title: Weak CD4+ T-cell responses to citrullinated vimentin in rheumatoid arthritis patients carrying HLA-DR9 alleles.
abstract: Citrullinated vimentin (cVIM) is one of the antigens specifically targeted by anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients. The association between ACPA and certain HLA-DRB1 alleles, those coding for the shared epitope (SE), suggests that this response could be T-cell mediated. HLA-DR9 alleles, which do not code for the SE, have recently been associated with ACPA (+) RA. The objective of this work was to study CD4+ T cell responses to cVIM in RA patients and healthy controls carrying HLA-DR9 alleles. Fourteen RA patients and ten healthy controls previously genotyped for HLA-DRB1 were studied for the presence of serum anti-cVIM antibodies by Western blot and ELISA. Peripheral blood mononuclear cells were stimulated with native vimentin and cVIM, and CD4+ T cells proliferation was assessed by flow cytometry. Citrulline-specific CD4+ T cells proliferation was found not only in RA patients but also in healthy controls. Although most patients carrying HLA-DR9 alleles present anti-cVIM antibodies, HLA-DR9 alleles were associated with weaker cVIM-driven CD4+ T-cell responses among RA patients. These results suggest that HLA-DR9 alleles could exert a protective effect on the recognition of cVIM epitopes by CD4+ T cells. In this context, other citrullinated proteins may break T and B cell tolerance, with cVIM only acting as a cross-reactive target for ACPA.
authors.affiliation: Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Av. Independencia #1027, Independencia, Santiago, Chile.
authors.forename: Diego
authors.initials: D
authors.lastname: Catalán
authors.forename: Octavio
authors.initials: O
authors.lastname: Aravena
authors.forename: Roberto
authors.initials: R
authors.lastname: Zúñiga
authors.forename: Natalia
authors.initials: N
authors.lastname: Silva
authors.forename: Alejandro
authors.initials: A
authors.lastname: Escobar
authors.forename: Francisca
authors.initials: F
authors.lastname: Sabugo
authors.forename: Pamela
authors.initials: P
authors.lastname: Wurmann
authors.forename: Lilian
authors.initials: L
authors.lastname: Soto
authors.forename: Rodrigo
authors.initials: R
authors.lastname: González
authors.forename: Jorge
authors.initials: J
authors.lastname: Alfaro
authors.forename: Milton
authors.initials: M
authors.lastname: Larrondo
authors.forename: Miguel
authors.initials: M
authors.lastname: Cuchacovich
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Aguillón
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D002677:Chile; D002956:Citrulline / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D059810:HLA-DR Serological Subtypes / Q000235:genetics*; D006801:Humans; D016056:Immunodominant Epitopes; D008213:Lymphocyte Activation; D008875:Middle Aged; D010641:Phenotype; D014746:Vimentin / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D059810:HLA-DR Serological Subtypes; C038988:HLA-DR9 antigen; D016056:Immunodominant Epitopes; D014746:Vimentin; D002956:Citrulline