Citrullination (deimination is an enzymatic, posttranslational conversion of arginine residues to citrulline residues) of joint-associated self-proteins may be a possible mechanism in the induction of autoimmune CD4 T-cell responses in rheumatoid arthritis. We have studied the immune response to normal or deiminated human fibrinogen (hFBG) in mouse strains expressing major histocompatibility complex (MHC) class II antigens similar to either RA-susceptible or non-susceptible HLA-DR4 alleles. Upon immunization with deiminated hFBG, all mouse strains analysed produced high amounts of anti-FBG antibodies, while relatively low levels of anti-citrulline antibodies and little or no anti-FBG antibodies crossreactive with mouse FBG (mFBG) were obtained. Mice immunized with normal hFBG also produced high amounts of anti-hFBG antibodies. However, whereas mice with MHC class II molecules similar to RA-non-susceptible HLA-DR4 alleles produced low levels of anti-hFBG antibodies with crossreactivity to mFBG, mouse strains with RA-susceptible HLA-DR4-equivalent MHC class II molecules contained high levels of such crossreactive anti-mFBG antibodies. Similar results were obtained with HLA-DR4*0401, human CD4-double-transgenic mice. However, none of the more than 600 mice investigated developed arthritis. These data indicate that the quality and/or quantity of anti-FBG autoantibodies or of anti-citrulline antibodies, produced in the studied mouse strains, are insufficient to induce arthritis.