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

Violeta Romero, Justyna Fert-Bober, Peter A. Nigrovic, Erika Darrah, Uzma J. Haque, David M. Lee, Jennifer Van Eyk, Antony Rosen, Felipe Andrade

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number209ra150
JournalScience translational medicine
Volume5
Issue number209
DOIs
StatePublished - Oct 30 2013

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Immune-mediated pore-forming pathways induce cellular hypercitrullination and generate citrullinated autoantigens in rheumatoid arthritis'. Together they form a unique fingerprint.

  • Cite this