[Frontiers in Bioscience 10, 54-64, January 1, 2005]

[Frontiers in Bioscience 10, 54-64, January 1, 2005]

CITRULLINATED PROTEINS IN RHEUMATOID ARTHRITIS

Ryo Yamada ¹, Akari Suzuki ¹, Xiaotian Chang ¹ and Kazuhiko Yamamoto ^{1, 2}

1 Laboratory for Rheumatic Diseases, SNP Research Center, Riken, Yokohama, Japan, ² Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Citrullination: post-translational deimination of arginine residues: 3.1. Citrulline and arginine; 3.2. Peptidylarginine deiminase (PADI); 3.3. Citrullination: physiologic function and effects on protein structure
4. RA-related phenomena regarding citrullination and padi: 4.1. Anti-citrullinated peptide antibody; 4.2. RA-susceptible variant in the PADI4 gene; 4.3. Citrullination and autoimmune reaction to citrullinated proteins in arthritic synovial tissue
5. Summary and perspective
6. Acknowledgments
7. References

1. ABSTRACT

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.