title: Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis.
abstract: OBJECTIVE
  Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)-specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti-PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti-PAD-4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD-4 polymorphisms influence the anti-PAD-4 autoantibody response.
  
  
  METHODS
  Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti-PAD-4 autoantibodies by immunoprecipitation of in vitro-translated PAD-4. The epitope(s) recognized by PAD-4 autoantibodies were mapped using various PAD-4 truncations. PAD-4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method.
  
  
  RESULTS
  PAD-4 autoantibodies were found in 36-42% of RA patients, and were very infrequent in controls. Recognition by anti-PAD-4 autoantibodies required the 119 N-terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti-PAD-4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti-PAD-4 antibodies were associated with more severe joint destruction in RA.
  
  
  CONCLUSIONS
  Our findings indicate that anti-PAD-4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti-PAD-4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation.
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Harris
authors.forename: Erika
authors.initials: E
authors.lastname: Darrah
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Lam
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Bartlett
authors.forename: Jon T
authors.initials: JT
authors.lastname: Giles
authors.forename: Audrey V
authors.initials: AV
authors.lastname: Grant
authors.forename: Peisong
authors.initials: P
authors.lastname: Gao
authors.forename: William W
authors.initials: WW
authors.lastname: Scott
authors.forename: Hani
authors.initials: H
authors.lastname: El-Gabalawy
authors.forename: Livia
authors.initials: L
authors.lastname: Casciola-Rosen
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.forename: Joan M
authors.initials: JM
authors.lastname: Bathon
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D015551:Autoimmunity; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D012720:Severity of Illness Index
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases