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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.

Peptidylarginine Deiminase Autoimmunity and the Development of Anti–Citrullinated Protein Antibody in Rheumatoid Arthritis: The Hapten–Carrier Model