Development of inflammatory arthritis in DR4 transgenic and wild type DBA/1J mice immunized with human fibrinogen (49.9)

Abstract

Abstract The human MHC allele DR4 is associated with susceptibility for rheumatoid arthritis (RA). Citrullinated proteins, derived from the conversion of peptidyl-arginine to peptidyl-citrulline, are present in the joints of RA patients, who also uniquely produce high levels of anti-citrullinated protein antibodies (ACPAs). ACPAs enhance damage in animal models of autoimmune arthritis. DR4 molecules have been shown to preferentially bind citrullinated peptides over arginine controls. Recently, the DR4 allele was shown to be essential to develop arthritis in C57Bl/6 mice immunized with human citrullinated fibrinogen, but these mice demonstrated delayed arthritis at relatively low incidence and severity as compared to other arthritis models. To potentially obtain a more susceptible strain, we backcrossed the DR4 gene onto the DBA1/J strain. Following immunization with either human citrullinated or noncitrullinated fibrinogen, these mice developed inflammatory arthritis around day 24 regardless of whether they were DR4+ or DR4- littermates. Serum from both strains demonstrated ACPA generation as defined by reactivity to a citrullinated but not control peptide, as well as a splenic proliferative response to both citrullinated and noncitrullinated human, but not mouse, fibrinogen. The DR4 DBA/1J transgenic strain may provide a useful tool for the analysis of ACPA-related arthritis. Grant U19 AI146374