title: The role of citrullination of an immunodominant proteoglycan (PG) aggrecan T cell epitope in BALB/c mice with PG-induced arthritis.
abstract: The P70-84 peptide (also called 5/4E8 epitope) of the human cartilage proteoglycan (PG) aggrecan is the dominant/arthritogenic epitope in both humans and arthritis-prone BALB/c mice (PG-induced arthritis, PGIA). An elevated T cell reactivity was demonstrated to a citrullinated version of the P70-84 epitope in most of the patients with rheumatoid arthritis (RA). The goal of this study was to understand better how a T cell epitope, if citrullinated, may affect antigenicity/arthritogenicity in PGIA, a murine model of RA. T cell reactivity to differentially citrullinated versions of either the human PG aggrecan P70-84 peptide or the corresponding mouse sequence was assessed in peptide or aggrecan-immunized and arthritic BALB/c mice as well as in T cell receptor transgenic mice specific for peptide P70-84 sequence. Peripheral T cell responses were induced by priming BALB/c mice with either the human wild-type or its citrullinated versions. Unexpectedly, priming with the citrullinated self-peptide induced a higher T cell response compared to the wild-type sequence (p<0.001), and the citrullination of the human peptide abolished T cell reactivity in PGIA. Our data suggest that T cells reactive to the citrullinated P70-84 peptide escaped thymic selection and are present in the peripheral T cell repertoire. Results of this study provide evidence that citrullination of an immunodominant T cell epitope may substantially alter, either increase or abolish, T cell recognition at the periphery in an experimental model of arthritis.
authors.affiliation: Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary.
authors.forename: Petra
authors.initials: P
authors.lastname: Misják
authors.forename: Szilvia
authors.initials: S
authors.lastname: Bősze
authors.forename: Kata
authors.initials: K
authors.lastname: Horváti
authors.forename: Mária
authors.initials: M
authors.lastname: Pásztói
authors.forename: Krisztina
authors.initials: K
authors.lastname: Pálóczi
authors.forename: Marianna C
authors.initials: MC
authors.lastname: Holub
authors.forename: Ferenc
authors.initials: F
authors.lastname: Szakács
authors.forename: Borbála
authors.initials: B
authors.lastname: Aradi
authors.forename: Bence
authors.initials: B
authors.lastname: György
authors.forename: Tamás G
authors.initials: TG
authors.lastname: Szabó
authors.forename: György
authors.initials: G
authors.lastname: Nagy
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
authors.forename: András
authors.initials: A
authors.lastname: Falus
authors.forename: Edit I
authors.initials: EI
authors.lastname: Buzás
mesh_terms: D053674:Aggrecans / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D002956:Citrulline / Q000737:chemistry; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D053674:Aggrecans; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D002956:Citrulline