ReviewAutoantibodies to PAD4 and BRAF in rheumatoid arthritis
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
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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.
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