title: Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis.
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.
authors.affiliation: Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Romero
authors.forename: Justyna
authors.initials: J
authors.lastname: Fert-Bober
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nigrovic
authors.forename: Erika
authors.initials: E
authors.lastname: Darrah
authors.forename: Uzma J
authors.initials: UJ
authors.lastname: Haque
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.forename: Jennifer
authors.initials: J
authors.lastname: van Eyk
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.forename: Felipe
authors.initials: F
authors.lastname: Andrade
mesh_terms: D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology*; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism*; D003167:Complement Activation / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D009504:Neutrophils / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism
chemical_list: D001324:Autoantigens; D015938:Complement Membrane Attack Complex; D002956:Citrulline; D053804:Granzymes