期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：47
页码：E10169-E10177
DOI：10.1073/pnas.1713112114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：rheumatoid arthritis ; PAD protein ; anticitrullinated protein antibody ; mouse model ; MHC
