title: 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.
authors.affiliation: Division of Rheumatology, The Johns Hopkins University, School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Darrah
authors.forename: Jon T
authors.initials: JT
authors.lastname: Giles
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Ols
authors.forename: Herbert G
authors.initials: HG
authors.lastname: Bull
authors.forename: Felipe
authors.initials: F
authors.lastname: Andrade
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
mesh_terms: D000906:Antibodies / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D001224:Aspartic Acid / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D002118:Calcium / Q000494:pharmacology*; D003429:Cross Reactions / Q000276:immunology; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007596:Joints / Q000473:pathology; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D006657:Histones; D001224:Aspartic Acid; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D002118:Calcium