THU0222 PLASMACYTOID DCS FROM PATIENTS WITH SJÖGREN’S SYNDROME ARE TRANSCRIPTIONALLY PRIMED FOR ENHANCED PRO-INFLAMMATORY CYTOKINE PRODUCTION
Authors: Maarten Hillen, Aridaman Pandit, Sofie Blokland, Sarita Ay Hartgring, Cornelis Bekker, Eefje van der Heijden, Nila Servaas, Marzia Rossato, Aike A. Kruize, Joel van Roon, Timothy R. Radstake
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> 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. <h3>Objectives:</h3> 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). <h3>Methods:</h3> 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. <h3>Results:</h3> 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 <i>in vitro</i> 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. <h3>Conclusion:</h3> 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. <h3>Disclosure of Interests:</h3> None declared