Abstract
Spondyloarthropathies consist of many inflammatory diseases that are closely associated with human leukocyte antigen (HLA)-B27. One of these diseases is reactive arthritis (ReA), which is a joint inflammation that occurs after infections that are caused by certain gram-negative bacteria. The importance of these infections as causative agents of ReA has been clearly established. It is not clear, however, whether these infections contribute to the development of other forms of spondyloarthropathies. The exact mechanism by which HLA-B27 influences disease susceptibility in spondyloarthropathies remains to be determined. The role of HLA-B27 as an antigen-presenting molecule is certainly important in the pathogenesis of these diseases; however, recent data indicate that this molecule may exhibit other functions unrelated to antigen presentation, which may be important in the pathogenesis of ReA. In this paper, the authors summarize the current knowledge of the role of infection in the spondyloarthropathies.
Similar content being viewed by others
References and Recommended Reading
Dougados M, van der Linden S, Juhlin R, et al.: The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991, 34:1218–1227.
Yu DT: Pathogenesis of reactive arthritis. Intern Med 1999, 38:97–101. The review discusses the pathogenesis of SpA in relation to HLA-B27 and ReA-triggering bacteria.
Sieper J, Braun J, Kingsley GH: Report on the Fourth International Workshop on Reactive Arthritis. Arthritis Rheum 2000, 43:720–734.
Braun J, Laitko S, Treharne J, et al.: Chlamydia pneumoniae-a new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis 1994, 53:100–105.
Hannu T, Puolakkainen M, Leirisalo-Repo M:Chlamydia pneumoniae as a triggering infection in reactive arthritis. Rheumatology 1999, 38:411–414.
Liu Y, Penttinen MA, Granfors K:Insights into the role of infection in the spondyloarthropathies. Curr Rheumatol Rep 2001, 3:428–434.
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 Rheum 1998, 41:855–862. This study demonstrates, for the first time, that bacterial antigens could be found even after several years in peripheral blood cells of patients who develop ReA after Yersinia enterocolitica O:3 infection. In addition, bacterial hsp60 was also found for the first time from peripheral blood cells of ReA patient.
Ekman P, Nikkari S, Putto-Laurila A, et al.: Detection of Salmonella infantis in synovial fluid cells of a patient with reactive arthritis. J Rheumatol 1999, 26:2485–2488.
Gaston JS, Cox C, Granfors K: Clinical and experimental evidence for persistent Yersinia infection in reactive arthritis. Arthritis Rheum 1999, 42:2239–2242.
Kempsell KE, Cox CJ, Hurle M, et al.: Reverse transcriptase- PCR analysis of bacterial rRNA for detection and characterization of bacterial species in arthritis synovial tissue. Infect Immun 2000, 68:6012–6026.
Wilkinson NZ, Kingsley GH, Jones HW, et al.:The detection of DNA from a range of bacterial species in the joints of patients with a variety of arthritides using a nested, broadrange polymerase chain reaction. Rheumatology 1999, 38:260–266.
Gerard HC, Branigan PJ, Schumacher HR, et al.: Synovial Chlamydia trachomatis in patients with reactive arthritis/ Reiter’s syndrome are viable but show aberrant gene expression. J Rheumatol 1998, 25:734–742. This study demonstrates that Chlamydia trachomatis found in the synovial tissue are viable.
Gerard HC, Schumacher HR, El-Gabalawy H, et al.: Chlamydia pneumoniae present in the human synovium are viable and metabolically active. Microb Pathog 2000, 29:17–24.
Villareal C, Whittum-Hudson JA, et al.: Persistent Chlamydiae and chronic arthritis. Arthritis Res 2002, 4:5–9.
Deng GM, Nilsson IM, Verdrengh M, et al.:Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med 1999, 5:702–705. This study demonstrates that intra-articularly localized bacterial DNA is sufficient to induce arthritis, which is dependent on TNFγ.
Braun J, de Keyser F, Brandt J, et al.: New treatment options in spondyloarthropathies: increasing evidence for significant efficacy of anti-tumor necrosis factor therapy. Curr Opin Rheumatol 2001, 13:245–249.
Lee VT, Schneewind O:Type III secretion machines and the pathogenesis of enteric infections caused by Yersinia and Salmonella spp. Immunol Rev 1999, 168:241–255.
Vazquez-Torres A, Fang FC:Cellular routes of invasion by enteropathogens. Curr Opin Microbiol 2000, 3:54–59.
Vazquez-Torres A, Jones-Carson J, Baumler AJ, et al.:Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 1999, 401:804–808. This study demonstrates the existence of alternative route of extraintestinal dissemination of Salmonella that is distinct from Salmonella pathogenity island-1-mediated M cell invasion.
Everest P, Ketley J, Hardy S, et al.: Evaluation of Salmonella typhimurium mutants in model of experimental gastroenteritis. Infect Immun 1999, 67:2815–2821.
Meyer-Bahlburg A, Brinkhoff J, Krenn V, et al.:Infection of synovial fibroblasts in culture by Yersinia enterocolitica and Salmonella enterica serovar Enteritidis: ultrastructural investigation with respect to the pathogenesis of reactive arthritis. Infect Immun 2001, 69:7915–7921.
Sieper J, Fendler C, Laitko S, et al.: No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: a three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum 1999, 42:1386–1396.
Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al.: Effect of a three-month course of ciprofloxacin on the outcome of reactive arthritis. Ann Rheum Dis 2000, 59:565–570.
Hannu T, Mattila L, Siitonen A, et al.: Reactive arthritis following an outbreak of Salmonella typhimurium phage type 193 infection. Ann Rheum Dis 2002, 61:264–266.
Granfors K, Märker-Hermann E, de Keyser F, et al.:The cutting edge of spondylarthropathy research in the millennium. Arthritis Rheum 2002, 46:606–613.
Mertz AK, Wu P, Sturniolo T, et al.:Multispecific CD4+ T cell response to a single 12-mer epitope of the immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersiniatriggered reactive arthritis: overlap with the B27-restricted CD8 epitope, functional properties, and epitope presentation by multiple DR alleles. J Immunol 2000, 164:1529–1537.
Kirveskari J, He Q, Leirisalo-Repo M, et al.: Enterobacterial infection modulates major histocompatibility complex class I expression on mononuclear cells. Immunology 1999, 97:420–428.
Braun J, Yin Z, Spiller I, et al.: Low secretion of tumor necrosis factor alpha, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis. Arthritis Rheum 1999, 42:2039–2044. The altered cytokine response was implicated in the pathogenesis of ReA.
Ekman P, Kirveskari J, Granfors K:Modification of disease outcome in Salmonella-infected patients by HLA- B27. Arthritis Rheum 2000, 43:1527–1534.
Ramos M, Alvarez I, Garcia-del-Portillo F, et al.:Minimal alterations in the HLA-B27-bound peptide repertoire induced upon infection of lymphoid cells with Salmonella typhimurium. Arthritis Rheum 2001, 44:1677–1688.
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. Human leukocyte antigen-B27 was observed to modulate Salmonellainduced signaling in Hela epithelial cells.
Ekman P, Saarinen M, He Q, et al.: Human monocytic U937 cells kill Salmonella in vitro by NO-independent mechanisms. Infect Immun 1999, 67:3670–3673.
Saarinen M, Ekman P, He Q, et al.: Elimination of Salmonella enterica serotype enteritidis in intestinal epithelial cells by mechanisms other than nitric oxide. J Med Microbiol 2002, 51:13–19.
Liu Y, Ekman P, Gripenberg-Lerche C, et al.: Elimination of bacteria and production of inflammatory cytokines by HLAB27- positive human peripheral blood monocytes during Salmonella enteritidis infection. Arthritis Rheum 2000, 43:S387.
Granfors K, Liu Y, Ekman P, et al.: Uptake and killing of Yersinia by human monocytic cells; the influence of HLA-B27. Arthritis Rheum 2000, 43:S267.
Granfors K:Host-microbe interaction in reactive arthritis: does HLA-B27 have a direct effect? J Rheumatol 1998, 25:1659–1661.
Colbert RA: HLA-B27 misfolding and spondyloarthropathies: not so groovy after all? J Rheumatol 2000, 27:1107–1109. A review on the role of HLA-B27 misfolding in the pathogenesis of SpA.
Dangoria NS, DeLay ML, Kingsbury DJ, et al.: HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum. J Biol Chem 2002, 26:26.
Penttinen MA, Holmberg CI, Sistonen L, et al.: HLA-B27 modulates nuclear factor (B activation in human monocytic cells exposed to lipopolysaccharide. Arthritis Rheum 2002, In press.
Ekman P, Saarinen M, He Q, et al.:HLA-B27-transfected (Salmonella permissive) and HLA-A2-transfected (Salmonella nonpermissive) human monocytic U937 cells differ in their production of cytokines. Infect Immun 2002, 70:1609–1614.
Repo H, Jäättela M, Leirisalo-Repo M, et al.: Production of tumour necrosis factor and interleukin 1 by monocytes of patients with previous Yersinia arthritis. Clin Exp Immunol 1988, 72:410–414.
Baeten D, Demetter P, Cuvelier CA, et al.: Macrophages expressing the scavenger receptor CD163: a link between immune alterations of the gut and synovial inflammation in spondyloarthropathy. J Pathol 2002, 196:343–350. Significantly higher amounts of CD163+ macrophages were observed in mucosal area and synovium of patients with spondyloarthropathy compared with patients with rheumatoid arthritis or healthy control individuals. Such upregulation of CD163+ macrophages may lead to altered immune reactions, as CD163+ macrophages produce TNFγ, but not interleukin-10 at LPS stimulation, whereas CD163- macrophages produce interleukin-10 and TNF-_(on LPS challenge). In addition, anti-TNFγ therapy in vivo induced a decrease of CD163+ macrophages in synovial lining.
Pahl HL:Signal transduction from the endoplasmic reticulum to the cell nucleus. Physiol Rev 1999, 79:683–701. A comprehensive review of signal transduction from endoplasmic reticulum.
Pahl HL, Baeuerle PA: The ER-overload response: activation of NF-kappa B. Trends Biochem Sci 1997, 22:63–67.
Höhler T, Hug R, Schneider PM, et al.:Ankylosing spondylitis in monozygotic twins: studies on immunological parameters. Ann Rheum Dis 1999, 58:435–440.
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.
Khare SD, Luthra HS, David CS: Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin: a model of human spondyloarthropathies. J Exp Med 1995, 182:1153–1158.
Rath HC, Herfarth HH, Ikeda JS, et al.:Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest 1996, 98:945–953.
Wang Q, Vasey FB, Mahfood JP, et al.: V2 regions of 16S ribosomal RNA used as a molecular marker for the species identification of streptococci in peripheral blood and synovial fluid from patients with psoriatic arthritis. Arthritis Rheum 1999, 42:2055–2059.
Duchmann R, May E, Heike M, et al.:T cell specificity and cross reactivity towards enterobacteria, bacteroides, bifidobacterium, and antigens from resident intestinal flora in humans. Gut 1999, 44:812–818.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Penttinen, M.A., Liu, Y. & Granfors, K. The role of infection in the pathogenesis of spondyloarthropathies with special reference to human leukocyte antigen-b27. Curr Rheumatol Rep 4, 518–524 (2002). https://doi.org/10.1007/s11926-002-0060-7
Issue Date:
DOI: https://doi.org/10.1007/s11926-002-0060-7