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Anti‐GITR treatment in collagen‐induced arthritis results in enhanced epitope spreading and increased antibodies to citrullinated antigens
Author(s) -
Cozine Cassy,
BenBarak Maya,
Robinson William H.,
Holers V. Michael
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1068.16
Subject(s) - autoantibody , epitope , immunology , medicine , antigen , effector , rheumatoid arthritis , antibody , arthritis , autoimmunity , type ii collagen
Patients with rheumatoid arthritis display highly specific autoantibodies to citrullinated protein Ags (ACPA). We previously demonstrated that pathogenic ACPA develop in collagen‐induced arthritis, but the mechanisms of ACPA generation and regulation remain unknown. We hypothesized that effector and/or regulatory T cells (Tregs) play a role in the generation of ACPA. DBA1/J mice were immunized with bovine type II collagen (bCII) in CFA followed by a booster of bCII in IFA. Treg and T effector cells were modified by treating mice with either anti‐CD25 or anti‐GITR mAb. Anti‐GITR treated mice exhibited a significant increase in clinical disease activity. While none of the treatment groups demonstrated a change in autoantibody levels to bovine or murine type II collagen, ACPA titers were significantly elevated in anti‐GITR treated mice. Synovial antigen arrays further demonstrated that anti‐GITR treatment led to an increase in epitope spreading to citrullinated and non‐citrullinated Ags. Furthermore, splenocytes from anti‐GITR treated mice showed an increased proliferative response to bCII and citrullinated peptide. These results suggest that co‐stimulatory effects of anti‐GITR on effector T cells drive autoreactive T cells to expand subsets of pathogenic autoantibodies, particularly ACPA. This work was supported by: NIH R01 AR51749.