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Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity.

ABSTRACT: Peptidylarginine deiminases (PADs) play a critical role in generating autoantigens in rheumatoid arthritis (RA), but the mechanisms underlying their dysregulation in this disease remain unknown. Although PADs require supraphysiologic concentrations of calcium for activity in vitro, the enzymes are active in vivo (for example, in RA synovial fluid) where calcium concentrations are much lower. We have discovered a subset of anti-PAD4 autoantibodies (identified by their cross-reactivity with PAD3) that markedly increase the catalytic efficiency of PAD4 by decreasing the enzyme's requirement for calcium into the physiologic range. Patients with these PAD3/PAD4 cross-reactive autoantibodies had higher baseline radiographic damage scores and a higher likelihood of radiographic progression compared to individuals negative for these antibodies. The ability of autoantibodies to activate an enzyme that itself generates citrullinated autoantigens identifies an important feed-forward loop, which may drive the erosive outcome observed in RA patients with these autoantibodies. PAD3 autoantibodies may therefore identify RA patients who would benefit from early aggressive treatment or addition of PAD inhibitor therapy.

SUBMITTER: Darrah E

PROVIDER: S-EPMC3740946 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity.

Darrah Erika E Giles Jon T JT Ols Michelle L ML Bull Herbert G HG Andrade Felipe F Rosen Antony A

Science translational medicine 20130501 186

Peptidylarginine deiminases (PADs) play a critical role in generating autoantigens in rheumatoid arthritis (RA), but the mechanisms underlying their dysregulation in this disease remain unknown. Although PADs require supraphysiologic concentrations of calcium for activity in vitro, the enzymes are active in vivo (for example, in RA synovial fluid) where calcium concentrations are much lower. We have discovered a subset of anti-PAD4 autoantibodies (identified by their cross-reactivity with PAD3) ...[more]

PMID: 23698378

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Project description:BACKGROUND: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. METHODS:Purified 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. RESULTS:The 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. CONCLUSIONS:The 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.

Dataset Information

Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity.

Publications

Erosive rheumatoid arthritis is associated with antibodies that activate PAD4 by increasing calcium sensitivity.

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