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02.09 Identification of a novel pro-inflammatory T cell epitope from his-trna-synthetase associated with interstitial lung disease in anti-jo-1 positive patients
  1. Angeles Shunashy Galindo-Feria1,
  2. Inka Albrecht1,
  3. Antonella Notarnicola1,
  4. Maryam Dastmalchi1,
  5. Anatoly Dubnovitsky2,
  6. Tatiana Sandalova2,
  7. Genadiy Kozhukh2,
  8. Lars Rönnblom3,
  9. Adnane Achour2,
  10. Vivianne Malmström1,
  11. Ingrid E Lundberg1
  1. 1Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
  2. 2Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  3. 3Uppsala University, Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala, Sweden

Abstract

Background Previous studies have demonstrated that CD4+ T cells from peripheral blood of anti-histidyl-tRNA synthetase (anti-His-tRNA) also known as anti-Jo-1 positive patients proliferate in response to stimulation with full-length His-tRNA and a N-terminal fragment comprising residues 1–60. In this study we present a novel epitope that identifies patients with moderate-severe interstitial lung disease (ILD).

Materials and Methods Sixteen anti-Jo-1 positive patients with antisynthetase syndrome followed at the Karolinska University Hospital were enrolled. As controls we included HLA-DRB1*03-positive healthy individual (HCs, n=8). Peripheral blood mononuclear cells were isolated by Ficoll-Hypaque density centrifugation and in vitro stimulated with: a) full length His-tRNA protein; b) a novel HLA-DR*03:01 binding peptide from native His-tRNA; c) an altered peptide ligand (APL) variant of His-tRNA designed to prevent recognition by HLA-DR3/His-tRNA-specific TCRs. T cell activation was assessed by CD40L up-regulation and expression of pro-inflammatory cytokines (IFN-g, IL-2 and IL-17A) by flow cytometry. Clinical and laboratory data were documented and analysed by Student’s T test or Mann-Withney U-test.

Results At the time of blood sampling the patients had a mean age of 58 years (48–83 years), median disease duration of 50 months (11–70 months), MMT8 score 80 (79-80), HAQ 0.25 (0 13-0.75). Eighty-four percent were female, 13/16 patients had ILD and 13/16 had muscle weakness. T cell activation towards the novel His-tRNA peptide was observed in 2/16 anti-Jo-1 positive patients. When stimulating with the APL, no T cell activation was observed in one of the patients that was reactive for the peptide. For evaluation of pro-inflammatory features, the His-tRNA-specific T cells displayed significant up-regulated levels of IFN-γ (p<0.05) compared to HC (p<0.05). Additionally, 1/8 HCs displayed a modest response to both the novel His-tRNA peptide and the full length His-tRNA protein. In this context only IL-2 was observed. The patients that showed an upregulation of CD40L had a moderate-severe clinical progression of ILD.

Conclusion In this study, we demonstrate the presence of His-tRNA-reactive CD4+ T cells in peripheral blood from anti-Jo-1 positive patients and a novel His-tRNA peptide, characterised by the expression of IFN-g. This phenotype seemed to correlate to a moderate-severe clinical progression of ILD.

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