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Peptidyl arginine deiminase immunization induces anticitrullinated protein antibodies in mice with particular MHC types

Abstract : Autoantibodies to citrullinated proteins (ACPAs) are present in two-thirds of patients with rheumatoid arthritis (RA). ACPAs are produced in the absence of identified T cell responses for each citrullinated protein. Peptidyl arginine deiminase 4 (PAD4), which binds proteins and citrullinates them, is the target of autoantibodies in early RA. This suggests a model for the emergence of ACPAs in the absence of detectable T cells specific for citrullinated antigens: ACPAs could arise because PADs are recognized by T cells, which help the production of autoantibodies to proteins bound by PADs, according to a "hapten/carrier" model. Here, we tested this model in normal mice. C3H are healthy mice whose IEβk chain is highly homologous to the β1 chain HLA-DRB1*04:01, the allele most strongly associated with RA in humans. C3H mice immunized with PADs developed antibodies and T cells to PAD and IgG antibodies to citrullinated fibrinogen peptides, in the absence of a T cell response to fibrinogen. To analyze the MHC background effect on hapten/carrier immunization, we immunized DBA/2 mice (whose IEβd chain is similar to that of HLA-DRB1*04:02, an HLA-DR4 subtype not associated with RA). DBA/2 mice failed to develop antibodies to citrullinated fibrinogen peptides. Thus, T cell immunization to PAD proteins may trigger ACPAs through a hapten/carrier mechanism. This may constitute the basis for a new mouse model of ACPA-positive RA.
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Fanny Arnoux, Charlotte Mariot, Elisa Peen, Nathalie Lambert, Nathalie Balandraud, et al.. Peptidyl arginine deiminase immunization induces anticitrullinated protein antibodies in mice with particular MHC types. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2017, 114 (47), pp.E10169-E10177. ⟨10.1073/pnas.1713112114⟩. ⟨inserm-02440804⟩

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