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¹ Department of Microbiology and Immunology and ² Department of Medicine, University of Western Ontario, London, Ontario, Canada, N6A 5C1
³ Division of Rheumatology, ⁴ Department of Pathology, and ⁵ Division of Nephrology, London Health Sciences Centre, London, Ontario, Canada, N6A 5A5
⁶ Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02215
⁷ Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA 94305
⁸ Veterans Affairs Palo Alto Health Care System, Geriatric Research Education and Clinical Centers, Palo Alto, CA 94304

CORRESPONDENCE Ewa Cairns: ecairns{at}uwo.ca

Rheumatoid arthritis (RA) is a common autoimmune disease that afflicts the synovium of diarthrodial joints. The pathogenic mechanisms inciting this disease are not fully characterized, but may involve the loss of tolerance to posttranslationally modified (citrullinated) antigens. We have demonstrated that this modification leads to a selective increase in antigenic peptide affinity for major histocompatibility complex (MHC) class II molecules that carry the RA-associated shared epitope, such as HLA-DRB1*0401 (DR4). We describe the induction of arthritis in DR4-IE transgenic (tg) mice with citrullinated fibrinogen, a protein commonly found in inflamed synovial tissue and a frequent target of autoantibodies in RA patients. The disease induced in these mice was characterized by synovial hyperplasia followed by ankylosis, but lacked a conspicuous polymorphonuclear cell infiltrate. Immunological analysis of these mice through T cell epitope scanning and antibody microarray analysis identified a unique profile of citrulline-specific reactivity that was not found in DR4-IE tg mice immunized with unmodified fibrinogen or in wild-type C57BL/6 mice immunized with citrullinated fibrinogen, two conditions where arthritis was not observed. These observations directly implicate citrullinated fibrinogen as arthritogenic in the context of RA-associated MHC class II molecules.

J.A. Hill's present address is Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA 02215.

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