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• W4379522873 abstract "Background Idiopathic inflammatory myopathies (IIM) are rare autoimmune systemic diseases characterized by muscle weakness and presence of muscle-infiltrating T cells. IIM represent a clinical challenge due to heterogeneity of symptoms and variability of response to immunosuppressive treatment. Objectives We aimed to explore the mechanisms involved in T cell migration and persistence in the muscle tissues of patients with IIM. Methods We performed single-cell RNA sequencing on muscle-infiltrating and peripheral blood (PB) memory T cells from patients with recently diagnosed IIM (n=7) from the Rheumatology Clinic, Karolinska University Hospital. Briefly, after enzymatic digestion of fresh muscle tissue, we single-cell sorted T cells from seven patients who also presented muscle infiltrates by histopathological analysis: immune-mediated necrotizing myopathy (IMNM) n=2; inclusion body myositis (IBM) n=2; dermatomyositis (DM) n=1; and antisynthetase syndrome (ASyS) n=1 and a non-inflammatory myopathy. Muscle T cells were sorted based on the co-expression of CD45 and CD3, whereas PB memory T cells were sorted based on the exclusion of naïve CD45RA + CCR7 + CD3 + T cells. We also aligned the TCR sequences. We had access to additional muscle and PB samples from two patients after immunosuppressive treatment. Description of the methodology is presented in Figure 1. Results After quality control, filtering, and normalization processes of the gene expression matrix, the total number of T cells recovered from the analysis was 2,844, out of which 1,427 were isolated from the muscle and 1,417 cells from PB. Muscle and PB T cells grouped separately indicating different gene signature. Three different clusters containing muscle T cells (cluster 1), PB CD8+ T cells (cluster 2) and PB CD4+ T cells (cluster 3) were identified, showing different transcriptomic signature between muscle and PB T cells. After unsupervised clustering of gene expression, we identified 15 distinct T-cell clusters annotated based on differentially expressed genes and visualized by UMAP. We found enrichment in the muscle compartment compared to blood for the following clusters: tissue-resident memory (T RM ) T cells, muscle central memory (CM) CD4+ T cells, muscle effector memory (EM)T cells, EGR1hi and T RM genes, and Tregs. All clusters were present in all patients except for the Tregs cluster, which was not detected in the patient with ASyS. A distinct signature between muscle T cells and blood memory T cells was revealed by the differential expression of genes involved in transcription, migration, dephosphorylation, cell cycle, metabolism, cytoskeleton and signalling. Additionally, expanded T-cell clones were observed in all patients’ muscle tissue, ranging between 20-50% of all TCR sequences. We could identify expanded T-cell clones persisting at follow-up in the muscle of one patient with IMNM and another with ASyS after immunosuppressive treatment. Conclusion Our study reveals a muscle T-cell signature in patients with IIM and a transcriptomic map to identify possible novel therapeutic targets in IIM, where muscle-infiltrating T cells are predominantly composed of cytotoxic, effector memory, tissue-resident, proliferating and regulatory T cells. The expression of tissue-resident memory (T RM ) receptors and the presence of clonally expanded T-cell clones in the muscle of all patients with IIM imply the role of these cells in disease pathogenesis. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests Angeles Shunashy Galindo-Feria: None declared, Alexandra Argyriou: None declared, Begum Horuluoglu: None declared, Juan Sebastian Díaz-Boada: None declared, Antonella Notarnicola: None declared, Lara Dani: None declared, Annika van Vollenhoven: None declared, Daniel Ramsköld: None declared, Inger Nennesmo: None declared, Maryam Dastmalchi: None declared, Ingrid E. Lundberg Shareholder of: Stock shares in Roche and Novartis., Paid instructor for: Has been serving on the advisory board for Corbus Pharmaceutical, EMD Serono. Research & Development Institute, Argenx, Octapharma, Pfizer, Kezaar, Orphazyme and Janssen, Consultant of: Corbus Pharmaceuticals, Inc, Grant/research support from: Astra Zeneca, Lina M. Diaz-Gallo: None declared, Karine Chemin: None declared." @default.
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• W4379522873 date "2023-05-30" @default.
• W4379522873 modified "2023-09-30" @default.
• W4379522873 title "POS0143 TISSUE RESIDENT MEMORY AND CYTOTOXIC T CELLS ARE CLONALLY EXPANDED IN THE MUSCLE OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHIES" @default.
• W4379522873 doi "https://doi.org/10.1136/annrheumdis-2023-eular.261" @default.
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