.99.CrossRefPubMedGoogle Scholar
  93. 93.
    Schiffman MH, Castle P. Epidemiologic studies of a necessary causal risk factor: human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst. 2003;95(6):E2.CrossRefPubMedGoogle Scholar
  94. 94.
    Georgopoulos NT, Proffitt JL, Blair GE. Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins. Oncogene. 2000;19(42):4930–5. doi:10.1038/sj.onc.1203860.CrossRefPubMedGoogle Scholar
  95. 95.
    Mehta AM, Jordanova ES, van Wezel T, Uh HW, Corver WE, Kwappenberg KM, et al. Genetic variation of antigen processing machinery components and association with cervical carcinoma. Genes Chromosom Cancer. 2007;46(6):577–86. doi:10.1002/gcc.20441.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Emma Reeves
    • 1
  • Tim Elliott
    • 1
    • 2
  • Edward James
    • 1
    • 2
  • Christopher J. Edwards
    • 2
    • 3
  1. 1.Cancer Sciences Unit, Somers Cancer Research BuildingSouthampton General HospitalSouthamptonUK
  2. 2.Institute for Life SciencesUniversity of SouthamptonSouthamptonUK
  3. 3.NIHR Wellcome Trust Clinical Research Facility, Southampton General HospitalUniversity Hospital Southampton NHS Foundation TrustSouthamptonUK

Personalised recommendations