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

Arthritis Research & Therapy

Jill M. Norris¹  Erika Darrah²  Hong Wang²  Ryan L. Davis²  M. Kristen Demoruelle³  Johnny Hoang³  Kevin D. Deane³  V. Michael Holers³  Ashley Visser³ 

[1] Colorado School of Public Health, Aurora, CO, USA;Division of Rheumatology, The Johns Hopkins University, 5200 Eastern Ave. Suite 5300, 21224, Baltimore, MD, USA;Division of Rheumatology, University of Colorado Anschutz Medical Campus, 1775 Aurora Court, Mail Stop B-115, 80045, Aurora, CO, USA;

关键词: Rheumatoid arthritis;    Anti-PAD4 antibodies;    Lung;    Sputum;    Saliva;   

DOI  :  10.1186/s13075-021-02528-5

来源: Springer

【 摘 要 】

BackgroundMucosal 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.MethodsWe 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.ResultsAnti-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.ConclusionsAnti-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.

【 授权许可】

CC BY