Abstract
IntroductionBoth 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.MethodsPAD4 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.ResultsPAD4 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.ConclusionsPAD4 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.
Highlights
Both murine and human genome-wide association studies have implicated peptidyl arginine deiminase (PAD4) as a susceptibility gene in rheumatoid arthritis (RA)
Our results suggest that PAD4 activity and subsequent neutrophil extracellular trap (NET) formation is present in the K/BxN serum transfer model, but is not required for this model of effector phase of disease
NET formation is known to correlate with inflammatory disease [28,32,33,52,53], NET formation has not been reported in RA
Summary
Both murine and human genome-wide association studies have implicated peptidyl arginine deiminase (PAD4) as a susceptibility gene in rheumatoid arthritis (RA). There are five PAD family members, but only PAD2 and PAD4 expression are closely linked with inflammation in RA synovial tissue [1,2]. Plasma and synovial biopsy specimens from patients with RA contain high levels of citrullinated proteins [5,6], and PAD4 shows elevated expression in RA [1,9], and RA patients generate high affinity anti-PAD4 autoantibodies which correlate with more severe disease [10,11,12]. The development of autoantibodies to citrullinated epitopes and PAD4 and elevated PAD4 expression in RA, suggests that aberrant PAD activity may contribute to disease pathogenesis
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