The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues.
Antifilaggrin autoantibodies (AFA) are a population of IgG autoantibodies associated to rheumatoid arthritis (RA), which includes the so-called "antikeratin" Abs and antiperinuclear factor. AFA are the most specific serological markers of RA. We previously showed that they recognize human epidermal filaggrin and other profilaggrin-related proteins of various epithelial tissues. Here, we report further characterization of the protein Ags and epitopes targeted by AFA. All the Ags that exhibit numerous neutral/ acidic isoelectric variants were immunochemically demonstrated to be deiminated proteins. In vitro deimination of a recombinant human filaggrin by a peptidylarginine deiminase generated AFA epitopes on the protein. Moreover, two of three filaggrin-derived synthetic peptides with a citrulline in the central position were specifically and widely recognized by AFA affinity-purified from a series of RA sera. These results indicate that citrulline residues are constitutive of the AFA epitopes, but only in the context of specific amino acid sequences of filaggrin. In competition experiments, the two peptides abolished the AFA reactivity of RA sera, showing that they present major AFA epitopes. These data should help in the identification of a putative deiminated AFA-inducing or cross-reactive articular autoantigen and provide new insights into the pathogenesis of RA. They could also open the way toward specific immunosuppressive and/or preventive therapy of RA.
Girbal-Neuhauser
E
E
Department of Biology and Pathology of the Cell, Institut National de la Santé et de la Recherche Médicale, Toulouse-Purpan School of Medicine, University Toulouse III, France.
Durieux
J J
JJ
Arnaud
M
M
Dalbon
P
P
Sebbag
M
M
Vincent
C
C
Simon
M
M
Senshu
T
T
Masson-Bessière
C
C
Jolivet-Reynaud
C
C
Jolivet
M
M
Serre
G
G
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D004817:Epidermis / Q000276:immunology; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000378:metabolism*; D000091344:Filaggrin Proteins; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D000939:Epitopes; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D011994:Recombinant Proteins; D002956:Citrulline; D001120:Arginine; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases