Citrullinated proteins in rheumatoid arthritis.
Citrullinated proteins that are produced by enzymatic deimination of arginine residues in proteins by peptidylarginine deiminases (PADIs) are of particular interest in the pathogenesis of rheumatoid arthritis (RA). First, peptidylarginine deiminase type 4 (PADI4) gene, which codes one of the PADI enzyme isotypes, has a genetic variant that increases susceptibility to RA. The RA-susceptible variant of PADI4 seems to increase the risk of RA by increasing its enzymatic activity. Second, this post-translational protein modification unfolds proteins by loss of a positive charge in arginine residues, with a subsequent change in antigenicity of the self-proteins. Third, these citrullinated proteins are recognized by anti-citrullinated peptide antibodies that are the most RA-specific autoantibodies. Finally, the expression of the PADI enzyme, citrullination of proteins, and production of anti-citrullinated protein antibodies occur in synovium. These data suggest that citrullination of proteins by PADI is related to alteration of antigenicity of peptides and very closely linked to pathogenesis of RA autoimmunity.
Yamada
Ryo
R
Laboratory for Rheumatic Diseases, SNP Research Center, Riken, Yokohama, Japan. ryamada@src.riken.go.jp <ryamada@src.riken.go.jp>
Suzuki
Akari
A
Chang
Xiaotian
X
Yamamoto
Kazuhiko
K
D001120:Arginine / Q000737:chemistry; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D015551:Autoimmunity; D002956:Citrulline / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D006867:Hydrolases / Q000502:physiology*; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D013583:Synovial Membrane / Q000378:metabolism
D010455:Peptides; D002956:Citrulline; D001120:Arginine; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases