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A molecular insight on the association of HLA-B27 with spondyloarthropathies

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Abstract

This article focuses on molecular studies concerning HLA-B27 and their relevance for its pathogenetic role in spondyloarthropathy. The peptide binding and T-cell antigen presenting properties of HLA-B27 are discussed, mainly in connection with differential subtype association to ankylosing spondylitis. Molecular studies in transgenic rodents are also considered, with an emphasis on their relevance to the various pathogenetic mechanisms. Recent studies on the putative role of HLA-B27 in bacteria-host interactions are also discussed, as they suggest another level of implication of HLA-B27 in disease whose molecular basis is obscure.

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References and Recommended Reading

  1. López de Castro JA: The pathogenetic role of HLA-B27 in chronic arthritis. Curr Op Immunol 1998, 10:59–66.

    Article  Google Scholar 

  2. López-Larrea C, González S, Martínez-Borra M: The role of HLA-B27 polymorphism and molecular mimicry in spondyloarthropathy. Mol Med Today 1998, 4:540–549.

    Article  PubMed  Google Scholar 

  3. Granfors K: Host-microbe interaction in reactive arthritis: does HLA-B27 have a direct effect? J Rheumatol 1998, 25:1659–1661.

    PubMed  CAS  Google Scholar 

  4. Khare SD, Luthra HS, David CS: HLA-B27 and other predisposing factors in spondyloarthropathies. Curr Opin Rheumatol 1998, 10:282–291.

    Article  PubMed  CAS  Google Scholar 

  5. López de Castro JA: Structural polymorphism and function of HLA-B27. Curr Opin Rheumatol 1995, 7:270–278.

    Article  PubMed  Google Scholar 

  6. González-Roces S, Alvarez MV, González S, et al.: HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis. Tissue Antigens 1997, 49:116–123. A subtyping study performed with a large sample of AS patients and controls from 17 different populations. This is the most comprehensive analysis to our knowledge on the association of HLA-B27 subtypes to AS.

    PubMed  Google Scholar 

  7. Hasegawa T, Ogwa A, Sugahara Y, et al.: A novel HLA-B27 allele (B*2711) encoding an antigen reacting with both B27- and B40-specific antisera. Tissue Antigens 1997, 49:649–652. Description of the novel HLA-B27 allele B*2711 based on crossreactivity with B40-group-specific antiserum.

    PubMed  CAS  Google Scholar 

  8. Balas A, Santos S, García-Sánchez F, et al.: Complete coding sequence of HLA-B*2712: a serologic B27-negative antigen associated to Bw6. Tissue Antigens 1998, 51:394–397. Description of B*2712, a B27-negative serologic antigen, which is the only one lacking the Lys70 residue.

    Article  PubMed  CAS  Google Scholar 

  9. Seurynch K, Baxter-Lowe LA: Novel polymorphism detected in exon 1 of HLA-B*2713. Tissue Antigens 1998, 52:187–189.

    Google Scholar 

  10. Hildebrand WH, Domena JD, Shen SY, et al.: The HLA-B7Qui antigen is encoded by a new subtype of HLA-B27 (B*2708). Tissue Antigens 1994, 44:4–51.

    Google Scholar 

  11. Armas JB, González S, Martínez-Borra J, et al.: Susceptibility to ankylosing spondylitis is independent of the Bw4 and Bw6 epitopes of HLA-B27 alleles. Tissue Antigens 1999, 53:237–243.

    Article  PubMed  CAS  Google Scholar 

  12. Brown M, Wordsworth P: Predisposing factors to spondyloarthropathies. Curr Opin Rheumatol 1997, 9:308–314.

    Article  PubMed  CAS  Google Scholar 

  13. Brown M, Jepson A, Young A, et al.: Spondyloarthritis in West Africa: evidence for a non-B27 protective effect. Ann Rheum Dis 1997, 56:68–70. A large population study in the Fula, from Gambia, showed absence of AS in spite of a 6% frequency of HLA-B27. This could not be explained by subtype frequencies (B*2703, 32%; B*2705, 68%) suggesting that other protective factors exist in this ethnic group. This study confirms that lack of association of B*2703 to AS in this population does not imply a differential pathogenetic role of this subtype.

    PubMed  CAS  Google Scholar 

  14. López-Larrea C, Sujirachato K, Mehra NK, et al.: HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Tissue Antigens 1995, 45:169–176.

    PubMed  Google Scholar 

  15. Ren EC, Koh WH, Sim D, et al.: Possible protective role of HLA-B*2706 for ankylosing spondylitis. Tissue Antigens 1997, 49:67–69. B*2705, B*2704 and B*2706 are the only subtypes found in the Singapore-Chinese population. B*2706 is absent in the AS group, but its frequency in the control group is low.

    PubMed  CAS  Google Scholar 

  16. Nasution AR, Mardjuandi Kunmartini S, et al.: HLA-B27 subtypes positively and negatively associated with spondyloarthropathy. J Rheumatol 1997, 24:1111–1114. A study of subtype association to spondyloarthropathy among Indonesians of Javanese and Chinese origin. The association of B*2704 and B*2705 to spondyloarthropathy was determined. However no B*2706 patients were found in spite of high frequency of this subtype among controls from both populations.

    PubMed  CAS  Google Scholar 

  17. Sudarsono D, Hadi S, Mardjuadi A, et al.: Evidence that HLA-B*2706 is not protective against spondyloarthropathy. J Rheumatol 1999, 7:1534–1536.

    Google Scholar 

  18. 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, 25:3199–3201.

    Article  PubMed  CAS  Google Scholar 

  19. Gomard E, Sitbon M, Toubert A, et al.: HLA-B27, a dominant restricting element in antiviral responses? Immunogenetics 1984, 20:197–204.

    Article  PubMed  CAS  Google Scholar 

  20. Kaslow RA, Carrington M, Apple R, et al.: Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nature Med 1996, 2:405–411.

    Article  PubMed  CAS  Google Scholar 

  21. Mustonen J, Partanen J, Kanerca M, et al.: Association of HLA-B27 with benign clinical course of nephropathia epidemica caused by Puumala Hantavirus. Scan J Immunol 1998, 47:277–279.

    Article  CAS  Google Scholar 

  22. Yagüe J, Ramos M, Vázquez J, et al.: The South Amerindian allotype HLA-B*3909 has the largest known similarity in peptide specificity and common natural ligands with HLA-B27. Tissue Antigens 1999, 53:227–236.

    Article  PubMed  Google Scholar 

  23. Jardetzky TS, Lane WS, Robinson RA, et al.: Identification of self peptides bound to purified HLA-B27. Nature 1991, 353:326–329.

    Article  PubMed  CAS  Google Scholar 

  24. Rötzschke O, Falk K, Stevanovic S, et al.: Dominant aromatic/ aliphatic C-terminal anchor in HLA-B*2702 and B*2705 peptide motifs. Immunogenetics 1994, 39:74–77.

    Article  PubMed  Google Scholar 

  25. Boisgérault F, Tieng V, Stolzenberg MC, et al.: Differences in endogenous peptides presented by HLA-B*2705 and B*2703 allelic variants: implications for susceptibility to spondyloarthropathies. J Clin Invest 1996, 98:2764–2770.

    PubMed  Google Scholar 

  26. 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. Peptide sequencing and in vitro binding study concerning B*2703. The results suggest that binding of peptides to B*2703 is more dependent on the P1 residue than B*2705, and that basic residues are favored at this position.

    PubMed  CAS  Google Scholar 

  27. García F, Marina A, López de Castro JA: Lack of carboxylterminal tyrosine distinguishes the B*2706-bound peptide repertoire from those of B*2704 and other HLA-B27 subtypes associated to ankylosing spondylitis. Tissue Antigens 1997, 49:215–221. Peptide sequencing showed that a major difference between the natural B*2704 and B*2706 ligands is the absence of peptides with C-terminal Tyr in B*2706.

    PubMed  Google Scholar 

  28. Tieng V, Dulphy N, Boisgérault F, et al.: HLA-B*2707 peptide motif: Tyr C-terminal anchor is not shared by all diseaseassociated subtypes. Immunogenetics 1997, 47:103–105. Characterization of the B*2707 peptide motif. This subtype, which is associated to AS, does not bind peptides with C-terminal Tyr in vivo.

    Article  PubMed  CAS  Google Scholar 

  29. Fiorillo MT, Meadows L, D’Amato M, et al.: Susceptibility to ankylosing spondylitis correlates with the C-terminal residue of peptides presented by various HLA-B27 subtypes. Eur J Immunol 1997, 27:368–373. B*2709, which is not associated to AS, differs from B*2705 in its failure to bind peptides with C-terminal Tyr in vivo.

    Article  PubMed  CAS  Google Scholar 

  30. García F, Rognan D, Lamas JR, et al.: An HLA-B27 polymorphism (B*2710) that is critical for T-cell recognition has limited effects on peptide specificity. Tissue Antigens 1998, 51:1–9. Characterization of the natural B*2710-bound peptides. This subtype shares many peptide ligands with B*2705, but shows very low cross-reaction with CTL. This is due to direct impairment of TCR recognition by the V152E change in this subtype.

    PubMed  Google Scholar 

  31. Villadangos JA, Galocha B, Garcia F, et al.: Modulation of peptide binding by HLA-B27 polymorphism in pockets A and B, and peptide specificity of B*2703. Eur J Immunol 1995, 25:2370–2377.

    Article  PubMed  CAS  Google Scholar 

  32. Galocha B, Lamas JR, Villadangos JA, et al.: Binding of peptides naturally presented by HLA-B27 to the differentially diseaseassociated B*2704 and B*2706 subtypes and to mutants mimicking their polymorphism. Tissue Antigens 1996, 48:509–518.

    PubMed  CAS  Google Scholar 

  33. Raghavan M, Lebron JA, Johnson JL. et al.: Extended repertoire of permissible peptide ligands for HLA-B*2702. Protein Sci 1996, 5:2080–2088.

    PubMed  CAS  Google Scholar 

  34. Simmons WA, Summerfield SG, Roopenian DC. et al.: Novel HY peptide antigens presented by HLA-B27. J Immunol 1997, 159:275–2759. Characterization of B*2705-restricted HY antigens in transgenic rats. Peptide sequencing showed two natural ligands lacking Arg2 (with Gln2 and Val2, respectively) that were recognized by B27-restricted HY specific CTL.

    Google Scholar 

  35. García F, Galocha B, Villadangos JA, et al.: HLA-B27 (B*2701) specificity for peptides lacking Arg2 is determined by polymorphism outside the B pocket. Tissue Antigens 1997, 49:580–587. Sequence analysis of B*2701-bound peptides showed that this subtype binds in vivo peptides with either Arg2 and Gln2. Its good acceptance of Gln2 is due to the D74Y change in this subtype.

    PubMed  Google Scholar 

  36. Krebs S, Rognan D, López de Castro JA: Long-range effects in protein-ligand interactions mediate peptide specificity in the human major histocompatibility antigen HLA-B27 (B*2701). Protein Sci 1999, in press.

  37. López D, García-Hoyo R, López de Castro JA: Clonal analysis of alloreactive T cell responses against the closely related B*2705 and B*2703 subtypes. Implications for HLA-B27 association to spondyloarthropathy. J Immunol 1994, 152:5557–5571.

    PubMed  Google Scholar 

  38. Villadangos JA, Galocha B, García-Hoyo R, et al.: Structure of HLA-B27-specific T cell epitopes. Antigen presentation in B*2703 is limited mostly to a subset of the antigenic determinants on B*2705. Eur J Immunol 1994, 24:2548–2555.

    Article  PubMed  CAS  Google Scholar 

  39. Colbert RA, Rowland-Jones SL, McMichael AJ, et al.: 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.

    Article  PubMed  CAS  Google Scholar 

  40. Rognan D, Krebs S, Kuonen O, et al.: Fine specificity of antigen binding to two class I major histocompatibility proteins (B*2705 and B*2703) differing in a single amino acid residue. J Comput Aided Mol Des 1997, 11:463–478.

    Article  PubMed  CAS  Google Scholar 

  41. Krebs S, Folkers G, Rognan D: Binding of rationally designed non-natural peptides to the human leukocyte antigen HLAB* 2705. J Pept Sci 1998, 4:378–388.

    Article  PubMed  CAS  Google Scholar 

  42. Krebs S, Lamas JR, Poenaru S, et al.: Substituting nonpeptidic spacers for the T cell receptor-binding part of class I major histocompatibility complex-binding peptides. J Biol Chem 1998, 273:19072–19079. Substitution of organic spacers for the P4-P8 residues of HLA-B27 ligands is still compatible with significant binding. Bifunctional spacers that provide additional interactions with HLA-B27 have a higher affinity than the parental peptide ligand.

    Article  PubMed  CAS  Google Scholar 

  43. Peh CA, Burrows SR, Barnden M, et al.: HLA-B27-restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading. Immunity 1998, 8:531–542. The different requirements of HLA proteins for antigen loading are described in this article. HLA-B27 shows less dependence on tapasin for loading endogenous peptides than B8 or B*4402. Putative alterations in the repertoire of peptides bound to B*2705 in the absence of tapasin need to be confirmed by HPLC analysis of eluted peptides from B27 molecules expressed on tapasin-negative cells.

    Article  PubMed  CAS  Google Scholar 

  44. Paradela A, García-Peydró M, Vázquez J, et al.: The same natural ligand is involved in allorecognition of multiple HLA-B27 subtypes by a single T cell clone: Role of peptide and the MHC molecule in alloreactivity. J Immunol 1998, 161:5481–5490. The natural epitope recognized by an alloreactive CTL clone raised against B*2705 was identified. This clone cross-reacts with B*2702 and B*2703 but not with other subtypes. The clone lysed TAPdeficient cells transfected with B*2702 or B*2703 when sensitized with the peptide epitope. B*2704, B*2706, and B*2710 targets were not lysed, although the peptide bound well to these subtypes. B*2701 cells were sensitized for lysis in vitro, suggesting lack of the endogenous peptide epitope in this subtype.

    PubMed  CAS  Google Scholar 

  45. Brooks JM, Murray RJ, Thomas WA, et al.: Different HLA-B27 subtypes present the same immunodominant Epstein-Barr virus peptide. J Exp Med 1993, 178:879–887.

    Article  PubMed  CAS  Google Scholar 

  46. Lamas JR, Brooks JM, Galocha B, et al.: Relationship beween peptide binding and T cell epitope selection: a study with subtypes of HLA-B27. Int Immunol 1998, 10:259–266. The article shows that there is no correlation between cell surface binding efficiency of EBV peptide epitopes to multiple B27 subtypes and the immunogenicity or antigenicity of these peptides in the context of only some subtypes.

    Article  PubMed  CAS  Google Scholar 

  47. Brooks JM, Colbert RA, Mear JP, et al.: 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. A new B27-restricted EBV-derived epitope was identified. It bound similarly to B*2705 and B*2702, but was immunogenic only in B*2702 donors. The B*2705-peptide complex was less stable than the B*2702-peptide complex. It was concluded that the stability of the class I-peptide complex could influence CTL epitope choice.

    PubMed  CAS  Google Scholar 

  48. Fiorillo MT, Greco G, Maragno M, et al.: The naturally occurring polymorphism Asp116-His116, differentiating the ankylosing spondylitis-associated HLA-B*2705 from the nonassociated HLA-B*2709 subtype, influences peptides-specific CD8 T cell recognition. Eur J Immunol 1998, 28:2508–2516. A B*2709-restricted CTL clone specific for an EBV-derived epitope recognized less efficiently this epitope when presented by B*2709. Critical peptide residues for recognition of this epitope in either context were different.

    Article  PubMed  CAS  Google Scholar 

  49. Ugrinovic S, Mertz A, Wu P, et al.: A single nonamer from the Yersinia 60-kDa heat shock protein is the target of HLA-B27 restricted CTL response in Yersinia induced reactive arthritis. J Immunol 1997, 159:5715–5723. A peptide spanning residues 321–329 of the 60 kDa heat shock protein from Y. enterocolitica was immunodominant in the CTL responses against this bacterium in reactive arthritis patients. The pathogenic role of these CTL was not addressed.

    PubMed  CAS  Google Scholar 

  50. Mertz AK, Ugrinovic S, Lauster R, et al.: Characterization of the synovial T cell response to various recombinant Yersinia antigens in Yersinia enterocolitica-triggered reactive arthritis. Heat-shock protein 60 drives a major immune response. Arthritis Rheum 1998, 41:315–326. The same protein involved in the major B27-restricted CTL response to Y. enterocolitica drives also major CD4 T cell responses.

    Article  PubMed  CAS  Google Scholar 

  51. Granfors K, Merilahti-Palo R, Luukkainen R, et al.: Persistence of Yersinia antigens in peripheral blood cells from patients with Yersinia enterocolitica O:3 infection with or without reactive arthritis. Arthritis and Rheum 1998, 41:855–862. Peripheral blood cells from patients infected with Y. enterocolitica with or without ReA were analyzed for intracellular bacterial LPS and HSP. Bacterial antigens were detected in cells of most of the patients with ReA 4 years after the onset of infection.

    Article  CAS  Google Scholar 

  52. Kuon W, Lauster R, Böttcher U, et al.: Recognition of chlamydial antigen by HLA-B27-restricted cytotoxic T cells in HLA-B*2705 transgenic CBA (H-2k) mice. Arthritis Rheum 1997, 40:945–954.

    Article  PubMed  CAS  Google Scholar 

  53. Gao X-M, Wordsworth P, McMichael AJ, et al.: Homocysteine modification of HLA antigens and its immunological consequences. Eur J Immunol 1996, 26:1443–1450.

    Article  PubMed  CAS  Google Scholar 

  54. Chilvers M-M, Wordsworth P, Stubbs, et al.: TCR usage by homocysteine-specific human CTL. J Immunol 1998, 160:3737–3742.

    PubMed  CAS  Google Scholar 

  55. Parham P: Presentation of HLA class I-derived peptides: potential involvement in allorecognition and HLA-B27-associated arthritis. Immunol Rev 1996, 154:137–154.

    Article  PubMed  CAS  Google Scholar 

  56. Khare SD, Bull MJ, Hanson J, et al.: 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. Spontaneous inflammatory arthritis was demonstrated in B*2705 transgenic mice in which both the b2m-microglobulin and IA genes were knocked out. Because these mice did not express class II proteins, a class II-mediated pathogenetic mechanism was ruled out. This study provides strong evidence that HLA-B27-associated disease in mice is not based on class II-mediated presentation of B27 peptides. Free HLA-b27 heavy chains were expressed at the cell surface in these animals, and arthritis was partially prevented by in vivo injection of an antibody specific for free HLA class I heavy chains. It was hypothesized that antigen presentation by free B27 heavy chains could be involved in disease development.

    PubMed  CAS  Google Scholar 

  57. Märker-Hermann E, Meyer zum Büschenfelde K-H, Wildner G:HLA-B27 derived peptides as autoantigens for T lymphocytes in ankylosing spondylitis. Arthritis Rheum 1997, 40:2047–2054. A 13-mer peptide derived from the sequence of HLA-B27 induced proliferative responses in patients with AS and in some HLA-B27+ controls. Expansion of g/d T cells was predominant.

    Article  PubMed  Google Scholar 

  58. Taurog JD: Arthritis in HLA-B27 transgenic animals. Am J Med Sci 1998, 316:250–256.

    Article  PubMed  CAS  Google Scholar 

  59. Taurog JD, Richardson JA, Croft JT, et al.: The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994, 180:2359–2364.

    Article  PubMed  CAS  Google Scholar 

  60. Rath HC, Herfarth HH, Ikeda JS, et al.: Normal luminal bacteria, specially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/humanb2 microglobulin transgenic rats. J Clin Invest 1996, 98:945–953.

    PubMed  CAS  Google Scholar 

  61. Onderdonk AB, Richardson JA, Hammer RE, et al.: Correlation of cecal microflora of HLA-B27 transgenic rats with inflammatory bowel disease. Infect Immun 1998, 66:6022–6023.

    PubMed  CAS  Google Scholar 

  62. Khare SD, Luthra HS, David CS: Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking 2-microglobulin: a model of human spondyloarthropathies. J Exp Med 1995, 182:1153–1158.

    Article  PubMed  CAS  Google Scholar 

  63. Taurog JD, Maika SD, Simmons WA, et al.: Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression. J Immunol 1993, 150:4168–4178.

    PubMed  CAS  Google Scholar 

  64. Zhou M, Sayad A, Simmons WA, et al.: The specificity of peptides bound to human histocompatibility leukocyte antigen (HLA)-B27 influences the prevalence of arthritis in HLA-B27 transgenic rats. J Exp Med 1998, 188:877–886. The expression of a B27-restricted viral NP1 peptide in B27+hb2m+ transgenic rats, shift the peptide repertoire bound to HLA-B27, causing reduction in the prevalence of arthritis, especially in males. Approximately 90% of the endogenous peptides bound to HLA-B27 were displaced by the NP1 peptide. No differences were observed in the prevalence of colitis, suggesting that gut inflammation is not related to B27-bound peptides. Although compatible with alternative mechanisms, this study strongly supports the arthritogenic peptide hypothesis.

    Article  PubMed  CAS  Google Scholar 

  65. Khare SD, Hansen J, Luthra HS, et al.: HLA-B27 heavy chains contribute to spontaneous inflammatory disease in B27/ human b2-microglobulin double transgenic mice with disrupted mouse b2m. J Clin Invest 1996, 98:2746–2755.

    PubMed  CAS  Google Scholar 

  66. Wuorela M, Granfors K: Infectious agents as triggers of reactive arthritis. Am J Med Sci 1998, 316:264–270.

    Article  PubMed  CAS  Google Scholar 

  67. Ikeda M, Yu DTY: The pathogenesis of HLA-B27 arthritis: role of HLA-B27 in bacterial defense. Am J Med Sci 1998, 316:257–263.

    Article  PubMed  CAS  Google Scholar 

  68. Kapasi K, Inman RD: HLA-B27 expression modulates gram-negative bacterial invasion into transfected L cells. J Immunol 1992, 148:3554–3559.

    PubMed  CAS  Google Scholar 

  69. Kapasi K, Inman RD: ME1 epitope of HLA-B27 confers class Imediated modulation of gram-negative bacterial invasion. J Immunol 1994, 153:833–840.

    PubMed  CAS  Google Scholar 

  70. Huppertz HI, Hessemann J: Invasion and persistence of Salmonella in human fibroblasts positive or negative for endogenous HLA-B27. Ann Rheum Dis 1997, 56:671–676. HLA-B27 did not influence the entry and survival of S. enteritidis in human fibroblasts. Addition of IFN-g decreased both invasion and survival of bacteria. Furthermore, Salmonella LPS persisted intracellularly after disappearance of live bacteria.

    Article  PubMed  CAS  Google Scholar 

  71. Ortiz-Alvarez O, Yu DTY, Petty RE, et al.: HLA-B27 does not affect invasion of arthritogenic bacteria into human cells. J Rheumatol 1998, 25:1765–1771. Infections with S. typhimurium and Y. enterocolitica of B27-or B27+ HeLa, U937, C1R, Jurkat, and L cells were performed, and no differences in the number of intracellular bacteria were found. Likewise, there were no significant variations in the percentage of internalized bacteria in peripheral blood cells from B27+ and B27-individuals.

    PubMed  CAS  Google Scholar 

  72. Granfors K: Host-microbe ineraction in reactive arthritis: does HLA-B27 have a direct effect? J Rheumatol 1998, 25:1659–1661.

    PubMed  CAS  Google Scholar 

  73. Boisgérault F, Mounier J, Tieng V, et al.: Alteration of HLA-B27 peptide presentation after infection of transfected murine L cells by Shigella flexneri. Infect Immun 1998, 66:4484–4490.

    PubMed  Google Scholar 

  74. Macksymowych WP, Ikawa T, Yamaguchi A, et al.: Invasion by Salmonella typhimurium induces increased expression of the LMP, MECL, and PA28 proteasome genes and changes in the peptide repertoire of HLA-B27. Infect Immun 1998, 66:4624–4632.

    Google Scholar 

  75. Wuorela M, Jalkanen S, Kirveskari J, et al.: Yersinia enterocolitica serotype O:3 alters the expression of serologic HLA-B27 epitopes on human monocytes. Infect Immun 1997, 65:2060–2066. This study reports downregulation of some HLA-B27 serologic epitopes, and decreased B27 synthesis, in Y. enterocolitica infected monocytes. The specificity of this phenomenon was limited, because antigenic downregulation was also observed in HLA-A2 and for HLA-B27 with E. coli, albeit in fewer individuals.

    PubMed  CAS  Google Scholar 

  76. Huang F, Yamaguchi A, Tsuchiya N, et al.: Induction of alternative splicing of HLA-B27 by bacterial invasion. Arthritis Rheum 1997, 40:694–703. This study showed alternative splicing of the HLA-B27 RNA, leading to the production of soluble HLA-B27, and its amplification upon infection with S. typhimurium or Y. enterocolitica. The specificity of this effect for either HLA-B27 or arthritogenic bacteria was not analysed.

    Article  PubMed  CAS  Google Scholar 

  77. Ikawa T, Ikeda M, Yamaguchi A, et al.: Expression of arthritis-causing 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. Salmonella invasion of B27+ HeLa cells induced expression of c-fos. This did not happen in nontransfected HeLa cells and required the B27 cytoplasmic tail. Furthermore, it promoted the generation of monocyte chemoattractant protein-1.

    Article  PubMed  CAS  Google Scholar 

  78. 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. This study demonstrates longer persistence of live intracellular bacteria inside the monocytic U937 cell line transfected with HLA-B27, relative to HLA-A2 transfectants. A chance effect of transfected DNA on bactericidal mechanisms was ruled out. This is, to our knowledge, the first clear-cut evidence that HLA-B27 favors the intracellular life of arthritogenic bacteria.

    Article  PubMed  CAS  Google Scholar 

  79. 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 Immun 1997, 65:4236–4242. This article reports on the longer survival of S. enteritidis in murine L cells transfected with HLA-B27/hb2m, relative to HLA-B7/hb2m or hb2m alone. Nitric oxide production was impaired in the HLA-B27 transfectant cells, relative to the other transfectants, which correlated with longer survival of Salmonella. The differences among transfectants in the survival of intracellular bacteria were abolished with an inhibitor of nitric oxide production. Because multiple HLA-B27 transfectant lines were not tested, the direct involvement of HLA-B27 in impairing nitric oxide production was not formally established.

    PubMed  CAS  Google Scholar 

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Martí, M., Álvarez, I. & López de Castro, J.A. A molecular insight on the association of HLA-B27 with spondyloarthropathies. Curr Rheumatol Rep 1, 78–85 (1999). https://doi.org/10.1007/s11926-999-0029-x

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