Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis.
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.
Mydel
Piotr
P
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden. piotr.mydel@rheuma.gu.se
Wang
Zeneng
Z
Brisslert
Mikael
M
Hellvard
Annelie
A
Dahlberg
Leif E
LE
Hazen
Stanley L
SL
Bokarewa
Maria
M
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
D016207:Cytokines; C001352:homocitrulline; D002956:Citrulline