Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis

Michelle L. Harris, Erika Darrah, Gordon K. Lam, Susan J. Bartlett, Jon T. Giles, Audrey V. Grant, Peisong Gao, William W Scott, Hani El-Gabalawy, Livia Casciola-Rosen, Kathleen C. Barnes, Joan M. Bathon, Antony Rosen

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


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. Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)1958-1967
Number of pages10
JournalArthritis and rheumatism
Issue number7
StatePublished - Jul 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)


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