title: Identification of citrullinated vimentin peptides as T cell epitopes in HLA-DR4-positive patients with rheumatoid arthritis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anouk L
authors.initials: AL
authors.lastname: Feitsma
authors.forename: Ellen I H
authors.initials: EI
authors.lastname: van der Voort
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.forename: Hanane
authors.initials: H
authors.lastname: el Bannoudi
authors.forename: Berendina G
authors.initials: BG
authors.lastname: Elferink
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: René R P
authors.initials: RR
authors.lastname: de Vries
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.forename: A
authors.initials: A
authors.lastname: Ioan-Facsinay
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D018604:Epitope Mapping; D000939:Epitopes; D005260:Female; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014746:Vimentin / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D015804:HLA-DR4 Antigen; D010456:Peptides, Cyclic; D014746:Vimentin; C487763:cyclic citrullinated peptide