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

Abstract

Objective. The presence of autoantibodies to citrullinated proteins (ACPAs) often precedes the development of rheumatoid arthritis (RA). Citrullines are arginine residues that have been modified by peptidylarginine deiminases (PADs). PAD4 is the target of autoantibodies in RA. ACPAs could arise because PAD4 is recognized by T cells, which facilitate the production of autoantibodies to proteins bound by PAD4. We previously found evidence for this haptencarrier model in mice. This study was undertaken to investigate whether there is evidence for this model in humans.Methods. We analyzed antibody response to PAD4 and T cell proliferation in response to PAD4 in 41 RA patients and 36 controls. We tested binding of 65 PAD4 peptides to 5 HLA-DR alleles (DRB1and selected 11 PAD4 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 CD3, CD4, CD154, and tumor necrosis factor expression after PAD4 stimulation.Results. Only patients with RA had both antibodies and T cell responses to PAD4. T cell response to peptide 8, a PAD4 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 PAD4 and T cell responses to PAD4 and PAD4 peptides. These findings are consistent with a hapten-carrier model in which PAD4 is the carrier and citrullinated proteins are the haptens.

First flare of ACPA-positive rheumatoid arthritis after SARS-CoV-2 infection

“…Our patient had antibody responses and Tcell proliferation to PAD4 and peptide 8 from PAD4, consistent with the haptencarrier model in rheumatoid arthritis. 10 To the best of our knowledge, this is the first definitive case of ACPApositive rheumatoid arthritis developing after SARSCoV2 infection (ie, with samples taken before and after arthritis onset), with infection as a poten tial trigger for epitope spreading and onset of clinical rheumatoid arthritis symptoms.…”

“…Our patient had antibody responses and T-cell proliferation to PAD4 and peptide 8 from PAD4, consistent with the hapten-carrier model in rheumatoid arthritis. 10 …”

The role of posttranslational modifications in generating neo-epitopes that bind to rheumatoid arthritis-associated HLA-DR alleles and promote autoimmune T cell responses

“…Altogether, these data demonstrate that the generation of an autoimmune response to citrullinated proteins and peptides is a complex process. Several hypotheses have been proposed including autoimmune responses to the PAD4 protein in which the PAD4 acts as carrier and the citrullinated proteins act as a hapten [ 58 , 59 ], as well as a potential role of non-SE MHC-II alleles participating in the presentation of citrullinate peptides [ 60 ]. Additionally, citrullination is only one of many PTMs that can occur to proteins, raising the possibility that autoimmune T cell responses could be targeting multiple neo-antigens that have been generated at the site of inflammation.…”

The Expression of Non-Coding RNAs and Their Target Molecules in Rheumatoid Arthritis: A Molecular Basis for Rheumatoid Pathogenesis and Its Potential Clinical Applications

“…On the other hand, Martinez-Prat et al [ 46 ] showed that PAD4 as a cognate antigen to induce anti-PAD4 autoantibodies in RA patients was associated with specific clinical features that can help improve disease diagnosis. In consideration of PAD4 as an effector and target molecule in RA pathogenesis, Auger et al [ 47 ] further proved that ACPAs are induced after PAD4 is recognized by T cells to facilitate the production of antibodies against “citrullinated peptides” bound by PAD4, mimicking a so-called “hapten-carrier” model. Recently, Darrah et al [ 48 ] investigated the antibodies against native and auto-citrullinated PADs in patients with RA.…”