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 α‐ and β‐chains of fibrin, their synovial target, requires conversion of their arginyl residues into citrullyl residues, but is also affected by thei...

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Bibliographic Details
Published in:European journal of immunology 2006-08, Vol.36 (8), p.2250-2263
Main Authors: Sebbag, Mireille, Moinard, Nathalie, Auger, Isabelle, Clavel, Cyril, Arnaud, Jacques, Nogueira, Leonor, Roudier, Jean, Serre, Guy
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Antibody Specificity
Anti‐citrullinated protein autoantibodies
Arthritis, Rheumatoid - immunology
Arthritis, Rheumatoid - metabolism
Autoantibodies - immunology
Citrulline
Citrulline - immunology
Citrulline - metabolism
Deimination
Enzyme-Linked Immunosorbent Assay
Epitopes - chemistry
Epitopes - immunology
Fibrin
Fibrin - chemistry
Fibrin - immunology
Fibrin - metabolism
Fibrinogen - chemistry
Fibrinogen - immunology
Fibrinogen - metabolism
Humans
Intermediate Filament Proteins - immunology
Intermediate Filament Proteins - metabolism
Life Sciences
Models, Molecular
Molecular Sequence Data
Protein Structure, Quaternary
Rheumatoid arthritis
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Summary:Formation of the epitopes recognized by the rheumatoid arthritis (RA)‐specific autoantibodies to citrullinated proteins (ACPA) on filaggrin and on the α‐ and β‐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 α‐ and β‐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.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.200535790