Current Rheumatology Reports

, Volume 3, Issue 5, pp 404–411 | Cite as

Predisposing factors in the Spondyloarthropathies: New insights into the role of HLA-B27

  • Robert A. Colbert
  • Sampath Prahalad
Article

Abstract

Spondyloarthropathies represent complex genetic diseases whose development is influenced by environmental factors. Estimates suggest that three to nine loci may be responsible for the majority of the genetic susceptibility to ankylosing spondylitis. The only susceptibility locus identified to date in multiple populations is HLA-B, where several HLA-B27 alleles (subtypes) are strongly associated with disease. Recent evidence implicates cytochrome P450 2D6 as a second locus, although its influence on overall risk appears small. Despite considerable efforts to define how HLA-B27 contributes to disease, its role remains enigmatic. Increasing evidence suggests it has effects that are unrelated to its physiologic function. The basis for this is unknown but may be a consequence of the unusual tendency of this allele to misfold.

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References and Recommended Reading

  1. 1.
    Taurog JD, Maika SD, Satumtira N, et al.: Inflammatory disease in HLA-B27 transgenic rats. Immunol Rev 1999, 169:209–223. A comprehensive review of studies on the spondyloarthropathy-like disease produced by expressing HLA-B27 and human b2m in rats. This review contains previously unpublished data and discusses several possible mechanisms.PubMedCrossRefGoogle Scholar
  2. 2.
    Breban M, Fernandez-Sueiro JL, Richardson JA, et al.: T cells, but not thymic exposure to HLA-B27, are required for the inflammatory disease of HLA-B27 transgenic rats. J Immunol 1996, 156:794–803.PubMedGoogle Scholar
  3. 3.
    Rehman MI, Dorris MI, Kaushik P, Satumitra N, Taurog JD:Depletion of CD8 T cells does not prevent the development of spondyloarthropathy in HLA-B27 transgenic rats. Arthritis Rheum 2000, 43:S395.Google Scholar
  4. 4.
    Zhou M, Sayad A, Simmons WA, et al.: The specificity of peptides bound to HLA-B27 influences the prevalence of arthritis in HLA-B27 transgenic rats. J Exp Med 1998, 188:877–886. This paper demonstrates that expressing an HLA-B2-binding peptide (NP1) in the ER of disease-prone HLA-B27/hb2m transgenic rats reduces the prevalence of arthritis by approximately 50%. Some of the data in this paper demonstrating the presentation of NP1 and the displacement of endogenous ligands have been retracted. Whether the effect of NP1 on arthritis is related to the specificity of peptide presentation or other effects such as reduced HLA-B27 misfolding is unclear.PubMedCrossRefGoogle Scholar
  5. 5.
    Weinreich S, Eulderink F, Capkova J, et al.: HLA-B27 as a relative risk factor in ankylosing enthesopathy in transgenic mice. Hum Immunol 1995, 42:103–115.PubMedCrossRefGoogle Scholar
  6. 6.
    Khare SD, Luthra HS, David CS: Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking b2-microglobulin: a model of human spondyloarthropathies. J Exp Med 1995, 182:1153–1158.PubMedCrossRefGoogle Scholar
  7. 7.
    Khare SD, Hansen J, Luthra HS, David CS: HLA-B27 heavy chains contribute to spontaneous inflammatory disease in B27/human b2-microglobulin (b2m) double transgenic mice with disrupted mouse b2m. J Clin Invest 1997, 98:2746–2755.CrossRefGoogle Scholar
  8. 8.
    Khare SD, Hansen J, Luthra HS, David CS: Spontaneous inflammatory disease in HLA-B27 transgenic mice is independent of MHC class II molecules: a direct role for B27 heavy chains and not B27-derived peptides. J Immunol 1998, 160:101–106.PubMedGoogle Scholar
  9. 9.
    Weinreich S, Hoebe-Hewryk B, van der Horst AR, Boog CJP, Ivanyi P: The role of MHC class I heterodimer expression in mouse ankylosing enthesopathy. Immunogenetics 1997, 46:35–40.PubMedCrossRefGoogle Scholar
  10. 10.
    Rehakova Z, Capkova J, Stepankova R, et al.: Germ-free mice do not develop ankylosing enthesopathy, a spontaneous joint disease. Hum Immunol 2000, 61:555–558.PubMedCrossRefGoogle Scholar
  11. 11.
    Kingsbury DJ, Mear JP, Witte DP, et al.: Development of spontaneous arthritis in b2-microglobulin-deficient mice without expression of HLA-B27: association with deficiency of endogenous major histocompatibility complex class I expression. Arthritis Rheum 2000, 43:2290–2296. βb(in2)m-deficient mice are shown to develop spontaneous arthritis in the absence of HLA-B27, which was not observed in previous studies. This is shown also to occur in TAP1-deficient mice, suggesting that the pathogenesis may be related to MHC class I deficiency. The development of arthritis depends highly on the genetic background of the mouse strain.PubMedCrossRefGoogle Scholar
  12. 12.
    Ljunggren H-G, Glas R, Sandberg JK, Karre K: Reactivity and specificity of CD8+ T cells in mice with defects in the MHC class I antigen-presenting pathway. Immunol Rev 1996, 151:123–148.PubMedCrossRefGoogle Scholar
  13. 13.
    Hughes EA, Hammond C, Cresswell P: Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome. Proc Natl Acad Sci USA 1997, 94:1896–1901.PubMedCrossRefGoogle Scholar
  14. 14.
    Glas R, Ohlen C, Hoglund P, Karre K: The CD8+ T cell repertoire in b2-microglobulin-deficient mice is biased towards reactivity against self-major histocompatibility class I. J Exp Med 1994, 179:661–672.PubMedCrossRefGoogle Scholar
  15. 15.
    Aldrich CJ, Ljunggren H-G, Van Kaer L, et al.: Positive selection of self- and alloreactive CD8+ T cells in Tap-1 mutant mice. Proc Natl Acad Sci USA 1994, 91:6525–6528.PubMedCrossRefGoogle Scholar
  16. 16.
    Ho AM, Johnson MD, Kingsley DM: Role of the mouse ank gene in control of tissue calcification and arthritis. Science 2000, 289:265–270. The ank gene, which is responsible for murine progressive ankylosis, is identified. ANK plays an important role in pyrophosphate metabolism, which may protect against aberrant hydroxyapatite crystal deposition.PubMedCrossRefGoogle Scholar
  17. 17.
    Krug HE, Wietgrefe MM, Ytterberg SR, Taurog JD, Mahowald ML: Murine progressive ankylosis is not immunologically mediated. J Rheum 1997, 24:115–122.PubMedGoogle Scholar
  18. 18.
    Krug HE, Taurog JD: HLA-B27 has no effect on the phenotypic expression of progressive ankylosis in ank/ank mice. J Rheumatol 2000, 27:1257–1259.PubMedGoogle Scholar
  19. 19.
    Ringrose JH: HLA-B27 associated spondyloarthropathy, an autoimmune disease based on crossreactivity between bacteria and HLA-B27? Ann Rheum Dis 1999, 58:598–610. This is a comprehensive review of clinical studies reporting evidence for cross-reactive antibody or T-cell responses to HLA-B27.PubMedCrossRefGoogle Scholar
  20. 20.
    Albert LJ, Inman RD: Molecular mimicry and autoimmunity. N Engl J Med 1999, 341:2068–2074. The authors take a critical look at the evidence supporting molecular mimicry in the autoimmune diseases including spondyloarthropathies.PubMedCrossRefGoogle Scholar
  21. 21.
    Hermann E, Yu DTY, Meyerzum Buschenfelde K-H, Fleischer B:HLA-B27-restricted CD8 T cells from synovial fluids of patients with reactive arthritis and ankylosing spondylitis. Lancet 1993, 342:646–650.PubMedCrossRefGoogle Scholar
  22. 22.
    Fiorillo MT, Maragno M, Butler R, Dupuis ML, Sorrentino R:CD8+ T cell autoreactivity to an HLA-B27-restricted self-epitope correlates with ankylosing spondylitis. J Clin Invest 2000, 106:47–53. Self-reactive CD8+ T cells recognizing a peptide derived from the vasoactive intestinal protein and presented by HLA-B27 are found in patients with AS but not in healthy controls with B*2705 or B*2709. Because this peptide appears to bind better to the more weakly associated B*2709 subtype, the authors argue that the lack of reactivity is due to better negative selection of autoreactive T cells. If this is correct, it suggests that the notion that certain subtypes may not cause disease because they cannot bind arthritogenic peptides is incorrect, and that the reverse may be true.PubMedCrossRefGoogle Scholar
  23. 23.
    Khan MA: HLA-B27 polymorphism and association with disease. J Rheumatol 2000, 27:1110–1114. An editorial with a well-balanced discussion of studies supporting the presence or absence of disease association for the more prevalent HLA-B27 subtypes, and a comparison of the sequence differences distinguishing B*2701-B*2713.PubMedGoogle Scholar
  24. 24.
    Brooks JM, Colbert RA, Mear JP, Leese AM, Rickinson AB:HLA-B27 subtype polymorphism and CTL epitope choice: studies with EBV peptides link immunogenicity with stability of the B27:peptide complex. J Immunol 1998, 161:5252–5259.PubMedGoogle Scholar
  25. 25.
    van der Burg SH, Visseren MJW, Brandt RMP, Kast WM, Melief CJM: Immunogenicity of peptides bound to MHC class I molecules depends on the MHC-peptide complex stability. J Immunol 1996, 156:3308–3314.PubMedGoogle Scholar
  26. 26.
    Levitsky V, Zhang Q-J, Levitskaya J, Masucci MG: The life span of major histocompatibility complex-peptide complexes influences the efficiency of presentation and immunogenicity of two class I-restricted cytotoxic T lymphocyte epitopes in the Epstein-Barr virus nuclear antigen 4. J Exp Med 1996, 183:915–926.PubMedCrossRefGoogle Scholar
  27. 27.
    Dulphy N, Peyrat MA, Tieng V, et al.: Common intra-articular T cell expansions in patients with reactive arthritis: identical beta-chain junctional sequences and cytotoxicity toward HLA-B27. J Immunol 1999, 162:3830–3839.PubMedGoogle Scholar
  28. 28.
    Kapasi K, Inman RD: HLA-B27 expression modulates gram-negative bacterial invasion into transfected target cells. J Immunol 1992, 148:3554–3559.PubMedGoogle Scholar
  29. 29.
    Ortiz-Alvarez O, Yu DT, Petty RE, Finlay BB: HLA-B27 does not affect invasion of arthritogenic bacteria into human cells. J Rheumatol 1998, 25:1765–1771.PubMedGoogle Scholar
  30. 30.
    Laitio P, Virtala M, Salmi M, et al.: HLA-B27 modulates intracellular survival of Salmonella enteritidis in human monocytic cells. Eur J Immunol 1997, 27:1331–1338.PubMedCrossRefGoogle Scholar
  31. 31.
    Virtala M, Kirveskari J, Granfors K: HLA-B27 modulates the survival of Salmonella enteritidis in transfected L cells, possibly by impaired nitric oxide production. Infect Immunol 1997, 65:2436–4242.Google Scholar
  32. 32.
    Ikawa T, Ikeda M, Yamaguchi A, et al.: Expression of arthritiscausing HLA-B27 on Hela cells promotes induction of c-fos in response to in vitro invasion by Salmonella typhimurium. J Clin Invest 1998, 101:263–272. The authors show that expression of HLA-B27 can alter how cells respond to external stimuli such as bacterial invasion. Downstream effects of this may include the induction of proinflammatory chemokines with potential relevance to the initiation of an immune response.PubMedCrossRefGoogle Scholar
  33. 33.
    Mear JP, Schreiber KL, Munz C, 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, 163:6665–6670. HLA-B27 is shown to misfold as evidenced by prolonged ER retention and degradation of heavy chains. This characteristic is associated with the composition of its unique B pocket because replacement of these amino acids corrects this abnormality and restores rapid folding. Consequences of misfolding and their potential to be related to the pathogenesis of spondyloarthropathies are discussed.PubMedGoogle Scholar
  34. 34.
    Colbert RA, Dangoria NS, Mear JP: Mechanism and consequences of HLA-B27 misfolding. Arthritis Rheum 2000, 43:S399.Google Scholar
  35. 35.
    Hill A, Takiguchi M, McMichael A: Different rates of HLA class I molecule assembly which are determined by amino acid sequence in the a2 domain. Immunogenetics 1993, 37:95–101.PubMedCrossRefGoogle Scholar
  36. 36.
    Parham P, Adams EJ, Arnett KL: The origins of HLA-A, B, C polymorphism. Immunol Rev 1995, 143:141–180.PubMedCrossRefGoogle Scholar
  37. 37.
    Colbert RA: HLA-B27 misfolding: a solution to the spondyloarthropathy conundrum? Mol Med Today 2000, 6:224–230. Hypothesis paper drawing potential links between protein misfolding in the ER and spontaneous or bacteria-induced inflammatory disease.PubMedCrossRefGoogle Scholar
  38. 38.
    Colbert RA: HLA-B27 misfolding and spondyloarthropathies: not so groovy after all? J Rheumatol 2000, 27:1107–1109.PubMedGoogle Scholar
  39. 39.
    Urano F, Bertolotti A, Ron D: IRE1 and efferent signaling from the endoplasmic reticulum. J Cell Science 2000, 113:3697–3702.PubMedGoogle Scholar
  40. 40.
    Cavigelli M, Dolfi F, Claret FX, Karin M: Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J 1995, 14:5957–5964.PubMedGoogle Scholar
  41. 41.
    Kaufman RJ: Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Devel 1999, 13:1211–1233.PubMedCrossRefGoogle Scholar
  42. 42.
    Pahl HL: Signal transduction from the endoplasmic reticulum to the cell nucleus. Physiol Rev 1999, 79:683–701.PubMedGoogle Scholar
  43. 43.
    Aridor M, Balch WE: Integration of endoplasmic reticulum signaling in health and disease. Nature Med 1999, 5:745–751.PubMedCrossRefGoogle Scholar
  44. 44.
    Aderem A, Ulevitch RJ: Toll-like receptors in the induction of the innate immune response. Nature 2000, 406:782–787.PubMedCrossRefGoogle Scholar
  45. 45.
    Penttinen MA, Holmberg CI, Sistonen L, Granfors K: MHC class I molecules modulate LPS-induced NF-kB activation in U937 human monocytic cells. Arthritis Rheum 1999, 42:S385.Google Scholar
  46. 46.
    Allen RL, O’Callaghan CA, McMichael AJ, Bowness P: HLA-B27 can form a novel b2-microglobulin-free heavy chain homodimer structure. J Immunol 1999, 162:5045–5048. Aberrant folding of HLA-B27 is demonstrated in vitro by the formation of disulfide-bound heavy chain homodimers. Evidence that they also form in TAP-deficient cells is presented.PubMedGoogle Scholar
  47. 47.
    Edwards JCW, Bowness P, Archer JR: Jekyll and Hyde: the transformation of HLA-B27. Immunol Today 2000, 21:256–260. Hypothesis paper linking HLA-B27 dimerization with the pathogenesis of spondyloarthropathies.PubMedCrossRefGoogle Scholar
  48. 48.
    Colbert RA, Rowland-Jones SL, McMichael AJ, Frelinger JA:Differences in peptide presentation between B27 subtypes: the importance of the P1 side chain in maintaining high affinity peptide binding to B*2703. Immunity 1994, 1:121–130.PubMedCrossRefGoogle Scholar
  49. 49.
    Griffin TA, Yuan J, Friede T, et al.: Naturally occurring A pocket polymorphism in HLA-B*2703 increases the dependence on an accessory anchor residue at P1 for optimal binding of nonamer peptides. J Immunol 1997, 159:4887–4897.PubMedGoogle Scholar
  50. 50.
    Brown MA, Jepson A, Young A, et al.: Ankylosing spondylitis in West Africans—evidence for a non-HLA-B27 protective effect. Ann Rheum Dis 1997, 56:68–70.PubMedCrossRefGoogle Scholar
  51. 51.
    Nasution AR, Mardjuadi A, Kunmartini S, et al.: HLA-B27 subtypes positively and negatively associated with spondyloarthropathy. J Rheumatol 1997, 24:1111–1114.PubMedGoogle Scholar
  52. 52.
    Ren EC, Koh WH, Sim D, et al.: Possible protective role of HLA-B*2706 for ankylosing spondylitis. Tissue Antigens 1997, 49:67–69.PubMedCrossRefGoogle Scholar
  53. 53.
    Wei JCC, Chen S-D, Lin H-Y, Chan K-W, Liu H-C: HLA-B27 subtypes in Chinese with ankylosing spondylitis and normal controls. J Rheumatol 1998, 25:27.Google Scholar
  54. 54.
    Mardjuadi A, Nasution AR, Kunmartini S, et al.: Clinical features of spondyloarthropathy in Chinese and native Indonesians. Clin Rheumatol 1999, 18:442–445.PubMedCrossRefGoogle Scholar
  55. 55.
    D’Amato M, Fiorillo MT, Carcassi C, et al.: Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis. Eur J Immunol 1995, 25:3199–201.PubMedCrossRefGoogle Scholar
  56. 56.
    Gonzalez-Roces S, Alvarez MV, Gonzalez S, et al.: HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis. Tissue Antigens 1997, 49:116–123.PubMedCrossRefGoogle Scholar
  57. 57.
    Olivieri I, Padula A, Ciancio G, et al.: The HLA-B*2709 subtype in a patient with undifferentiated spondarthritis. Ann Rheum Dis 2000, 59:654–655.PubMedCrossRefGoogle Scholar
  58. 58.
    Olivieri I, Ciancio G, Padula A, et al.: The B*2709 subtype does not give absolute protection against spondyloarthropathy. Arthritis Rheum 2000, 43:S265.Google Scholar
  59. 59.
    Brown MA, Laval SH, Brophy S, Calin A: Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000, 59:883–886. A meta-analysis of recurrence risk ratios in different degree relatives of individuals with AS. This study suggests that single gene and polygenic models for susceptibility are unlikely, and that the data best fit a multiplicative interaction model involving three to nine genes.PubMedCrossRefGoogle Scholar
  60. 60.
    Calin A, Brophy S, Blake D: Impact of sex on inheritance of ankylosing spondylitis: a cohort study. Lancet 1999, 354:1687–1690.PubMedCrossRefGoogle Scholar
  61. 61.
    Miceli-Richard C, Said-Nahal R, Breban M: Impact of sex on inheritance of ankylosing spondylitis. Lancet 2000, 355:1097.PubMedCrossRefGoogle Scholar
  62. 62.
    Brown MA, Pile KD, Kennedy LG, et al.: A genome-wide screen for susceptibility loci in ankylosing spondylitis. Arthritis Rheum 1998, 41:588–595.PubMedCrossRefGoogle Scholar
  63. 63.
    Brown MA, Laval SH, Timms A, et al.: Confirmation of non-MHC genetic loci by whole genome linkage studies in ankylosing spondylitis. Arthritis Rheum 2000, 43:S395.Google Scholar
  64. 64.
    Djouadi K, Nedelec B, Tamouza R, et al.: Interleukin 1 gene cluster polymorphisms in multiplex families with spondyloarthropathies. Cytokine 2000, 13:98–103.CrossRefGoogle Scholar
  65. 65.
    Brown MA, Edwards S, Hoyle E, et al.: Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis. Human Mol Genet 2000, 9:1563–1566. This study provides evidence for linkage and association of AS with the cytochrome P450 2D6 gene, in particular, the CYP2D6*4 allele and the poor debrisoquine metabolizer phenotype. However, the increased risk due to homozygosity for this allele is small.CrossRefGoogle Scholar
  66. 66.
    Beyele C, Armstrong M, Bird HA, Idle JR, Daly AK: Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis 1996, 55:66–68.CrossRefGoogle Scholar
  67. 67.
    Maksymowych WP, Tao S, Vaile J, et al.: LMP2 polymorphism is associated with extraspinal disease in HLA-B27 negative Caucasian and Mexican Mestizo patients with ankylosing spondylitis. J Rheumatol 2000, 27:183–189.PubMedGoogle Scholar
  68. 68.
    Fraile A, Collado MD, Mataran L, Martin J, Nieto A: TAP1 and TAP2 polymorphisms in Spanish patients with ankylosing spondylitis. Exp Clin Immunogenet 1999, 17:199–204.CrossRefGoogle Scholar
  69. 69.
    Collado-Escobar MD, Nieto A, Mataran L, Raya E, Martin J:Interleukin 6 gene promoter polymorphism is not associated with ankylosing spondylitis. J Rheumatol 2000, 27:1461–1463.PubMedGoogle Scholar
  70. 70.
    Fishman D, Faulds G, Jeffrey R, et al.: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998, 102:1369–1376.PubMedCrossRefGoogle Scholar
  71. 71.
    McGarry F, Walker R, Sturrock R, Field M: The -308.1 polymorphism in the promoter region of the tumor necrosis factor gene is associated with ankylosing spondylitis independent of HLA-B27. J Rheumatol 1999, 26:1110–1116.PubMedGoogle Scholar
  72. 72.
    Kaijzel EL, Brinkman BM, van Krugten MV, et al.:Polymorphism within the tumor necrosis factor alpha (TNF) promoter region in patients with ankylosing spondylitis. Hum Immunol 1999, 60:140–144.PubMedCrossRefGoogle Scholar
  73. 73.
    Martinez-Borra J, Gonzalez S, Lopez-Vazquez A, et al.: HLA-B27 alone rather than B27-related class I haplotypes contributes to ankylosing spondylitis susceptibility. Hum Immunol 2000, 61:131–139.PubMedCrossRefGoogle Scholar
  74. 74.
    Ricci-Vitiani L, Vacca A, Potolicchio I, et al.: MICA gene triplet repeat polymorphism in patients with HLA-B27 positive and negative ankylosing spondylitis from Sardinia. J Rheumatol 2000, 27(9):2193–2197.PubMedGoogle Scholar
  75. 75.
    Ekman P, Kirveskari J, Granfors K: Modification of disease outcome in Salmonella-infected patients by HLA-B27. Arthritis Rheum 2000, 43:1527–1534. This is an interesting clinical study prospectively evaluating patients infected with Salmonella. The development of arthralgias and enthesitis even in the absence of ReA is correlated with the presence of HLA-B27. The frequency of HLA-B27 was only slightly higher in patients infected with Salmonella than population controls, suggesting no large effect on overall susceptibility to this organism.PubMedCrossRefGoogle Scholar
  76. 76.
    Baudoin P, van der Horst-Bruinsma IE, Dekker-Saeys AJ, et al.:Increased risk of developing ankylosing spondylitis among first-born children. Arthritis Rheum 2000, 43:2818–2822.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • Robert A. Colbert
    • 1
  • Sampath Prahalad
    • 1
  1. 1.William S. Rowe Division of RheumatologyChildren’s Hospital Medical CenterCincinnatiUSA

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