Pos0431 pdgf-bb, tnf-α, and lt-β regulate follicular dendritic cell development in the rheumatoid synovium

BackgroundFollicular dendritic cells (FDCs) fundamentally contribute to the formation of synovial ectopic lymphoid-like structures in rheumatoid arthritis (RA) which is associated with poor clinical prognosis. Despite this critical role in RA pathogenesis, FDC development in the RA synovium has not been fully elucidated.ObjectivesTo investigate the role of TNF-α/LT-β and PDGF-BB in the ontogeny of RA synovial FDCs and the differentiation of lymphoid and fibroid RA synovitis.MethodsRA Synovial tissues were obtained from the Pathobiology of Early Arthritis Cohort (PEAC) of the Centre for Experimental Medicine and Rheumatology of Queen Mary University of London. RNA-Seq analysis and confocal imaging of early and late FDC differentiation markers were carried out and the stromal cell subsets were sorted by flow cytometry. The stromal cell subsets were treated with TNF-α/LT-β and/or PDGF-BB and the expression of FDC differentiation genes was assessed by qPCR. Germinal centre reactions were setup in vitro using TNF-α/LT-β activated stromal cells, and antibody production by naive human B cells stimulated with anti IgM was measured by ELISA.ResultsOur results indicate that PDGF-BB induces the FDC marker CNA.42+ on NG2+/αSMA+ type-1 pericytes, stimulates THY-1 and αSMA gene expression, and strongly correlates with fibroid synovitis using RNA-Seq analysis. On the other hand, TNF-α/LT-β downregulate PDGFR-β, THY-1, αSMA; induce CD21, FcɣRIIB expression, and significantly correlate with lymphoid synovial pathotype. Ultrastructural examination of antigen trapping on TNF-α/LT-β-activated RA synovial fibroblasts (RASFs) showed periodically retained surface antigens and these fibroblasts were able to induce T cell independent B cell activation in in vitro germinal centre reactions. The transition from an early PDGFR-β+ pre FDCs to a late TNF-α/LT-β-responsive mature FDCs is promoted by PDGF-BB. PDGF-BB induces TNF-αR expression in RASFs and facilitates B cell recruitment via pericyte CXCL13 expression and stromal cell migration.ConclusionTo the best of our knowledge, this is the first report describing the crosstalks between PDGF-BB and TNF-α/LT-β in FDC development in the rheumatoid synovium and its association with the evolution of lymphoid and fibroid synovitis. Selective targeting of this interplay could inhibit FDC differentiation and potentially ameliorate RA in clinically severe and drug-resistant patients.Disclosure of InterestsNone declared.