Abstract
Autoantibodies against citrullinated proteins are a hallmark of rheumatoid arthritis, a destructive inflammatory arthritis. Peptidylarginine deiminase 4 (PAD4) has been hypothesized to contribute to rheumatoid arthritis by citrullinating histones to induce neutrophil extracellular traps (NETs), which display citrullinated proteins that are targeted by autoantibodies to drive inflammation and arthritis. Consistent with this theory, PAD4-deficient mice have reduced NETs, autoantibodies, and arthritis. However, PAD4′s role in human rheumatoid arthritis is less clear. Here, we determine if single nucleotide polymorphism rs2240335 in PADI4, whose G allele is associated with reduced PAD4 in neutrophils, correlates with NETs, anti-histone antibodies, and rheumatoid arthritis susceptibility in North Americans. Control and rheumatoid arthritis subjects, divided into anti-cyclic citrullinated peptide (CCP) antibody positive and negative groups, were genotyped at rs2240335. In homozygotes, in vitro NETosis was quantified in immunofluorescent images and circulating NET and anti-histone antibody levels by enzyme linked immunosorbent assay (ELISA). Results were compared by t-test and correlation of rheumatoid arthritis diagnosis with rs2240335 by Armitage trend test. NET levels did not significantly correlate with genotype. G allele homozygotes in the CCP− rheumatoid arthritis group had reduced anti-native and anti-citrullinated histone antibodies. However, the G allele conferred increased risk for rheumatoid arthritis diagnosis, suggesting a complex role for PAD4 in human rheumatoid arthritis.
Highlights
Rheumatoid arthritis is an autoimmune destructive arthritis with a lifetime risk of 2.6% [1]
There may be multiple sources of citrullinated antigens in rheumatoid arthritis, neutrophil extracellular traps (NETs), extracellular structures composed of chromatin and antimicrobial proteins, have been hypothesized to be a significant source based on observations that NETs are increased in rheumatoid arthritis and contain some of the same citrullinated proteins targeted by anti-citrullinated protein antibodies (ACPAs) [4,5,6]
We found that the G allele of rs2240335 does not correlate with NETs, but does correlate with reduced anti-histone antibodies and increased risk of rheumatoid arthritis, suggesting that Peptidylarginine deiminase 4 (PAD4) has a complex role in human rheumatoid arthritis
Summary
Rheumatoid arthritis is an autoimmune destructive arthritis with a lifetime risk of 2.6% [1]. In a murine model of rheumatoid arthritis, total IgG levels, autoantibodies, and arthritis are reduced in the absence of PAD4 [17]. These data suggest that PAD4 might contribute to the development of rheumatoid arthritis via enhanced NETosis and increased autoantibodies against histones driving disease. Despite the importance of PAD4 for NETosis and the theory that NETs provide citrullinated antigen in rheumatoid arthritis, citrullination is not reduced in the absence of PAD4 in serum, lungs, or joints in murine inflammatory arthritis [9,17,18]. The importance of PAD4 in human rheumatoid arthritis is unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
