[Peptidylarginine deiminase type4 (PADI4) role in immune system]

Abstract

Rheumatoid arthritis (RA) is one of the representative auto-immune diseases, characterized by systemic inflammatory synovitis. Various genetic and environmental factors which contribute to RA pathogenesis, has been suggested, however, detailed mechanism remained unknown. While around 100 genetic risk factors for RA have been reported, Peptidylarginine deiminase type4 (PADI4) was firstly identified as a non-MHC RA genetic risk factor. Furthermore, PADI4 risk allele possessed the association with bone damage regardless of anti citrullinated peptide antibody (ACPA) positivity in Asian RA patients. PADI4 gene codes PAD4 protein which has post-translational modification activity (citrullination). Padi4 is mainly expressed in myeloid cells and granulocytes. PADI4 RA risk haplotype showed an increase of mRNA stability, which resulted in excess translation into PAD4 protein. According to ACPA specificity for RA, increasing PADI4 mRNA stability suggested a hypothesis that excess expression of PAD4 induces a large amount of citrullinated protein, which causes the induction of ACPA. On the other hand, PADI4 has nuclear trans-locational signals and is associated with regulation of various gene expression and formation of neutrophil extracellular traps. These information provide the possibility that PADI4 contributes to not only excess citrullinated protein production, but also various roles in the immune system. We summarize PADI4 function in the immune system and discuss PADI4 roles in RA.