Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice.
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.
Hill
Jonathan A
JA
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada, N6A 5C1.
Bell
David A
DA
Brintnell
William
W
Yue
David
D
Wehrli
Bret
B
Jevnikar
Anthony M
AM
Lee
David M
DM
Hueber
Wolfgang
W
Robinson
William H
WH
Cairns
Ewa
E
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced* / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D000939:Epitopes / Q000276:immunology; D005260:Female; D005340:Fibrinogen / Q000737:chemistry / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D007249:Inflammation; D007596:Joints / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D040081:Protein Array Analysis; D011499:Protein Processing, Post-Translational; D013583:Synovial Membrane / Q000737:chemistry; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D000939:Epitopes; D015804:HLA-DR4 Antigen; D007074:Immunoglobulin G; D005340:Fibrinogen