Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins.
Formation of the epitopes recognized by the rheumatoid arthritis (RA)-specific autoantibodies to citrullinated proteins (ACPA) on filaggrin and on the alpha- and beta-chains of fibrin, their synovial target, requires conversion of their arginyl residues into citrullyl residues, but is also affected by their amino-acyl environment. Using competition with five citrullinated filaggrin-derived peptides bearing major ACPA epitopes, we confirmed the close cross-reactivity between filaggrin and citrullinated fibrin. To identify the sequential epitopes recognized on fibrin by ACPA, 71 citrullinated 15-mer peptides derived from all the sites of the alpha- and beta-chains of fibrin harboring arginyl residues were tested by ELISA using ACPA-positive RA sera exhibiting different reactivity profiles to the five filaggrin peptides. We identified 18 fibrin-derived peptides bearing ACPA epitopes. Regarding the ability of fibrinogen arginyl residues to be citrullinated in vitro, 11 of the peptides likely correspond to in vivo targeted epitopes. Two out of them bear major epitopes and are located in the central globular domain of the protein. In the synovial tissue, fibrin citrullination and ACPA binding could impair fibrin degradation by plasmin. The immunological conflict between ACPA and fibrin could therefore sustain synovial inflammation not only via pro-inflammatory effector mechanisms but also via impairment of fibrinolysis.
Sebbag
Mireille
M
Laboratory of "Epidermis Differentiation and Rheumatoid Autoimmunity", UMR 5165 CNRS-Toulouse III University, IFR30 (CNRS-INSERM-Université Paul Sabatier-CHU de Toulouse), Toulouse, France.
Moinard
Nathalie
N
Auger
Isabelle
I
Clavel
Cyril
C
Arnaud
Jacques
J
Nogueira
Leonor
L
Roudier
Jean
J
Serre
Guy
G
D000595:Amino Acid Sequence; D000918:Antibody Specificity; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology*; D002956:Citrulline / Q000276:immunology* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005337:Fibrin / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D000091344:Filaggrin Proteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary
D001323:Autoantibodies; D000939:Epitopes; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D002956:Citrulline; D005337:Fibrin; D005340:Fibrinogen