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

Mertz, A.; Ugrinović, Sanja; Lauster, Roland; Wu, Peng; Grolms, Martina; Böttcher, Ute; Appel, Heiner; Yin, Zhinan; Schiltz, Emile; Batsford, Steven; Schauer-Petrowski, Christiana; Braun, J.; Distler, A.; Sieper, Joachim

doi:10.1002/1529-0131(199802)41:2<315::aid-art16>3.3.co;2-r

Cited by 20 publications

(28 citation statements)

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“…In addition, SFMC from seven other Yersinia-triggered ReA-patients (5 male, 2 female; mean age 25 (range, 18 -39)) were stimulated with the Yersinia-specific 19-kDa protein (12), the Ye-hsp60, its three recombinant fragments, and overlapping synthetic peptides spanning the complete fragment II at a final concentration of 10 g/ml over 6 days. Lymphocyte proliferation was measured as previously described (19).…”

Section: R Eactive Arthritis (Rea)supporting

confidence: 91%

“…However, it seems to be also a relevant Ag in more chronic immune responses such as in ReA. We could recently show that the Ye-hsp60 is preferentially seen by both CD4 ϩ and CD8 ϩ T cells derived from synovial fluid of patients with Yersinia-induced ReA (12,13). Synovial T cell responses to CT-hsp60 have also been described in Chlamydia-induced ReA (37), and the immune response to CT-hsp60 have been implicated in the immunopathology of trachoma of the eye (38).…”

Section: Discussionmentioning

confidence: 99%

“…First, it has recently been found to be the major bacterial component recognized by synovial Th cells in a series of ReA patients (12). Second, nonamers derived from it stimulate synovial CD8 ϩ T cells from patients with Yersinia-ReA in a HLA-B27-restricted way (13).…”

Section: R Eactive Arthritis (Rea)mentioning

confidence: 99%

“…Outgrowing T cell clones (TCC) were further expanded as described (12,20) and then tested for Ag specificity in T cell proliferation assays (19) using irradiated (80 Gy) EBV-transformed autologous B lymphoblastoid cell lines (LCL) (10 4 T cells and 10 4 EBV-B-LCL). In some cases, irradiated (40 Gy) autologous PBMC (2 ϫ 10 4 ) were used as APC.…”

Section: R Eactive Arthritis (Rea)mentioning

confidence: 99%

“…Recombinant proteins (three fragments spanning the Ye-hsp60, the whole Chlamydia-hsp60 (CT-hsp60), the Borrelia-hsp60 (Bb-hsp60), and the human-hsp60 (hu-hsp60) were tested at a final optimal concentration of 10 g/ml as previously tested (12). Peptides were tested at a final concentration of 10 g/ml.…”

Section: R Eactive Arthritis (Rea)mentioning

confidence: 99%

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Multispecific CD4+ T Cell Response to a Single 12-mer Epitope of the Immunodominant Heat-Shock Protein 60 ofYersinia enterocoliticainYersinia-Triggered Reactive Arthritis: Overlap with the B27-Restricted CD8 Epitope, Functional Properties, and Epitope Presentation by Multiple DR Alleles

Mertz

Sturniolo

et al. 2000

The Journal of Immunology

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Yersinia heat-shock protein 60 (Ye-hsp60) has recently been found to be a dominant CD4 and CD8 T cell Ag in Yersinia-triggered reactive arthritis. The nature of this response with respect to the epitopes recognized and functional characteristics of the T cells is largely unknown. CD4+ T cell clones specific for Ye-hsp60 were raised from synovial fluid mononuclear cells from a patient with Yersinia-triggered reactive arthritis. and their specificity was determined using three recombinant Ye-hsp60 fragments, overlapping 18-mer synthetic peptides as well as truncated peptides. Functional characteristics were assessed by cytokine secretion analysis in culture supernatants after specific antigenic stimulation. Amino acid positions relevant for T cell activation were detected by single alanine substitutions within the epitopes. Fragment II comprising amino acid sequence 182–371 was recognized by the majority of clones. All these clones were specific for peptide 319–342. Th1 clones and IL-10-secreting clones occurred in parallel, sometimes with the same fine specificity. The 12-mer core epitope 322–333 is a degenerate MHC binder and is presented to some T cell clones in a “promiscuous” manner. This epitope is almost identical with a B27-restricted CTL epitope of Ye-hsp60. Cross-reactivity of Ye-hsp60-specific T cell clones with self-hsp60 was not observed. In conclusion, an interesting Ye-hsp60 T cell epitope has been identified and characterized. It remains to be determined whether this epitope is also relevant in other reactive arthritis patients.

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Section: R Eactive Arthritis (Rea)supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: R Eactive Arthritis (Rea)mentioning

confidence: 99%

Section: R Eactive Arthritis (Rea)mentioning

confidence: 99%

Section: R Eactive Arthritis (Rea)mentioning

confidence: 99%

See 3 more Smart Citations

Multispecific CD4+ T Cell Response to a Single 12-mer Epitope of the Immunodominant Heat-Shock Protein 60 ofYersinia enterocoliticainYersinia-Triggered Reactive Arthritis: Overlap with the B27-Restricted CD8 Epitope, Functional Properties, and Epitope Presentation by Multiple DR Alleles

Mertz

Sturniolo

et al. 2000

The Journal of Immunology

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Report on the fourth International workshop on reactive arthritis

Sieper

Braun

Kingsley³

2000

Arthritis & Rheumatism

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114

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There are large differences in the antigenicity and biology of the ReA-associated bacteria. For induction of arthritis, the relevance seems to be only that antigenic material reaches the joint, alive or dead. If there is a common antigen, it has to be a highly conserved one. Bacterial hsp60 seems to be an immunodominant T cell antigen in ReA, but there must be other relevant antigens shared by these different bacteria. An ineffective immune response (for example, low production of TNFalpha) seems to contribute to the manifestations and course of ReA. Although arthritis can also occur in its absence, HLA-B27 plays an important role in the pathogenesis of ReA and the other SpA. Current data suggest that B27 probably acts as an antigen-presenting molecule for a still-unknown arthritogenic molecule. Comparison of ReA with IBD-associated arthritis suggests that there might indeed be a common antigen shared by ReA-associated bacteria and bacteria of the gut flora. CD8+ T cells seem to be important in ReA and other SpA. In some parts of the world, such as in Mexico, ReA could be a major predisposing cause of the development of AS. Antibiotic treatment is not effective, probably because the triggering bacteria are already dead or in a partly latent state at the time arthritis occurs. Based on this knowledge and on new technologies, it should be possible in future years to derive answers to the questions about ReA and the other SpA and, as a consequence, to find a cure.

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Analysis of the antigen-specific T cell response in reactive arthritis by flow cytometry

Thiel

Lauster

et al. 2000

Arthritis & Rheumatism

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Objective In reactive arthritis (ReA) a bacteria‐specific T cell response to the triggering microbe is detected in synovial fluid (SF), and an impaired Th1 cytokine response has been described. The recent identification of immunodominant bacterial proteins/peptides and new technologies make a more detailed analysis of the immune response possible. The aim of the present study was to use these new techniques to determine the antigen‐specific T cell frequency and the cytokine secretion pattern on stimulation with bacteria‐derived recombinant proteins in the peripheral blood (PB) and SF from patients with ReA. Methods In 3 patients with Chlamydia‐induced ReA and 2 patients with Yersinia‐induced ReA, the SF T cell response was investigated after stimulation with the Chlamydia‐derived proteins major outer membrane protein (MOMP) and heat‐shock protein 60 (Hsp60) and the Yersinia‐derived proteins 19‐kd protein and Hsp60. In 3 of these patients, the PB T cell response was investigated in parallel. T cells were stimulated in whole blood or whole SF with antigen plus anti‐CD28 for 6 hours, brefeldin A was added after 2 hours, and cells were fixed and stained with antibodies against the surface markers CD4 and CD69 and against the cytokines interferon‐γ (IFNγ), tumor necrosis factor α, interleukin‐10 (IL‐10), and IL‐4. Positive cells were quantified by flow cytometry. Results In the 3 patients with Chlamydia‐induced ReA, the antigen‐specific T cell frequency (percentage of IFNγ CD69 double‐positive CD4+ T cells) in response to MOMP (mean ± SD 1.2 ± 1.38%) and to Hsp60 (1.21 ± 1.45%) in SF was about the same. In the 2 patients with Yersinia‐induced ReA, the mean ± SD frequency was 0.66 ± 0.36% in response to the Hsp60 and 0.3% ± 0.22 in response to the 19‐kd protein. In the 3 patients whose PB was evaluated, the corresponding T cell response was ≥10 times lower. In 2 patients with Chlamydia‐induced ReA, antigen‐specific IL‐10–positive CD4+ T cells were detected in 0.10–0.23% of the CD4+ T cell subpopulation. Conclusion The frequency of antigen‐specific T cells to Chlamydia‐ and Yersinia‐derived antigens in the SF of ReA patients is between 1:200 and 1:50. Both the chlamydial Hsp60 and MOMP are dominant T cell antigens in Chlamydia‐induced ReA. In patients with Chlamydia‐induced ReA, we detected antigen‐specific IL‐10 secretion, which might mediate an inhibition of effective bacterial clearance.

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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

Cited by 20 publications

References 0 publications

Multispecific CD4+ T Cell Response to a Single 12-mer Epitope of the Immunodominant Heat-Shock Protein 60 ofYersinia enterocoliticainYersinia-Triggered Reactive Arthritis: Overlap with the B27-Restricted CD8 Epitope, Functional Properties, and Epitope Presentation by Multiple DR Alleles

Multispecific CD4+ T Cell Response to a Single 12-mer Epitope of the Immunodominant Heat-Shock Protein 60 ofYersinia enterocoliticainYersinia-Triggered Reactive Arthritis: Overlap with the B27-Restricted CD8 Epitope, Functional Properties, and Epitope Presentation by Multiple DR Alleles

Report on the fourth International workshop on reactive arthritis

Analysis of the antigen-specific T cell response in reactive arthritis by flow cytometry

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