Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Rheumatoid arthritis (RA) is characterized by development of humoral and cellular autoimmunity to citrullinated proteins and peptides. Autoimmunity to citrullinated antigens appears years before the onset of clinical symptoms of RA Neutrophil extracellular traps (NETs) are a source of citrullinated autoantigens and activate RA synovial fibroblasts (FLS), cells crucial in joint damage. We investigated the molecular mechanisms by which NETs promote proinflammatory phenotypes in FLS, and whether these interactions generate pathogenic anti-citrulline adaptive immune responses.
Methods: Shared epitope-positive RA FLS and control Osteoarthritis FLS were co-cultured with RA NETs and interactions visualized by confocal microscopy. Induction of inflammatory responses and MHC class II expression were assessed by qPCR. RA-FLS and Ag-specific RA T cells were co-cultured for 5 days and T cell activation was examined. HLADRB1*0401 transgenic mice were immunized with mouse FLS loaded with NETs or FLS alone. Antibodies to citrullinated proteins antigens (ACPAs) were quantified by ELISA, immunoblot and epitope mapping array. Cartilage integrity was assessed by safranin-O staining.
Results: NETs containing citrullinated peptides are internalized by FLS through a RAGE-TLR9 pathway promoting FLS inflammatory phenotype and their upregulation of MHC class II. Once internalized, arthritogenic citrullinated NET-peptides are loaded into FLS MHC class II and presented to Ag-specific T cells. HLADRB1*0401 transgenic mice immunized with mouse FLS loaded with NETs develop cartilage damage as well as ACPAs specific to citrullinated forms of relevant RA autoantigens implicated in disease pathogenesis.
Conclusion: These results suggest that NETs are a source of arthritogenic peptides in the synovium and implicate FLS as mediators in RA pathogenesis, through the internalization and presentation of citrullinated peptides to the adaptive immune system leading to pathogenic autoimmunity and cartilage damage.
To cite this abstract in AMA style:Carmona-Rivera C, Moore E, Lingampalli N, Uchtenhagen H, James E, Bicker KL, Wähämaa H, Hoffmann V, Catrina AI, Thompson P, Buckner JH, Robinson W, Fox D, Kaplan M. Synovial Fibroblast-Neutrophil Interactions Promote Pathogenic Adaptive Immunity in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/synovial-fibroblast-neutrophil-interactions-promote-pathogenic-adaptive-immunity-in-rheumatoid-arthritis/. Accessed April 17, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/synovial-fibroblast-neutrophil-interactions-promote-pathogenic-adaptive-immunity-in-rheumatoid-arthritis/