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Abstract

Objective

Antibodies directed against citrullinated proteins (ACPAs) are highly specific for rheumatoid arthritis (RA). The production of ACPAs is most likely dependent on the presence of T cells, since ACPAs undergo isotype switching and are associated with the shared epitope (SE)–containing HLA–DRB1 alleles. Vimentin is a likely candidate protein for T cell recognition, since >90% of patients positive for ACPAs that are reactive with (peptides derived from) citrullinated vimentin carry SE-containing HLA–DRB1 alleles. The aim of this study was to identify citrullinated vimentin peptides that are presented to HLA–DRB1*0401–restricted T cells.

Methods

HLA–DR4–transgenic mice were immunized with all possible citrulline-containing peptides derived from vimentin, and T cell reactivity was analyzed. Peptides recognized in a citrulline-specific manner by T cells were selected and analyzed for their ability to be processed from the entire vimentin protein. A first inventory of the selected epitopes recognized by T cells was performed using peripheral blood mononuclear cells (PBMCs) from ACPA+, HLA–DR4+ patients with RA.

Results

A citrulline-specific response was observed for 2 of the peptides analyzed in DR4-transgenic mice. These peptides were found to be naturally processed from the vimentin protein, since citrullinated vimentin was recognized by peptide-specific T cells. T cell reactivity against these peptides was also observed in cultures of PBMCs from RA patients.

Conclusion

This study identifies, for the first time, 2 naturally processed peptides from vimentin that are recognized by HLA–DRB1*0401–restricted T cells in a citrulline-specific manner. These peptides can be recognized by T cells in ACPA+, HLA–DR4+ patients with RA, as shown in a first inventory.