In the rat, citrullinated autologous fibrinogen is immunogenic but the induced autoimmune response is not arthritogenic.
Conversion of arginyl to citrullyl residues (citrullination) is essential for the formation of the epitopes recognized by rheumatoid arthritis (RA)-associated autoantibodies to citrullinated proteins (ACPA). ACPA are secreted by plasma cells of the rheumatoid synovial tissue where their major target, citrullinated fibrin, is abundant. Although numerous arguments suggest that ACPA play an important role in RA, their pathological relevance remains to be established. In the present study, we assessed the immunogenicity and arthritogenicity of complete Freund's adjuvant-emulsified autologous citrullinated (C-rFBG) or non-citrullinated (NC-rFBG) fibrinogen in Lewis (LEW) and Brown-Norway rats, which exhibit drastic differences in their susceptibility to induced autoimmune diseases. NC-rFBG induced no antibody response. In contrast, a single injection of C-rFBG induced an IgG response directed mainly to citrullinated determinants of rFBG. However, all rat strains remained devoid of clinical and histological signs of arthritis up to 3 months after C-rFBG inoculation. Next, in LEW rats, we tested whether autoimmunity to C-rFBG could aggravate acute ankle arthritis triggered by intra-articular injection of incomplete Freund's adjuvant (IFA). However, such arthritis evolved identically in the presence or absence of anti-C-rFBG autoantibodies. However, IFA-injected joints were devoid of citrullinated fibrin deposits. Therefore, citrullination allows breakdown of immunological tolerance but the autoimmune response developed is not spontaneously arthritogenic. Whether or not it can aggravate arthritis with citrullinated fibrin deposits remains to be evaluated.
Duplan
V
V
Laboratory of Epidermis Differentiation and Rheumatoid Autoimmunity, Unité Mixte de Recherche 5165, Centre National de la Recherche Scientifique, Université Paul Sabatier, Institut Fédératif de Recherche, 30, Toulouse, France.
Foulquier
C
C
Clavel
C
C
Al Badine
R
R
Serre
G
G
Saoudi
A
A
Sebbag
M
M
D000818:Animals; D001168:Arthritis / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D002956:Citrulline / Q000378:metabolism*; D004198:Disease Susceptibility; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005340:Fibrinogen / Q000276:immunology* / Q000378:metabolism; D006614:Hindlimb; D015151:Immunoblotting / Q000379:methods; D007074:Immunoglobulin G / Q000276:immunology; D007279:Injections, Subcutaneous; D007596:Joints / Q000276:immunology; D023421:Models, Animal; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew
D001323:Autoantibodies; D007074:Immunoglobulin G; D002956:Citrulline; D005340:Fibrinogen