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Peptidylarginine Deiminase Autoimmunity and the Development of Anti–Citrullinated Protein Antibody in Rheumatoid Arthritis: The Hapten–Carrier Model
Author(s) -
Auger Isabelle,
Balandraud Nathalie,
Massy Emmanuel,
Hemon Marie F.,
Peen Elisa,
Arnoux Fanny,
Mariot Charlotte,
Martin Marielle,
Lafforgue Pierre,
Busnel JeanMarc,
Roudier Jean
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41189
Subject(s) - autoantibody , immunology , antibody , medicine , rheumatoid arthritis , flow cytometry , t cell , epitope , autoimmunity , immune system , arthritis , citrullination , biology , arginine , citrulline , amino acid , biochemistry
Objective The presence of autoantibodies to citrullinated proteins ( ACPA s) often precedes the development of rheumatoid arthritis ( RA ). Citrullines are arginine residues that have been modified by peptidylarginine deiminases ( PAD s). PAD 4 is the target of autoantibodies in RA . ACPA s could arise because PAD 4 is recognized by T cells, which facilitate the production of autoantibodies to proteins bound by PAD 4. We previously found evidence for this hapten–carrier model in mice. This study was undertaken to investigate whether there is evidence for this model in humans. Methods We analyzed antibody response to PAD 4 and T cell proliferation in response to PAD 4 in 41 RA patients and 36 controls. We tested binding of 65 PAD 4 peptides to 5 HLA – DR alleles ( DRB 1*04:01, *04:02, *04:04, *01:01, and *07:01) and selected 11 PAD 4 peptides for proliferation studies using samples from 22 RA patients and 27 controls. Peripheral blood lymphocytes from an additional 10 RA patients and 7 healthy controls were analyzed by flow cytometry for CD 3, CD 4, CD 154, and tumor necrosis factor expression after PAD 4 stimulation. Results Only patients with RA had both antibodies and T cell responses to PAD 4. T cell response to peptide 8, a PAD 4 peptide, was associated with RA ( P = 0.02), anti‐PAD4 antibodies ( P = 0.057), and the shared epitope ( P = 0.05). Conclusion ACPA immunity is associated with antibodies to PAD 4 and T cell responses to PAD 4 and PAD 4 peptides. These findings are consistent with a hapten–carrier model in which PAD 4 is the carrier and citrullinated proteins are the haptens.