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Synovial T cell proliferation to the Yersinia enterocolitica 19 kDa antigen differentiates yersinia triggered reactive arthritis (ReA) from ReA triggered by other enterobacteria
  1. H Appel1,
  2. M Rudwaleit1,
  3. P Wu1,2,
  4. M Grolms1,
  5. J Sieper1,2,
  6. A Mertz3
  1. 1Benjamin Franklin Medical Centre, Division of Gastroenterology and Rheumatology, Free University Berlin, Germany
  2. 2Deutsches Rheumaforschungszentrum Berlin, Germany
  3. 3Medical Centre Augsburg, Division of Nephrology, Augsburg, Germany
  1. Correspondence to:
    Professor J Sieper;
    hjsieper{at}zedat.fu-berlin.de

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Reactive arthritis (ReA) mostly presents as an asymmetrical oligoarthritis, usually affecting the leg joints.1 It is a T cell dependent inflammatory disease following infections with various enteropathic bacteria—for example, Yersinia enterocolitica 0:3, Salmonella enteritidis, Shigella fexneri, or microbes pathogenic for the urogenital tract such as Chlamydia trachomatis.2 Identification of the structure of antigens of triggering microbes which drive immune responses in the synovial fluid would be of great interest.

We recently described two major antigens, the Ye 19 kDa and the Ye HSP60 inducing synovial T cell proliferation in patients with Ye triggered ReA.3–7 They seemed to overcome the specificity problem of proliferation assays with T cells cultured from the site of inflammation to ReA triggering bacteria, because the local immune response to whole bacteria is accompanied by a restricted specificity probably due to cross reactivity with common epitopes.8 Since Ye is the only known ReA triggering bacteria expressing the Ye 19 kDa protein from the β subunit of urease,6 we investigated the possibility that synovial T cell proliferation to this protein might help to differentiate Ye triggered arthritis from arthritides caused by other bacteria.

In view of this specificity problem it was not unexpected to find a large number of patients in our clinic who showed clinical features of ReA and had synovial T cell proliferation to two or more enteropathic bacteria.

METHODS

We tested the synovial T cells of 66 patients with arthritis of one or more joints. Ye triggered ReA was diagnosed based on a typical history of previous symptomatic gastrointestinal infection or significant agglutinin titre. Chlamydia trachomatis triggered ReA was diagnosed in patients with arthritis and positive urogenital swabs or chlamydia-specific antibodies and a recent history of symptomatic urethritis or cervicitis. Synovial fluid mononuclear cells were cultured in the presence of heat inactivated bacterial antigens such as Yersinia enterocolitica, Salmonella enteritidis, Shigella flexneri, Campylobacter jejuni, and Chlamydia trachomatis. For stimulation with Ye 19 kDa we used 1 μg/ml recombinant protein, which was expressed as described previously.4 Stimulation indices were calculated in comparison with background activity by T cell medium. A stimulation index (SI) of >5 was classified as positive.

RESULTS

We identified 11 (28%) subjects among the 40 patients with T cell proliferation to Ye (mean (SD) SI 39.88 (30.22)) and at least to one more enterobacterium (SI 36.87 (34.62)), who responded also to Ye 19 kDa (SI 38.34 (32.97)) (group 1a), whereas 29 patients (Ye: SI 21.06 (16.71), other enterobacteria: SI 21.81 (20.23)) had no cellular immune response to Ye 19 kDa (SI 1.77 (1.27)) (group 1b, fig 1). We performed the same experiment with synovial T cells from 11 patients with chlamydia triggered ReA (SI 20.8 (15.51)) (group 2). In this case none of the patients had a T cell proliferation to Ye 19 kDa (SI 1.72 (1.5)) (fig 1). In 15 patients with the clinical diagnosis of ReA or undifferentiated oligoarthritis synovial T cells proliferated to mitogen, but not to any of the ReA triggering bacteria or Ye 19 kDa (SI 1.78 (1.25)) (group 3, fig 1).

Figure 1

Synovial T cell response to whole Yersinia enterocolitica (Ye) and recombinant Ye 19 kDa helps to differentiate yersinia triggered reactive arthritis (ReA) from ReA triggered by other bacteria. The synovial T cell proliferation to Ye 19 kDa protein was analysed in 66 patients with ReA. *Highest value for any enterobacterium other than yersinia.

Because the Ye 19 kDa as the β subunit of urease6 is a yersinia antigen not shared by other ReA triggering enterobacteria we believe that we have identified the cause of disease of a substantial number of patients with ReA in clinical practice which would not have been known by other means. We assume that Ye 19 kDa used in synovial T cell proliferation assays is a useful antigen to specify Ye as the disease triggering bacteria and might be of diagnostic value in ReA.

REFERENCES

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