Elsevier

Autoimmunity Reviews

Volume 4, Issue 4, April 2005, Pages 201-206
Autoimmunity Reviews

Peptidylarginine deiminase type 4, anticitrullinated peptide antibodies, and rheumatoid arthritis

https://doi.org/10.1016/j.autrev.2004.11.002Get rights and content

Abstract

Anticitrullinated peptide antibodies seem to be one of the most clinically reliable serologic markers for rheumatoid arthritis (RA). A genetic approach revealed that one of the citrullinating enzymes has a RA-susceptible variant. Peptidyl citrullination alters the chemical character of peptides and, subsequently, their antigenicity as well. This change in antigenicity of self-peptides seems to invoke citrulline-related autoimmunity. Although the precise physiologic role of citrullination is still unknown, accumulating data indicate that citrullination has a definite role in biologic phenomena, along with other posttranslational protein modifications, such as methylation and phosphorylation. In RA synovial tissue, two of five PADI isotypes are known to be expressed, and their expression is regulated at multiple steps: transcription, translation, intracellular localization, and activation/inactivation of PADI proteins. Further investigations on citrulline and PADIs from various aspects will provide a more profound understanding of RA-related autoimmunity.

Introduction

Rheumatoid arthritis (RA) is one of the most common human systemic autoimmune diseases and is characterized by autoantibody production and synovial inflammation. The fact that autoantibody production against citrullinated proteins is highly specific to RA [1] and that peptidylarginine deiminase type 4 (PADI4), a gene encoding one of the citrullinating enzymes, is associated with RA [2], leads us to believe that citrullination by PADI is a fundamental phenomenon in RA. This paper reviews the role of anticitrullinated peptide antibody, citrullination, and PADI in RA.

Section snippets

Anticitrullinated peptide antibodies in RA

Although various autoantibodies can be detected in the sera of patients with RA, several of these autoantibodies have been reported to be more specific and to have higher positive predictive value for RA than others. Many highly RA-specific autoantibodies, such as antiperinuclear factor [3], antikeratin antibody [4], [5], [6], and anti-Sa antibody [7], have been found to recognize citrullinated peptides [8], [9], [10], [11], [12] Based on these findings, an enzyme-liked immunosorbent assay,

Citrulline and arginine

Citrulline is a noncoding native amino acid. It is a deiminated form of arginine. The biggest difference between arginine and citrulline is that arginine is one of the most basic amino acids and citrulline lacks the charged feature. The enzyme responsible for the conversion of peptidyl arginine to peptidyl citrulline is PADI [20]. Although some biological events, such as inflammation, apoptosis, trauma, aging, and gene expression regulation by histones, have been reported to be associated with

Summary

Studies on RA-specific autoantibodies have revealed that autoimmunity against citrulline-containing self-peptides is highly specific to RA and that measurement of the quantity of anti-CCP, one of the anticitrullinated peptide antibodies, is useful and reliable in rheumatology clinics. Along with the immunologic findings on citrullination, a genetic approach has identified a genetic connection between RA and PADI4, a specific gene encoding one of the citrullinating enzymes. Two mutually

Acknowledgment

We thank all the members of the Laboratory for Rheumatic Diseases, SRC, RIKEN, particularly Ms. K. Komakine for providing illustrations.

Take-home messages

  • Anticitrullinated peptide antibodies are the most reliable autoantibody for RA.

  • PADI enzymes produce peptidyl citrulline by deimination/demethylimination of arginine/methylarginine residues in proteins.

  • The physiologic role of peptidyl citrullination is still unknown.

  • PADI2, PADI4, and citrullinated proteins are present in synovial tissues from

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