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SP0004 Peptidyl arginine deiminase 4 and rheumatoid arthritis: from human genetics to murine models
  1. K Yamamoto1,2
  1. 1The University of Tokyo, Tokyo
  2. 2RIKEN, Yokohama, Japan

Abstract

We have previously reported that functional haplotypes of peptidyl arginine deiminase 4 (PADI4) are associated with rheumatoid arthritis (RA). We found that transcripts of the risk haplotype of PADI4 are more stable than those of the non-risk haplotypes, suggesting that increased expression and function of PAD4 (encoded by PADI4 gene) increase the risk of RA. The association has been confirmed by several studies with different ethnics. Further, we also reported PADI4 polymorphisms highly predispose male smokers to RA. Since PAD4 catalyzes an arginine residue in a protein to citrulline and anti-citrullinated protein antibodies (ACPA) are highly specific in RA, it has been reasonable to speculate that increased PAD4 is associated with increased citrullinated proteins, leading to the initiations of tolerance breakdown or inflammatory arthritis.

However, the mechanisms of PAD4 involvement turned out to be more complex than previously thought in animal models. In order to investigate the pathological process in detail, we made Padi4 knockout mice. Decreased severity of experimental autoimmune arthritis wad observed in these mice. Further, we found PAD4 regulates the pro-apoptotic fate of neutrophils, and promotes the expression of pro-inflammatory cytokines in macrophages. These actions could result in the pro-arthritic roles of PADI4. Recently, neutrophil extracellular traps (NETs) were reported as an important immune stimulator in RA and SLE, and PADI4 is required for the generation of NETs. Especially, NET-containing immune complex (IC) stimulated plasmacytoid dendritic cells to accelerate the interferon secretion in SLE. Therefore, PADI4 could play several different roles in the immune system and also in the pathogenesis of autoimmune diseases.

Disclosure of Interest None declared

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