RESUMEN
INTRODUCTION: tRNA-derived fragments (tRFs) play an important role in immune responses. To clarify the role of tRFs in autoimmunity we studied circulating tRF-levels in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), and in a murine model for arthritis. MATERIAL AND METHODS: Circulating tRF-levels were quantified by miR-Q RT-qPCR. tRNA processing and modification enzyme expression was analysed by RT-qPCR and public transcriptomics data. RESULTS: Significant reduction (up to 3-fold on average) of tRF-levels derived from tRNA-Gly-GCC,CCC, tRNA-Glu-CTC and tRNA-Val-CAC,AAC was observed in RA patients, whereas tRNA-Glu-CTC and tRNA-Val-CAC,AAC tRFs were found at significantly higher levels (up to 3-fold on average) in PsA patients, compared to healthy controls. Also in arthritic IL1Ra-KO mice reduced levels of tRNA-Glu-CTC fragments were seen. The expression of NSUN2, a methyltransferase catalysing tRNA methylation, was increased in RA-peripheral blood mononuclear cells (PBMCs) compared to PsA, but this is not consistently supported by public transcriptomics data. DISCUSSION: The observed changes of specific tRF-levels may be involved in the immune responses in RA and PsA and may be applicable as new biomarkers. CONCLUSION: Circulating tRF-levels are decreased in RA and increased in PsA and this may, at least in part, be mediated by methylation changes.
Asunto(s)
Artritis Psoriásica , Artritis Reumatoide , Humanos , Animales , Ratones , Artritis Psoriásica/genética , Leucocitos Mononucleares/metabolismo , ARN de Transferencia/genética , Biomarcadores/metabolismoRESUMEN
Background: FSHD is a highly prevalent inherited myopathy with a still poorly understood pathology. Objective: To investigate whether proinflammatory cytokines are associated with FSHD and which specific innate immune cells are involved in its pathology. Methods: First, we measured circulating cytokines in serum samples: IL-6 (FSHD, nâ=â150; HC, nâ=â98); TNF (FSHD, nâ=â150; HC, nâ=â59); IL-1α (FSHD, nâ=â150; HC, nâ=â66); IL-1ß (FSHD, nâ=â150; HC, nâ=â98); MCP-1 (FSHD, nâ=â14; HC, nâ=â14); VEGF-A (FSHD, nâ=â14; HC, nâ=â14). Second, we tested trained immunity in monocytes (FSHD, nâ=â15; HC, nâ=â15) and NK cells (FSHD, nâ=â11; HC, nâ=â11). Next, we explored the cytokine production capacity of NK cells in response to different stimuli (FSHD, nâ=â39; HC, nâ=â22). Lastly, we evaluated the cytokine production of ex vivo stimulated MRI guided inflamed (TIRM+) and paired MRI guided non inflamed (TIRM-) muscle biopsies of 21 patients and of 8 HC muscle biopsies. Results: We included a total of 190 FSHD patients (Nâ=â190, 48±14 years, 49% men) and of 135 HC (Nâ=â135, 44±15 years, 47% men). We found that FSHD patients had higher concentrations of IL-6 and TNF measured (a) in the circulation, (b) after ex-vivo stimulation of NK cells, and (c) in muscle specimens. Besides, IL-6 circulating concentrations, as well as its production by NK cells and IL-6 content of FSHD muscle specimens, showed a mild correlation with disease duration, disease severity, and muscle weakness. Conclusion: These results show that IL-6 and TNF may contribute to FSHD pathology and suggest novel therapeutic targets. Additionally, the activation of NK cells in FSHD may be a novel pathway contributing to FSHD pathology.