title: PAD4 is not essential for disease in the K/BxN murine autoantibody-mediated model of arthritis.
abstract: BACKGROUND
  Both murine and human genome-wide association studies have implicated peptidyl arginine deiminase (PAD4) as a susceptibility gene in rheumatoid arthritis (RA). In addition, patients with RA commonly have autoantibodies which recognize PAD4 or and/or citrullinated peptides. This study aims to evaluate the role of PAD4 in the effector phase of arthritis.
  
  
  METHODS
  PAD4 knock out (KO) and wild type (WT) C57BL/6J mice were injected with K/BxN sera to induce disease. Progression of disease was monitored by measuring paw and ankle swelling and clinical indexes of disease, and pathogenesis was assessed by indexing of clinical progression on paws collected from WT and PAD4 KO mice injected with K/BxN serum. PAD4 activity was determined by visualization of neutrophil extracellular traps (NETs) and immunohistological analysis of histone citrullination.
  
  
  RESULTS
  PAD4 activity is readily detectable in the inflamed synovium of WT but not PAD4 deficient animals, as demonstrated by histone citrullination and NET formation. However, PAD4 WT and KO animals develop K/BxN serum transfer disease with comparable severity and kinetics, with no statistically significant differences noted in clinical scores, swelling, joint erosion or joint invasion.
  
  
  CONCLUSIONS
  PAD4 WT and KO mice develop disease in the K/BxN serum transfer model of arthritis with similar severity and kinetics, indicating that PAD4 is dispensable in this effector phase model of disease.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Rohrbach
authors.forename: Saskia
authors.initials: S
authors.lastname: Hemmers
authors.forename: Sanja
authors.initials: S
authors.lastname: Arandjelovic
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Mowen
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D001323:Autoantibodies / Q000633:toxicity; D004195:Disease Models, Animal; D006867:Hydrolases / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D007596:Joints / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D000080002:Protein-Arginine Deiminase Type 4
chemical_list: D001323:Autoantibodies; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse