[Impact of citrullination upon antigenicity of fibrinogen].
OBJECTIVE
To investigate the impact of citrullination upon the antigenicity of fibrinogen peptides and explore the molecular mechanism of autoimmunity against citrullinated fibrinogen in the pathogenesis of rheumatoid arthritis (RA).


METHODS
Human fibrinogen was citrullinated in vitro by peptidylarginine deiminase (PAD). Stimulation of citrullinated fibrinogen on PBMC (peripheral blood mononuclear cell) from RA patients and controls was studied by measuring cellular proliferation. Then the bindings of peptides derived from fibrinogen alpha chain and its citrullinated substitute to HLA-DR4 molecule were analyzed by the prediction software. One peptide was chosen and its arginine residues were altered by citrulline residues. Wild-type and altered peptides were synthesized and their bindings to HLA-DR4 molecules examined by peptide binding assay respectively. The effects of two peptides upon T cells were determined by T cell proliferation assay.


RESULTS
Compared with controls, the cellular responses to citrullinated fibrinogen or wild protein were slightly higher in RA patients. However no statistical difference was found (P > 0.05). As predicted, the citrullinated substitute peptide from fibrinogen alpha chain was more prone to bind to HLA-DR4 molecule than wild-type peptide and could induce a stronger proliferation of T cells than wild-type peptide (SI, 2.26 +/- 0.14 vs 1.65 +/- 0.53, P < 0.01) in the experiments of cell lines.


CONCLUSIONS
Citrullination can enhance the antigenicity of fibrinogen peptides by increasing the binding of fibrinogen peptides to HLA-DR4 molecules and inducing the specific T cell activation.
Zhao
Yi
Y
Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China.
Tian
Xin
X
Li
Zhan-guo
ZG
D000328:Adult; D000368:Aged; D020816:Amino Acid Motifs; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002956:Citrulline / Q000276:immunology*; D005260:Female; D005340:Fibrinogen / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology
D015804:HLA-DR4 Antigen; D002956:Citrulline; D005340:Fibrinogen