RT Journal Article
T1 Splicing machinery is impaired in rheumatoid arthritis, associated with disease activity and modulated by anti-TNF therapy
A1 Ibanez-Costa, Alejandro
A1 Perez-Sanchez, Carlos
A1 Patino-Trives, Alejandra Maria
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 Castano-Fuentes, Justo P.
A1 Luque, Raul M.
A1 Collantes-Estevez, Eduardo
A1 Lopez-Pedrera, Chary
K1 rheumatoid arthritis
K1 anti-citrullinated protein antibodies
K1 biological therapy
K1 tumor necrosis factor inhibitors
K1 Functional-significance
K1 Developmental disorder
K1 American-college
K1 Expression
K1 Variants
K1 Phosphorylation
K1 Autoimmunity
K1 Fibronectin
K1 Transcript
K1 Antibodies
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.
PB Bmj publishing group
SN 0003-4967
YR 2021
FD 2021-10-05
LK https://hdl.handle.net/10668/25884
UL https://hdl.handle.net/10668/25884
LA en
DS RISalud
RD Apr 17, 2025