RT Journal Article
SR Electronic
T1 Splicing machinery is impaired in rheumatoid arthritis, associated with disease activity and modulated by anti-TNF therapy
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 56
OP 67
DO 10.1136/annrheumdis-2021-220308
VO 81
IS 1
A1 Ibáñez-Costa, Alejandro
A1 Perez-Sanchez, Carlos
A1 Patiño-Trives, Alejandra María
A1 Luque-Tevar, Maria
A1 Font, Pilar
A1 Arias de la Rosa, Ivan
A1 Roman-Rodriguez, Cristobal
A1 Abalos-Aguilera, Mª Carmen
A1 Conde, Carmen
A1 Gonzalez, Antonio
A1 Pedraza-Arevalo, Sergio
A1 del Rio-Moreno, Mercedes
A1 Blazquez-Encinas, Ricardo
A1 Segui, Pedro
A1 Calvo, Jerusalem
A1 Ortega Castro, Rafaela
A1 Escudero-Contreras, Alejandro
A1 Barbarroja, Nuria
A1 Aguirre, Mª Angeles
A1 Castaño, Justo P
A1 Luque, Raul M
A1 Collantes-Estevez, Eduardo
A1 Lopez-Pedrera, Chary
YR 2022
UL http://ard.bmj.com/content/81/1/56.abstract
AB Objectives To 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.Methods Leucocyte 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.Results An 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.Conclusions Overall, 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.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. It would be also available from the corresponding author upon reasonable request.