Abstract
BackgroundAntibodies binding to cartilage proteins are present in the blood and synovial fluid of early rheumatoid arthritis patients. In order to develop animal models mimicking the human disease, we have characterized the arthritogenic capacity of monoclonal antibodies directed towards different joint proteins in the cartilage.MethodsPurified antibodies specific to unmodified or citrullinated collagen type II (CII), collagen type XI (CXI), and cartilage oligomeric matrix protein (COMP) were produced as culture supernatant, affinity purified, pooled as antibody cocktails (Cab3 and Cab4), and injected intravenously into mice to induce arthritis. An adjuvant (lipopolysaccharide or mannan) was subsequently injected intraperitoneally on either day 5 or day 60 to enhance arthritis. Antibody binding and complement activation on the cartilage surface were analyzed by immunohistochemical methods. Bone erosions and joint deformations were analyzed by histological assessments, enzyme-linked immunosorbent assays, and micro-CT. Luminex was used to detect CII-triple helical epitope-specific antibody responses.ResultsThe new cartilage antibody cocktails induced an earlier and more severe disease than anti-CII antibody cocktail. Many of the mouse strains used developed severe arthritis with 3 antibodies, binding to collagen II, collagen XI, and cartilage oligomeric matrix protein (the Cab3 cocktail). Two new models of arthritis including Cab3-induced LPS-enhanced arthritis (lpsCAIA) and Cab3-induced mannan-enhanced arthritis (mCAIA) were established, causing severe bone erosions and bone loss, as well as epitope spreading of the B cell response. Cab4, with addition of an antibody to citrullinated collagen II, induced arthritis more efficiently in moderately susceptible C57BL/6 J mice.ConclusionsThe new mouse model for RA induced with cartilage antibodies allows studies of chronic development of arthritis and epitope spreading of the autoimmune response and bone erosion.
Highlights
Antibodies binding to cartilage proteins are present in the blood and synovial fluid of early rheumatoid arthritis patients
Autoreactivity of selected cartilage-specific antibodies In order to improve the experimental models of antibody-induced arthritis in mice, we selected four different cartilage-binding antibodies: M2139 binding to collagen type II (CII), 15A11 binding to cartilage oligomeric matrix protein (COMP), L10D9 binding to collagen type XI (CXI), and ACC1 binding to citrullinated CII (Table 1)
These antibodies were selected based on their high efficiency to induce arthritis and that they all bind to cartilage in vivo [23, 25, 28, 36, 37]
Summary
Antibodies binding to cartilage proteins are present in the blood and synovial fluid of early rheumatoid arthritis patients. In order to develop animal models mimicking the human disease, we have characterized the arthritogenic capacity of monoclonal antibodies directed towards different joint proteins in the cartilage. Autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), develop in three distinct stages: priming, onset, and chronicity [1]. The Ncf locus has so far not been included in genome-wide association studies due to extensive and variable duplications of the Ncf gene in humans Both a specific single-nucleotide polymorphism leading to lower reactive oxygen species (ROS) production and a copy number variation polymorphism are associated with SLE and RA [6,7,8]
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