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Lookup NU author(s): Dr Faye Cooles, Gemma Vidal Pedrola, Najib NaamaneORCiD, Dr Arthur PrattORCiD, Dr Ben Barron-Millar, Dr Amy AndersonORCiD, Professor Catharien HilkensORCiD, John CasementORCiD, Dr Ruchi ShuklaORCiD, Professor John IsaacsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.Objective: Endogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in rheumatoid arthritis (RA). We investigated ERE expression in early RA (eRA), a period in which IFN-I levels are increased. Methods: ERE expression (long terminal repeat [LTR] 5, long interspersed nuclear element 1 [LINE-1], and short interspersed nuclear element [SINE]) in disease-modifying treatment-naïve eRA whole-blood and bulk synovial tissue samples was examined by reverse transcription–polymerase chain reaction and NanoString alongside IFN-α activity. Circulating lymphocyte subsets, including B cell subsets, from patients with eRA and early psoriatic arthritis (ePsA) were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data were reinterrogated to identify repeat elements, and associations were explored. Results: There was significant coexpression of all ERE classes and IFNA in eRA synovial tissue samples (n = 22, P < 0.0001) and significant positive associations between whole-blood LINE-1 expression (n = 56) and circulating IFN-α protein (P = 0.018) and anti–cyclic citrullinated peptide (anti-CCP) titers (P < 0.0001). ERE expression was highest in circulating eRA B cells, particularly naïve B cells compared with ePsA, with possible ERE regulation by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1 transcription (SAMDH1) implicated and associations with IFNA again observed. Finally, in established RA synovium, LTRs, particularly human endogenous retroviral sequence K (HERVK), were most increased in RA compared with OA, in which, for all synovial subsets (monocytes, B cells, T cells, and fibroblasts), ERE expression associated with increased IFN-I signaling (P < 0.001). Conclusion: Peripheral blood and synovial ERE expression is examined for the first time in eRA, highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.
Author(s): Cooles FAH, Vidal Pedrola G, Naamane N, Pratt AG, Barron-Millar B, Anderson AE, Hilkens CMU, Casement J, Bondet V, Duffy D, Zhang F, Shukla R, Isaacs JD
Publication type: Article
Publication status: Published
Journal: Arthritis and Rheumatology
Year: 2025
Pages: epub ahead of print
Online publication date: 16/12/2024
Acceptance date: 25/11/2024
Date deposited: 17/02/2025
ISSN (print): 2326-5191
ISSN (electronic): 2326-5205
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/art.43083
DOI: 10.1002/art.43083
Data Access Statement: Data availability statement and ethics statement The data are available for the purposes of academic research on reasonable request to the corresponding author. For the early disease data, all patients provided written, informed consent to participate in the study, which was approved by the Northeast – Newcastle and North Tyneside 2 Research Ethics Committee (12/NE/0251). For established RA and OA data, consent was obtained as previously outlined.
PubMed id: 39681508
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