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Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis

Romero, V and Fert-Bober, J and Nigrovic, PA and Darrah, E and Haque, UJ and Lee, DM and Van, EJ and Rosen, A and Andrade, F (2013) Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis. Science Translational Medicine.

Abstract

Autoantibodies to citrullinated protein antigens are specific markers of rheumatoid arthritis (RA). Although protein citrullination can be activated by numerous stimuli in cells, it remains unclear which of these produce the prominent citrullinated autoantigens targeted in RA. In these studies, we show that RA synovial fluid cells have an unusual pattern of citrullination with marked citrullination of proteins across the broad range of molecular weights, which we term cellular hypercitrullination. Although histone citrullination is a common event during neutrophil activation and death induced by different pathways including apoptosis, NETosis, and necroptosis/autophagy, hypercitrullination is not induced by these stimuli. However, marked hypercitrullination is induced by two immune-mediated membranolytic pathways, mediated by perforin and the membrane attack complex (MAC), which are active in the RA joint and of importance in RA pathogenesis. We further demonstrate that perforin and MAC activity on neutrophils generate the profile of citrullinated autoantigens characteristic of RA. These data suggest that activation of peptidylarginine deiminases during complement and perforin activity may be at the core of citrullinated autoantigen production in RA. These pathways may be amenable to monitoring and therapeutic modulation

Item Type: Article
Additional Information: pubid: 116 nvp_institute: NIBR contributor_address: (Romero, Darrah, Haque, Rosen, Andrade) Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, United States (Fert-Bober, Van Eyk) Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, United States (Nigrovic, Lee) Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham, Canada (Nigrovic) Women's Hospital, Harvard Medical School, Boston, MA 02115, United States (Nigrovic) Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, United States (Rosen) Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, United States (Lee) Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/21954

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