Elsevier

Autoimmunity Reviews

Volume 11, Issue 11, September 2012, Pages 801-803
Autoimmunity Reviews

Review
Autoantibodies to PAD4 and BRAF in rheumatoid arthritis

https://doi.org/10.1016/j.autrev.2012.02.009Get rights and content

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes cartilage and bone destruction. The mechanisms leading to RA are unknown. There is currently no reliable cure for RA. Early treatment can reduce inflammation, joint damage and bone destruction. Thus, early diagnosis of RA is critical.

However, definitive diagnosis of RA can be difficult. Immunologic tests that can be performed for the diagnosis of RA include detection of anti citrullinated protein antibodies (ACPAs). However, one third of RA patients have no ACPAs.

To identify new autoantibodies in RA, we used the sera of RA patients to screen protein arrays containing 8000 human proteins. We found and validated two major autoantigens: PAD4 (peptidyl arginine deiminase 4) and BRAF (v raf murine sarcoma viral oncogene homolog B1) catalytic domain. We identified peptide targets of anti PAD4 and BRAF autoantibodies. We observed that anti PAD4 are inhibitory whereas anti BRAF stimulate BRAF activity. Anti PAD4 and anti BRAF antibodies may be used to diagnose RA, particularly in the absence of anti citrullinated protein antibodies.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with a prevalence of 1% worldwide [1]. Although RA has been extensively studied, its cause is unknown. RA is an autoantibody mediated disease. Among the various autoantibodies known in RA, autoantibodies to citrullinated proteins (ACPA) are highly specific [2], [3]. Citrulline is generated by post translational conversion of arginine residues. This process is catalyzed by a group of calcium dependent peptidyl arginine deiminases (PAD) [4]. One of the PAD enzymes, PAD4, is genetically associated with development of RA in Asian populations [5], [6], [7], [8].

Section snippets

Identification of anti-PAD4 and anti-BRAF autoantibodies

ACPA recognize citrulline on different proteins like filaggrin, vimentin or fibrin [9], [10], [11], [12]. ACPAs are detected by a commercial enzyme-linked immunoabsorbent assay containing synthetic cyclic citrullinated peptides (anti CCP). Anti CCP antibodies identify 2/3 of RA patients. The specificity is 97% against rheumatic diseases other than RA and 99% against healthy individuals. However, a negative result in anti-CCP antibody testing does not exclude RA.

To identify new autoantibodies in

Functional effects of anti-PAD4 and anti-BRAF autoantibodies

Finally, we found that autoantibodies to PAD4 and BRAF influence their enzymatic activities.

For PAD4, we developed a citrullination assay using PAD4, fibrinogen and autoantibodies to PAD4 purified from RA patients' sera. We observed that autoantibodies to PAD4 inhibit the citrullination of fibrinogen by PAD4. Anti-PAD4 immunization may influence anti citrulline immunization by modifying the number of citrulline residues available on antigens, thus producing new B cell epitopes for recognition

Take-home message

  • Autoantibodies to PAD4 or BRAF peptides may help diagnosis of rheumatoid arthritis.

Acknowledgments

This work was supported by grants from INSERM, Arthritis Fondation Courtin and Société Française de Rhumatologie.

References (27)

  • T. Cantaert et al.

    Functional haplotypes of PADI4: relevance for rheumatoid arthritis specific synovial intracellular citrullinated proteins and anti citrullinated protein antibodies

    Ann Rheum Dis

    (2005)
  • M. Simon et al.

    The cytokeratin filament aggregating protein filaggrin is the target of the so called “antikeratin antibodies,” autoantibodies specific for rheumatoid arthritis

    J Clin Invest

    (1993)
  • E. Girbal-Neuhauser et al.

    The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues

    J Immunol

    (1999)
  • Cited by (0)

    View full text