title: Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis.
abstract: The posttranslational modification of proteins has the potential to generate neoepitopes that may subsequently trigger immune responses. The carbamylation of lysine residues to form homocitrulline may be a key mechanism triggering inflammatory responses. We evaluated the role of carbamylation in triggering immune responses and report a new role for this process in the induction of arthritis. Immunization of mice with homocitrulline-containing peptides induced chemotaxis, T cell activation, and Ab production. The mice also developed erosive arthritis following intra-articular injection of peptides derived from homocitrulline and citrulline. Adoptive transfer of T and B cells from homocitrulline-immunized mice into normal recipients induced arthritis, whereas systemic injection of homocitrulline-specific Abs or intra-articular injection of homocitrulline-Ab/citrulline-peptide mixture did not. Thus, the T cell response to homocitrulline-derived peptides, as well as the subsequent production of anti-homocitrulline Abs, is critical for the induction of autoimmune reactions against citrulline-derived peptides and provides a novel mechanism for the pathogenesis of arthritis.
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden. piotr.mydel@rheuma.gu.se
authors.forename: Piotr
authors.initials: P
authors.lastname: Mydel
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.forename: Mikael
authors.initials: M
authors.lastname: Brisslert
authors.forename: Annelie
authors.initials: A
authors.lastname: Hellvard
authors.forename: Leif E
authors.initials: LE
authors.lastname: Dahlberg
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Maria
authors.initials: M
authors.lastname: Bokarewa
mesh_terms: D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002956:Citrulline / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; C001352:homocitrulline; D002956:Citrulline