Anti-peptidylarginine deiminase-4 antibodies at mucosal sites can activate peptidylarginine deiminase-4 enzyme activity in rheumatoid arthritis

M. Kristen Demoruelle, Hong Wang, Ryan L. Davis, Ashley Visser, Johnny Hoang, Jill M. Norris, V. Michael Holers, Kevin D. Deane, Erika Darrah Darrah

Research output: Contribution to journalArticlepeer-review


Background: Mucosal sites are hypothesized to play a role in the development of rheumatoid arthritis (RA). Since serum anti-peptidylarginine deiminase (PAD)4 antibodies, including a subset that cross-react with PAD3 (PAD3/4), are specific for RA and associate with severe disease, we sought to examine whether anti-PAD4 and anti-PAD3/4 antibodies were present in the lung and oral mucosa of subjects with RA and “at-risk” for RA. Methods: We included 37 RA, 25 healthy control, and 46 subjects “at-risk” for RA based on familial RA and/or serum anti-citrullinated protein antibody (ACPA) positivity. Paired serum, sputum, and saliva were evaluated for anti-PAD4 and anti-PAD3/4 using immunoprecipitation and ACPA using ELISA. Immunoglobulins (Ig) were purified from representative samples, and their effect on citrullination of histone H3 by recombinant human PAD4 was measured by anti-citH3 immunoblot. Results: Anti-PAD4 antibodies were detected in the serum of 6/37 (16.2%), sputum of 3/37 (8.1%), and saliva of 3/33 (9.1%) RA subjects and in the serum and sputum of 1/46 (2.2%) at-risk subjects. None of the healthy controls had anti-PAD4 antibodies at any site. Serum, sputum, and salivary anti-PAD4 antibodies were more prevalent in RA subjects with RA duration >2 years. Purified antibodies from representative anti-PAD4-positive and anti-PAD3/4-positive sputum were primarily of the IgA isotype and able to increase PAD4 enzymatic activity. Conclusions: Anti-PAD4 antibodies are present in the sputum and saliva of a portion of RA patients and are infrequent in at-risk subjects. Importantly, the ability of anti-PAD4, and particularly anti-PAD3/4, antibodies in the sputum to enhance PAD4 enzymatic activity suggests that anti-PAD4 may play an active role in the RA lung.

Original languageEnglish (US)
Article number163
JournalArthritis Research and Therapy
Issue number1
StatePublished - Dec 2021


  • Anti-PAD4 antibodies
  • Lung
  • Rheumatoid arthritis
  • Saliva
  • Sputum

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology


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