Synovial Fibroblast-Neutrophil Interactions Promote Pathogenic Adaptive Immunity in Rheumatoid Arthritis

Carmelo Carmona-Rivera¹, Erica Moore², Nithya Lingampalli³, Hannes Uchtenhagen⁴, Eddie James⁵, Kevin L. Bicker⁶, Heidi Wähämaa⁷, Victoria Hoffmann⁸, Anca I Catrina⁷, Paul Thompson⁹, Jane H. Buckner⁵, William Robinson¹⁰, David Fox¹¹ and Mariana Kaplan², ¹Systemic Autoimmunity Branch/ NIAMS, National Institutes of Health, Bethesda, MD, ²Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ³Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, ⁴Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, ⁵Benaroya Research Institute at Virginia Mason, Seattle, WA, ⁶Middle Tennessee State University, Murfreesboro, TN, ⁷Rheumatology Unit, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden, ⁸Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, ⁹University of Massachusetts, Worcester, MA, ¹⁰Stanford University School of Medicine, Stanford, CA, ¹¹Department of Medicine [Division of Rheumatology], University of Michigan, Ann Arbor, MI

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Autoimmunity, citrullinated vimentin and rheumatoid arthritis (RA), Neutrophil Extracellular Traps

Session Information

Date: Sunday, November 13, 2016

Session Title: Rheumatoid Arthritis – Human Etiology and Pathogenesis - Poster I

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.

Disclosure: C. Carmona-Rivera, None; E. Moore, None; N. Lingampalli, None; H. Uchtenhagen, None; E. James, None; K. L. Bicker, Rh-PG probe, 9; H. Wähämaa, None; V. Hoffmann, None; A. I. Catrina, None; P. Thompson, Padlock Therapeutics, 1,Janssen Pharmaceutica Product, L.P. and Padlock Therapeutics, 2,Padlock Therapeutics, 5,Padlock Therapeutics, 6; J. H. Buckner, None; W. Robinson, None; D. Fox, None; M. Kaplan, None.

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 September 25, 2020.

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