Research ArticleRheumatoid Arthritis

Immune-Mediated Pore-Forming Pathways Induce Cellular Hypercitrullination and Generate Citrullinated Autoantigens in Rheumatoid Arthritis

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Science Translational Medicine  30 Oct 2013:
Vol. 5, Issue 209, pp. 209ra150
DOI: 10.1126/scitranslmed.3006869

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Costumed Targets in Rheumatoid Arthritis

Just as kids (and many adults) don their costumes for Halloween, proteins frequently change their appearance with posttranslational modifications. One such modification is citrullination, turning the amino acid arginine in a protein into the amino acid citrulline. However, citrullination can be either a trick or a treat: It helps control the expression of genes, but also makes the costumed proteins targets for the immune system, resulting in autoimmune diseases such as rheumatoid arthritis (RA). Now, Romero et al. find that RA-associated hypercitrullination may be induced by immune-mediated membrane pore-forming pathways.

Although antibodies to citrullinated protein antigens have been reported to be markers of RA, the mechanisms behind the production of citrullinated autoantigens have remained unclear. Here, the authors examined the citrullination pattern in RA-associated synovial fluid cells and found a cellular hypercitrullination not observed in either activated or dying neutrophils, another source of citrullinated proteins. They then found that this cellular hypercitrullination was induced by two immune-mediated changes in cell membrane: perforin and the complement membrane attack complex. This insight could lead to new approaches to treating RA.

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