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Because HLA-B27 is a class I histocompatibility antigen, it has been postulated that HLA-B27 presents arthritogenic microbial peptides to T cells stimulating an autoimmune response, so called "molecular mimicry.'' A previous study has shown a high degree of conservation in the T-cell responses obtained from the synovial fluid of patients with recent ReA irrespective of the triggering organism [70].

Conversely, B27 itself may serve as the autoantigen that is targeted by the immune system. It is possible that exposure to the triggering bacteria may alter tolerance to the B27 antigen. Animal data exist to support this theory. Unlike their wild-type counterparts, HLA-B27 transgenic rats are tolerant of B27 immunization using B27-positive splenocytes or plasmid DNA. If these same splenocytes are exposed to Chlamydia in vitro, however, a cytotoxic response is generated [71]. No such response was generated with targets transfected with control B7, B14, B40, B44, or HLA-A2. Self-tolerance to B27 may be subverted by Chlamydia and possibly by the other gram-negative-triggering bacteria.

The role of HLA-B27 may, at least in part, function outside of antigen presentation. It has been suggested that HLA-B27 enhances the invasion of Salmonella into human intestinal epithelial cells [72]. It has also been suggested that Salmonella invasion leads to significant recognizable changes in the B27-bound peptide repertoire [73]. A similar study, however, found only minimal changes in the peptide repertoire [74]. Invasion of Chlamydia may not be altered by HLA-B27, but intracellular replication and formation of inclusion bodies might be suppressed by the cytoplasmic tail of this antigen [75]. If true, this could predispose the cell to chlamydial persistence. Conversely, it has been suggested that HLA-B27 has no influence on invasion or replication of Ct serovar L2 within cell lines [76].

Recent data suggest that HLA-B27 restricted epitopes derived from proteo-glycans, specifically human aggrecan, serve as autoantigens, and are involved in the inflammation that is characteristic of the spondyloarthropathies and

ReA [77]. Perhaps the only clarity of HLA-B27's role in the pathophysiology of ReA is that its exact role is still undefined and it is not the sole determinant of disease predilection.

Cellular uptake

It is clear that the causative organisms of ReA are incorporated into peripheral blood mononuclear cells. These same organisms or bacterial products persist intracellularly in synovial cells (primarily macrophages). How this process of intracellular uptake occurs is less apparent. Chlamydial infection, specifically, is initiated when the elementary body binds to the target eukaryotic cell. There are some data that suggest that the elementary body of both Ct and Cpn interact with host cell surface glycosaminoglycans during cellular uptake [78]. Following invasion, however, the Ct was confined to distinct vacuoles that did not develop into characteristic inclusion bodies. Intriguing recent evidence suggests that apolipoprotein E, which is adherent to the surface of Ct and Cpn elementary bodies, attaches to the host cell LDL receptor family carrying the elementary body with it [79]. This could represent a truly remarkable adaptation of Chlamydia using a basic cellular function involving cell homeostasis as its pathway to host cell attachment and uptake.

Toll-like receptors

The Toll-like receptors (TLRs) recognize extracellular pathogens and activate immune cell responses as part of the innate immune system. TLR-4 recognizes lipopolysaccharide, thereby potentially playing a role in the path-ophysiology of ReA. Recent mice data have shown that effective host clearance of Ct depends on appropriate TLR-4 expression by neutrophils [80]. TLR-4-deficient mice exposed to Salmonella demonstrate dramatically increased bacterial growth and increased demise [81]. Certain polymorphisms of TLR-4 have been associated with gram-negative infections and Crohn's disease and ulcerative colitis, two inflammatory conditions related with the spondyloarthropathies [82-84]. These same polymorphisms, however, seem not to confer risk of ReA [85].

Peripheral blood mononuclear cells from eight patients with Salmonella infections (four with ReA and four without) have been analyzed in both the acute and recovery phase of the infection [86]. All patients revealed high levels of activation and adhesion molecules and increased inflammatory and anti-inflammatory cytokine levels. During the recovery phase, the patients with ReA demonstrated completed down-regulation of CD14, whereas it was similar to healthy controls in those without ReA. Interestingly, CD14 is expressed in particularly high levels on macrophages. It functions as a coreceptor with TLR-4 for the detection of bacterial lipopolysaccharide [87].

Chemokine involvement

After an acute infection with the causative bacteria, these organisms are trafficked to the synovial tissue and other target organs. It is possible that chemokines guide this process for it is known that chemokines and chemo-kine receptors regulate leukocyte recruitment into inflamed tissues. CCR1 and CCR5 are known to play a role recruiting Thl-type T cells under inflammatory conditions [88]. It has been demonstrated that there is increased expression of CCR1, CXCR4, and CCR5 in the synovial tissue of patients with several types of arthritis including ReA [89]. There was no apparent unique chemokine profile related to ReA, however, compared with the other types of arthritis studied.

Th1 versus Th2/Th3 response

Although the Th1 cytokines play a role in the clinical manifestations of ReA, their importance seems to be less than that in other types of inflammatory arthritis. This might be particularly true for chronic ReA. Tumor necrosis factor (TNF)-a has been measured in the peripheral blood of patients with ReA. Compared with patients with rheumatoid arthritis, ReA patients demonstrated significantly lower levels of TNF-a [90]. Further, patients who were HLA-B27 positive or had disease duration of greater than 6 months secreted significantly less TNF-a in their peripheral blood. Similar findings have been demonstrated in the joints of patients with ReA (ie, higher levels of interleukin-10 and lower levels of TNF-a and interferon-g, favoring a Th2 profile) [91,92].

Temporal relationships of these different Th1 and Th2 cytokines may also be important in disease manifestations and maintenance. Slight changes in the Th1-Th2 balance may explain the relapsing course that is frequently seen with ReA. Alterations in the initial Th1-Th2 balance may also predispose to disease initiation. A Chlamydia-induced arthritis rat model demonstrated that susceptible rats mounted a lesser initial TNF-a, interferon-g, and interleukin-4 response to their Chlamydia infection [93]. Lower initial responses of these Th1 cytokines may increase the likelihood of developing ReA compared with those patients who are exposed to the causative organism but do not develop ReA.

Other data suggest a role for the Th3 response. Gammadelta-positive synovial-based T cells from patients with ReA predominantly express transforming growth factor-b2 and granulocyte-monocyte-colony stimulating factor [94]. Compared with CD4+ and CD8+ T cells from the same patients, they expressed a more heterogeneous cytokine profile that favored that of the Th3 response.

Finally, background cytokine levels favoring a Th2 response might contribute to bacterial persistence. In vitro data have shown that low levels of TNF-a and interferon-g help to promote the persistent state of both Ct and

Cpn [95-99]. Indeed, if the levels of these cytokines are low enough this may stimulate increased metabolic activity of the organism.

Diagnostic tests

Unfortunately, there is not a diagnostic test for ReA. During the acute stage, individuals often display elevated acute phase reactants, such as an elevated sedimentation rate or C-reactive protein. Conversely, patients with chronic ReA typically display normal levels. HLA-B27 is generally increased in ReA, although rates have varied from 0% to 88% [100,101]. Most of the data regarding ReA suggest an HLA-B27 prevalence of 30% to 50% [44,48,51,52,54,55,102,103]. There may be an overreliance on this HLA type for diagnostic purposes. Isolation of the triggering infection is helpful, but this is usually not possible with routine cultures after the onset of arthritis. It has been suggested that chlamydial IgG or IgA titers are useful at diagnosing patients with persistent Chlamydia infections [104-107]. Most of these data, however, apply only to Cpn in disease states other than ReA. There is also cross-reactivity between chlamydial serotypes, so their use has been questioned. PCR analysis of synovial tissue or fluid for the causative organisms or degradation products is useful but not readily available to most practitioners.

The radiographic features of ReA include sacroiliitis, periostitis, nonmar-ginal syndesmophytes, periosteal new bone formation, joint erosions, and joint space narrowing. These findings, however, are only apparent on plain radiographs with chronic disease. There may be a role for MRI or ultrasound (of the sacroiliac or other joints) to detect earlier changes, but they have not been formally studied in ReA.


Traditional therapies for ReA include nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs. Nonste-roidal anti-inflammatory drugs have been used to treat the joint inflammation associated with ReA. Although they seem to improve the articular symptoms of ReA, they are not thought to have any impact on the associated extra-articular symptoms. Although a breadth of clinical experience suggests that they help with the inflammatory arthritis associated with ReA, there are no well-designed prospective trials analyzing their efficacy for this indication.

Corticosteroids have limited benefit for the axial symptoms and may be more effective for the peripheral arthritis of ReA [9]. Local corticosteroid injections into affected joints may provide short-term relief. Corticosteroids also seem to be helpful at treating some of the extra-articular manifestations, such as iritis. Topical corticosteroids may also be useful for circinate balanitis (CB) and keratoderma blennorrhagicum (KB).

Traditional disease-modifying antirheumatic drugs have also been used for patients with chronic ReA because these patients can develop radiographic abnormalities with subsequent joint deformities if left untreated. The best studied disease-modifying antirheumatic drug in the setting of ReA is sulfasalazine. A prospective trial of 134 subjects designed to assess the efficacy of sulfasalazine in ReA [108]. In this trial there was a trend favoring sulfasalazine compared with placebo, because improvement was documented in 62% of the participants on sulfasalazine and 47% on placebo (P = .089). There were no significant improvements in any of the clinical measures followed compared with placebo, however, including swollen and tender joint counts. Methotrexate, azathioprine, and cyclosporine have been advocated as potential treatments but never formally evaluated in a prospective trial.

The TNF-a antagonists have demonstrated great success in the treatment of other types of spondyloarthropathies. There are potential theoretical concerns, however, regarding TNF-a antagonism in ReA. Lower levels of TNF-a have been demonstrated in ReA compared with other types of inflammatory arthritis, and ReA is believed to be more of a Th2-driven disease [90-92]. Also, in vitro data suggest that persistent Ct and Cpn levels are inversely associated with TNF-a levels [95-99]. There are no randomized trials in ReA to assess accurately their efficacy in this setting. There have, however, been a small open label study and case reports suggesting clinical benefit with these drugs in the treatment of ReA [109-111]. In an open label study with etanercept, there were five patients who were PCR positive for Chlamydia at some time during the observation period. Of the five, three were PCR positive in the synovium for Ct before treatment. Of these three, two of the patients were PCR negative on therapy and one remained positive. Two patients, however, with negative PCR results at baseline became PCR positive for Cpn while on etanercept [109]. These equivocal results do not dissuade the theoretical concerns that exist regarding the use of these drugs in ReA. Conversely, patients with ReA do exhibit higher serum levels of TNF-a levels compared with normal controls [94], so this might suggest that these patients would benefit from TNF-a antagonists. The use of TNF-a antagonists in the treatment of ReA is unanswered.

The exact role of antibiotics as a treatment for ReA has yet to be fully defined. A trial assessing 3 months of treatment with lymecycline showed no benefit to patients with postdysentery ReA, whereas there was improvement in patients with Chlamydia-induced ReA [112]. A subgroup analysis of another previous trial studying ciprofloxacin as a treatment for ReA suggested benefit in postchlamydial patients with no such improvement in the other patients [113]. Other studies assessing doxycycline, ciprofloxacin, and azithromycin in ReA failed to show benefit, but there was no effort to separate postchlamydial patients [103,114-116]. Interestingly, a follow-up of one of the aforementioned ciprofloxacin trials suggested that this antibiotic significantly improved long-term prognosis [117]. Finally, another study suggested significant improvement in patients with postchlamydial ReA with a combination of knee synovectomy and 3 months of azithromy-cin [118]. It seems that there may be benefit in the postchlamydial form but not ReA that is secondary to the postdysentery organisms. The observation of viable Chlamydia, and the general lack of viable postdysentery organisms, in the synovial tissue of patients with ReA support this finding.

The complexity of antibiotics as a potential treatment for Chlamydia-induced ReA runs even deeper. In vitro data have shown that intracellular chlamydiae are driven into a persistent state when exposed to chronic mono-therapy with several antibiotics including doxycycline, azithromycin, rifam-pin, and ciprofloxacin [119-122]. These data suggest that chronic monotherapy with the aforementioned antibiotics is unlikely to eradicate the persistent infection. Interesting in vitro data suggest successful synergis-tic eradication of cells infected with persistent Chlamydia with a combination rifampin and azithromycin [120]. In this same study, monotherapy with both of these same antibiotics did not eradicate the persistent infection. A 2004 study revealed significant improvement in patients with presumed Chlamydia-induced ReA after 9 months of a combination of rifampin and doxycycline compared with doxycycline monotherapy [102]. It is possible that a prolonged combination of antibiotics may eradicate the persistent state of Chlamydia along with its pathogenic sequelae. As is the case with TNF-a antagonists, the exact role of antibiotics in ReA is still not clear. It seems, however, that their only potential role relates to the treatment of Chlamydia-induced ReA and not to the postenteric form.


ReA is unique in that it is one of the few disease states of which there is a known trigger. This insight into disease initiation has led to great advances in the pathophysiology. Despite this detailed knowledge, the proper treatment remains elusive. In the years to come it is possible that the specific treatment will be dictated by the triggering microbe.


[1] Amor B. Reiter's syndrome: diagnosis and clinical features. Rheum Dis Clin North Am 1998;24:677-95.

[2] Reiter H. Uber eine bisher unerkannate spirochateninfektion (Spirochetosis arthritica). Dtsch Med Wochenschr 1916;42:1535-6.

[3] Lu DW, Katz KA. Declining use of the eponym "Reiter's syndrome'' in the medical literature, 1998-2003. J Am Acad Dermatol 2005;53:720-3.

[4] Parker CT, Thomas D. Reiter's syndrome and reactive arthritis. J Am Osteopath Assoc 2000;100:101-4.

[5] Hannu T, Inman R, Granfors K, et al. Reactive arthritis or post-infectious arthritis? Best Pract Res Clin Rheumatol 2006;20:419-33.

[6] Braun J, Kingsley G, van der Heijde D, et al. On the difficulties of establishing a consensus on the definition of and diagnostic investigations of reactive arthritis. Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999. J Rheumatol 2000;27:2185-92.

[7] Michet CJ, Machado EBV, Ballard DJ, et al. Epidemiology of Reiter's syndrome in Rochester, Minnesota 1950-1980. Arthritis Rheum 1988;31:428-32.

[8] Leirisalo-Repo M, Suoranta H. Ten-year follow-up study on patients with Yersinia arthritis. Arthritis Rheum 1988;31:533-7.

[9] Flores D, Marquez J, Garza M, et al. Reactive arthritis: newer developments. Rheum Dis Clin North Am 2003;29:37-59.

[10] Leirisalo-Repo M. Treatment of reactive arthritis. Rheumatol Eur 1995;24:20-2.

[11] Rudwaleit M, Richter S, Braun J, et al. Low incidence of reactive arthritis in children following a salmonella outbreak. Ann Rheum Dis 2001;60:1055-7.

[12] Eastmond CJ, Rennie JA, Reid TM. An outbreak of Campylobacter enteritis: a rheumato-logical followup survey. J Rheumatol 1983;10:107-8.

[13] Dworkin MS, Shoemaker PC, Goldoft MJ, et al. Reactive arthritis and Reiter's syndrome following and outbreak of gastroenteritis caused by Salmonella enteritidis. Clin Infect Dis 2001;33:1010-4.

[14] Rich E, Hook EW III, Alarcon GS, et al. Reactive arthritis in patients attending and urban sexually transmitted disease clinic. Arthritis Rheum 1996;39:1172-7.

[15] Braun J, Laitko S, Treharne J, et al. Chlamydia pneumoniae: a new causative agent of reactive arthritis and undifferentiated oligoarthritis. Ann Rheum Dis 1994;53:100-5.

[16] Hannu T, Puolakkainen M, Leirisalo-Repo M. Chlamydia pneumoniae as a triggering infection in reactive arthritis. Rheumatology (Oxford) 1999;38:411-4.

[17] Saario R, Toivanen A. Chlamydia pneumonia as a cause of reactive arthritis. Br J Rheumatol 1993;32:1112.

[18] Stamm WE. Chlamydia trachomatis infections: progress and problems. J Infect Dis 1999; 179(Suppl 2):380-3.

[19] Miyashita N, Niki Y, Nakajima M, et al. Prevalence of asymptomatic infection with Chlamydia pneumoniae in subjectively healthy adults. Chest 2001;119:1416-9.

[20] Groseclose SL, Zaidi AA, Delisle SJ, et al. Estimated incidence and prevalence of genital Chlamydia trachomatis infections in the United States, 1996. Sex Transm Dis 1999;26: 339-44.

[21] Doran MF, Pond GR, Crowson CS, et al. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 2002;46: 625-31.

[22] Soderlin MK, Borjesson O, Kautiainen H, et al. Annual incidence of inflammatory joint disease in a population based study in southern Sweden. Ann Rheum Dis 2002;61:911-5.

[23] Iliopoulos A, Karras D, Ioakimidis D, et al. Change in the epidemiology of Reiter's syndrome (reactive arthritis) in the post-AIDS era? An analysis of cases appearing in the Greek Army. J Rheumatol 1995;22:252-4.

[24] Bardin T, Enel C, Cornelis F, et al. Antibiotic treatment of venereal disease and Reiter's syndrome in a Greenland population. Arthritis Rheum 1992;35:190-4.

[25] Braun J, Tuszewski M, Ehlers S, et al. Nested polymerase chain reaction strategy simultaneously targeting DNA sequences of multiple bacterial species in inflammatory joint diseases. II. Examination of sacroiliac and knee joint biopsies of patients with spondylo-arthropathies and other arthritides. J Rheumatol 1997;24:1101-5.

[26] Gaston JS, Cox C, Granfors K. Clinical and experimental evidence for persistent Yersinia infection in reactive arthritis. Arthritis Rheum 1999;42:2239-42.

[27] Gerard HC, Branigan PJ, Schumacher HR Jr, et al. Synovial Chlamydia trachomatis in patients with reactive arthritis/Reiter's syndrome are viable but show aberrant gene expression. J Rheumatol 1998;25:734-42.

[28] 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.

[29] Granfors K, Jalkanen S, Toivancn P, et al. Bacterial lipopolysaccharide in synovial fluid cells in Shigella triggered reactive arthritis. J Rheumatol 1992;19:500.

[30] Nikkari S, Merilahti-Palo R, Saario R, et al. Yersinia-triggered reactive arthritis. Use of polymerase chain reaction and immunocytochemical in the detection of bacterial components from synovial specimens. Arthritis Rheum 1992;35:682-7.

[31] Nikkari S, Rantakokko K, Ekman P, et al. Salmonella-triggered reactive arthritis: use of polymerase chain reaction, immunocytochemical staining, and gas-chromatography-mass spectrometry in the detection of bacterial components from synovial fluid. Arthritis Rheum 1999;42:84-9.

[32] Taylor-Robinson D, Gilroy CB, Thomas BJ, et al. Detection of Chlamydia trachomatis DNA in joints of reactive arthritis patients by polymerase chain reaction. Lancet 1992; 340:81-2.

[33] Viitanen AM, Arstila TP, Lahesmaa R, et al. Application of the polymerase chain reaction and immunoflourescence to the detection of bacteria in Yersinia-triggered reactive arthritis. Arthritis Rheum 1991;34:89-96.

[34] Barth WF, Segal K. Reactive arthritis (Reiter's syndrome). Am Fam Physician 1999;60: 499-503, 507.

[35] Rahman MU, Hudson AP, Schumacher HR. Chlamydia and Reiter's syndrome (reactive arthritis). Rheum Dis Clin North Am 1992;18:67-79.

[36] Gerard HC, Wang Z, Whittum-Hudson JA, et al. Cytokine and chemokine mRNA produced in synvovial tissue chronically infected with Chlamydia trachomatis and C. pneumoniae. J Rheumatol 2002;29:1827-35.

[37] Gerard HC, Whittum-Hudson JA, Schumacher HR, et al. Differential expression of three Chlamydia trachomatis hsp60-encoding genes in active vs. persistent infections. Microb Pathog 2004;36:35-9.

[38] Gerard HC, Wang Z, Wang GF, et al. Chromosomal DNA from a variety of bacterial species is present in synovial tissue from patients with various forms of arthritis. Arthritis Rheum 2001;44:1689-97.

[39] Schumacher HR Jr, Arayssi T, Crane M, et al. Chlamydia trachomatis nucleic acids can be found in the synovium of some asymptomatic subjects. Arthritis Rheum 1999;42: 1281-4.

[40] Ozgul A, Dede I, Taskaynatan MA, et al. Clinical presentations of chlamydial and non-chlamydial reactive arthritis. Rheumatol Int 2006;26:879-85.

[41] Paronen J. Reiter's disease: a study of 344 cases observed in Finland. Acta Med Scand 1948; 131(Suppl 212):1-112.

[42] Gaston JS. Shigella induced reactive arthritis. Ann Rheum Dis 2005;64:517-8.

[43] Barrett-Connor E, Connor JD. Extra-intestinal manifestations of shigellosis. Am J Gastroenterol 1970;52:234-45.

[44] Hannu T, Mattila L, Siitonen A, et al. Reactive arthritis attributable to Shigella infection: a clinical and epidemiological nationwide study. Ann Rheum Dis 2005;64:594-8.

[45] McColl GJ, Diviney MB, Holdswaorth RF, et al. HLA-B27 expression and reactive arthritis susceptibility in two patient cohorts infected with Salmonella typhimurium. Aust N Z J Med 2000;30:28-32.

[46] Buxton JA, Fyfe M, Berger S, et al. Reactive arthritis and other sequelae following sporadic Salmonella typhimurium infection in British Columbia, Canada: a case control study. J Rheumatol 2002;29:2154-8.

[47] Hannu T, Mattila L, Siitonen A, et al. Reactive arthritis following an outbreak of Salmonella typhimuriom phage type 193 infection. Ann Rheum Dis 2002;61:264-6.

[48] Inman RD, Johnston ME, Hodge M, et al. Postdysenteric reactive arthritis: a clinical and immunogenetic study following an outbreak of salmonellosis. Arthritis Rheum 1988;31: 1377-83.

[49] Lee AT, Hall RG, Pile KD. Reactive joint symptoms following an outbreak of Salmonella typhimurium phage type 135a. J Rheumatol 2005;32:524-7.

[50] Locht H, Kihlstrom E, Lindstrom FD. Reactive arthritis after Salmonella among medical doctors: study of an outbreak. J Rheumatol 1993;20:845-8.

[51] Mattila L, Leirisalo-Repo M, Koskimies S, et al. Reactive arthritis following an outbreak of Salmonella infection in Finland. Br J Rheumatol 1994;33:1136-41.

[52] Mattila L, Leirisalo-Repo M, Pelkonene P, et al. Reactive arthritis following an outbreak of Salmonella bovismorbificans infection. J Infect 1998;36:289-95.

[53] Altekruse SF, Stern NJ, Fields PI, et al. Campylobacter jejuni: an emerging foodborne pathogen. Emerg Infect Dis 1999;5:28-35.

[54] Hannu T, Mattila L, Rautelin H, et al. Campylobacter-triggered reactive arthritis: a population-based study. Rheumatology 2002;41:312-8.

[55] Hannu T, Kauppi M, Tuomala M, et al. Reactive arthritis following an outbreak of Campylobacter jejuni infection. J Rheumatol 2004;31:528-30.

[56] Hannu T, Mattila L, Nuorti JP, et al. Reactive arthritis after an outbreak of Yersinia pseudotuberculosis serotype O:3 infection. Ann Rheum Dis 2003;62:866-9.

[57] Press N, Fyfe M, Bowie W, et al. Clinical and microbiological follow-up of an outbreak of Yersinia pseudotuberculosis serotype Ib. Scand J Infect Dis 2001;33:523-6.

[58] Tinazzi E, Ficarra V, Simeoni S, et al. Reactive arthritis following BCG immunotherapy for urinary bladder carcinoma: a systematic review. Rheumatol Int 2006;26:481-8.

[59] Ahmed S, Ayoub EM, Scornik JC, et al. Poststreptococcal reactive arthritis: clinical characteristics and associations with HLA-DR alleles. Arthritis Rheum 1998;41: 1096-102.

[60] Cox CJ, Kempsell KE, Gaston JS. Investigation of infectious agents associated with arthritis by reverse transcription PCR of bacterial rRNA. Arthritis Res Ther 2003;5: R1-8.

[61] Cuchacovich R, Japa S, Huang WQ, et al. Detection of bacterial DNA in Latin American patients with reactive arthritis by polymerase chain reaction and sequencing analysis. J Rheumatol 2002;29:1426-9.

[62] 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 arthritidies using a nested, broad-range polymerase chain reaction. Rheumatology 1999;38:260-6.

[63] Hess S, Peters J, Bartling G, et al. More than just innate immunity: comparative analysis of Chlamydophilapneumoniae and Chlamydia trachomatis effects on host-cell gene regulation. Cell Microbiol 2003;5:785-95.

[64] Zugel U, Kaufmann SH. Role of heat shock proteins in protection from and pathogenesis of infectious diseases. Clin Microbiol Rev 1999;12:19-39.

[65] Zugel U, Kaufmann SH. Immune response against heat shock proteins in infectious diseases. Immunobiology 1999;201:22-35.

[66] Airenne S, Surcel HM, Tuukkanen J, et al. Chlamydia pneumoniae inhibits apoptosis in human epithelial and monocyte cell lines. Scand J Immunol 2002;55:390-8.

[67] Dean D, Powers VC. Persistent Chlamydia trachomatis infections resist apoptotic stimuli. Infect Immun 2001;69:2442-7.

[68] Qoronfleh MW, Gustafson JE, Wilkinson BJ. Conditions that induce Staphylococcus heat shock proteins also inhibit autolysis. FEMS Microbiol Lett 1998;166:103-7.

[69] Curry AJ, Portig I, Goodall JC, et al. T lymphocyte lines isolated from atheromatous plaque contain cells capable of responding to Chlamydia antigens. Clin Exp Immunol 2000; 121:261-9.

[70] 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;162:3830-9.

[71] Popov I, Dela Cruz CS, Barber BH, et al. Breakdown of CTL tolerance to self HLA-B*2705 induced by exposure to Chlamydia trachomatis. J Immunol 2002;169:4033-8.

[72] Saarinen M, Ekman P, Ikeda M, et al. Invasion of Salmonella into human intestinal epithelial cells is modulated by HLA-B27. Rheumatology (Oxford) 2002;41:651-7.

[73] Maksymowych 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;66:4624-32.

[74] 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;44:1677-88.

[75] Kuipers JG, Bialowons A, Dollmann P, et al. The modulation of chlamydial replication by HLA-B27 depends on the cytoplasmic domain of HLA-B27. Clin Exp Rheumatol 2001;19:47-52.

[76] Young JL, Smith L, Matyszak MK, et al. HLA-B27 expression does not modulate intracellular Chlamydia trachomatis infection of cell lines. Infect Immun 2001;69:6670-5.

[77] Kuon W, Kuhne M, Busch DH, et al. Identification of novel human aggrecan T cell epi-topes in HLA-B27 transgenic mice associated with spondyloarthropathy. J Immunol 2004; 173:4859-66.

[78] Matyszak MK, Young JL, Gaston JS. Uptake and processing of Chlamydia trachomatis by human dendritic cells. Eur J Immunol 2002;32:742-51.

[79] Hudson AP, Whittum-Hudson JA, Gerard HO. C trachomatis utilizes the LDL receptor family for host cell attachment. Arthritis Rheum 2006;54(9 Suppl):S783.

[80] Zhang X, Glogauer M, Zhu F, et al. Innate immunity and arthritis: neutrophil Rac and tolllike receptor 4 expression define outcomes in infection-triggered arthritis. Arthritis Rheum 2005;52:1297-304.

[81] Vazquez-Torres A, Vallance BA, Bergman MA, et al. Toll-like receptor 4 dependence of innate and adaptive immunity to Salmonella: importance of the Kupffer cell network. J Immunol 2004;172:6202-8.

[82] Agnese DM, Calvano JE, Hahm SJ, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 2002;186:1522-5.

[83] Brand S, Staudinger T, Schnitzler F, et al. The roll of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and pheno-type of Crohn's disease. Inflamm Bowel Dis 2005;11:645-52.

[84] Torok HP, Glas J, Tonenchi L, et al. Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis. Clin Immunol 2004;112:85-91.

[85] Gergely P Jr, Blazsek A, Weiszhar Z, et al. Lack of genetic association of the Toll-like receptor 4 (TLR4) Asp299Gly and THR399Ile polymorphisms with spondyloarthropathies in Hungarian population. Rheumatology (Oxford) 2006;45(10):1194-6.

[86] Kirveskari J, He Q, Holmstrom T, et al. Modulation of peripheral blood mononuclear cell activation status during Salmonella-triggered reactive arthritis. Arthritis Rheum 1999;42: 2045-54.

[87] Rallabhandi P, Bell J, Boukhvalova MS, et al. Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J Immunol 2006; 177:322-32.

[88] Weber C, Weber KS, Klier C, et al. Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)1-like/CD45RO(+) T cells. Blood 2001;97: 1144-6.

[89] Haringman JJ, Smeets TJ, Reinders-Blankert P, et al. Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis. Ann Rheum Dis 2006;65: 294-300.

[90] 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;42:2039-44.

[91] Thiel A, Wu P, Lauster R, et al. Analysis of the antigen-specific T cell response in reactive arthritis by flow cytometry. Arthritis Rheum 2000;43:2834-42.

846 [92

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