THU0222 PLASMACYTOID DCS FROM PATIENTS WITH SJÖGREN'S SYNDROME ARE TRANSCRIPTIONALLY PRIMED FOR ENHANCED PRO-INFLAMMATORY CYTOKINE PRODUCTION. (June 2019)

• Record Type: Journal Article
• Authors: Hillen, Maarten; Pandit, Aridaman; Blokland, Sofie; Hartgring, Sarita Ay; Bekker, Cornelis; Heijden, Eefje van der; Servaas, Nila; Rossato, Marzia; Kruize, Aike A.; Roon, Joel van; Radstake, Timothy R.
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 389
• Page End: 389
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.7019
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Type-I IFN activity is associated with pathogenesis and increased disease activity in primary Sjögren's syndrome (pSS). In addition, deficiency for the type-I IFN receptor in mice prevents experimental-Sjögren's syndrome. Plasmacytoid dendritic cells (pDC) are the premier type-I IFN producing immune cells and aberrances in their functional properties may underlie pSS immunopathology. Assessing the molecular basis of this may provide a better understanding of pSS pathogenesis and new opportunities for therapeutic intervention. Objectives: To delineate the dysregulation of pSS pDCs using RNA-sequencing and compare their transcriptional profile to pDCs obtained from patients with non-Sjögren's sicca (nSS) and healthy controls (HC). Methods: All pSS patients met the classification criteria. nSS patients presented with dryness complaints without a known cause, did not have any generalized autoimmune disease including pSS as evaluated by an experienced rheumatologist, and did not fulfil the classification criteria. pSS (n=25), nSS (n=20), and HC (n=17) donors were included in two independent cohorts (n=31 each). Circulating BDCA-4 expressing pDCs were isolated and RNA-sequencing was performed, after which data-driven networks and modular analysis were used to identify signatures of consistently differentially-expressed genes. pSS and HC pDCs were cultured in the presence of endosomal TLR ligands, after which gene expression and secreted cytokine levels were measured. Results: We identified signatures of consistently co-expressed and differentially expressed genes that indicated transcriptional activation in patient pDCs, which was remarkably reproducible in two independent cohorts. These included a type-I IFN-associated signature, a ribosomal protein signature, and a transcriptional machinery signature. Corroborating the transcriptomic profile, stimulated pSS pDCs produced higher levels of type-I interferon upon in vitro stimulation. nSS patients formed an intermediate group in which some patients were molecularly similar to pSS patients. Finally, we developed a discriminative classifier on the basis of the identified transcriptional profiles that discriminated pSS patients from HC with ∼100% sensitivity and ∼80% specificity, and identified a group of pSS-like patients within the nSS group. Conclusion: Circulating pSS pDCs exhibit a transcriptional signature similar to activated pDCs and are primed for enhanced production of pro-inflammatory cytokines, including type-I IFN. Our data provide in-depth characterization of the aberrant regulation of pSS pDCs and substantiate their perceived role in the immunopathology of pSS and other type-I interferon-associated autoimmune diseases. Disclosure of Interests: None declared