Lee, David and Andrade, Felipe (2013) Cytotoxic cells induce cellular hypercitrullination and citrullinated autoantigen production via perforin. Science Translational Medicine.

Abstract

Autoantibodies to citrullinated protein antigens (ACPA) are specific markers of rheumatoid arthritis (RA). Although cellular 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 (SF) cells (predominantly neutrophils) have an unusual pattern of cellular citrullination (with striking citrullination of proteins across the broad range of molecular weights), which we term hypercitrullination. Cells exhibiting hypercitrullination show striking cleavage of substrates characteristic of extrinsic apoptotic cell death. Analysis of the effects of different activation and death stimuli that induce histone citrullination (including Fas and TNFα) shows that the cytotoxic granule pathway is the only inducer of extrinsic apoptosis which causes hypercitrullination. We show that this is mediated through the activity of perforin. Furthermore, perforin-induced hypercitrullination results in the production of citrullinated autoantigens recognized by autoantibodies in RA, while the pathways that induce histone citrullination in the absence of hypercitrullination do not. Together, our results focus on cytotoxic cell-induced hypercitrullination as a mechanism of production of citrullinated autoantigens in RA.

Item Type:	Article
Additional Information:	This work was performed on samples from my previous laboratory at BWH/HMS. No Novartis resources were utilized in these studies
Keywords:	Rheumatoid Arthritis Citrullination Cytotoxic T Cells
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9389