Splicing machinery is impaired in rheumatoid arthritis, associated with disease activity and modulated by anti-TNF therapy
| Autor: | Antonio González, Chary López-Pedrera, Mª Angeles Aguirre, Raúl M. Luque, Rafaela Ortega Castro, Eduardo Collantes-Estevez, Nuria Barbarroja, Iván Arias de la Rosa, Carlos Perez-Sanchez, J. Calvo, A. M. Patiño-Trives, Carmen Conde, Alejandro Escudero-Contreras, M. D. C. Abalos-Aguilera, María Luque-Tévar, Mercedes del Rio-Moreno, Justo P Castano-Fuentes, Ricardo Blazquez-Encinas, P. Segui, Pilar Font, Cristóbal Román-Rodríguez, Sergio Pedraza-Arevalo, Alejandro Ibáñez-Costa |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Neutrophils tumor necrosis factor inhibitors Fc receptor Gene Expression Cell Cycle Proteins Anti-Citrullinated Protein Antibodies Monocytes Arthritis Rheumatoid Mice RNA Small Nuclear Synovial Fluid Immunology and Allergy Lymphocytes Cells Cultured biology Serine-Arginine Splicing Factors Anti–citrullinated protein antibody RNA-Binding Proteins Middle Aged Ribonucleoproteins Small Nuclear DNA-Binding Proteins biological therapy Rheumatoid arthritis Antirheumatic Agents Cytokines Tumor necrosis factor alpha Female RNA Splicing Factors medicine.symptom Antibody Adult Immunology Inflammation Rheumatoid Arthritis General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine Ribonucleoprotein U1 Small Nuclear Rheumatology medicine Synovial fluid Animals Humans Adaptor Proteins Signal Transducing business.industry Sequence Analysis RNA Tumor Necrosis Factor-alpha medicine.disease Splicing Factor U2AF Repressor Proteins Alternative Splicing Case-Control Studies biology.protein Spliceosomes RNA Citrullination business |
| Zdroj: | Annals of the Rheumatic Diseases |
| ISSN: | 1468-2060 |
| Popis: | ObjectivesTo characterise splicing machinery (SM) alterations in leucocytes of patients with rheumatoid arthritis (RA), and to assess its influence on their clinical profile and therapeutic response.MethodsLeucocyte subtypes from 129 patients with RA and 29 healthy donors (HD) were purified, and 45 selected SM elements (SME) were evaluated by quantitative PCR-array based on microfluidic technology (Fluidigm). Modulation by anti-tumour necrosis factor (TNF) therapy and underlying regulatory mechanisms were assessed.ResultsAn altered expression of several SME was found in RA leucocytes. Eight elements (SNRNP70, SNRNP200, U2AF2, RNU4ATAC, RBM3, RBM17, KHDRBS1 and SRSF10) were equally altered in all leucocytes subtypes. Logistic regressions revealed that this signature might: discriminate RA and HD, and anti-citrullinated protein antibodies (ACPAs) positivity; classify high-disease activity (disease activity score-28 (DAS28) >5.1); recognise radiological involvement; and identify patients showing atheroma plaques. Furthermore, this signature was altered in RA synovial fluid and ankle joints of K/BxN-arthritic mice. An available RNA-seq data set enabled to validate data and identified distinctive splicing events and splicing variants among patients with RA expressing high and low SME levels. 3 and 6 months anti-TNF therapy reversed their expression in parallel to the reduction of the inflammatory profile. In vitro, ACPAs modulated SME, at least partially, by Fc Receptor (FcR)-dependent mechanisms. Key inflammatory cytokines further altered SME. Lastly, induced SNRNP70-overexpression and KHDRBS1-overexpression reversed inflammation in lymphocytes, NETosis in neutrophils and adhesion in RA monocytes and influenced activity of RA synovial fibroblasts.ConclusionsOverall, we have characterised for the first time a signature comprising eight dysregulated SME in RA leucocytes from both peripheral blood and synovial fluid, linked to disease pathophysiology, modulated by ACPAs and reversed by anti-TNF therapy. |
| Databáze: | OpenAIRE |
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