Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis.
Rheumatoid arthritis (RA) is associated with certain MHC class II alleles and is characterized by a chronic autoimmune response in the joints. Using transgenic mice expressing human DR4 (DRB1*0401) and human CD4, but lacking endogenous MHC class II, we show that posttranslational glycosylation of type II collagen (CII) influences the level of T cell tolerance to this candidate cartilage-specific autoantigen. In such mice, the expression of human CII resulted in a tolerized murine T cell response to human CII. However, tolerance induction remained incomplete, preferentially deleting responses to the nonmodified CII 263-270 epitope, whereas T cell recognition of a glycosylated variant of this epitope was affected to a lesser degree. A similar dominance of T cell responses to CII-glycopeptides was recorded in a cohort of severely affected RA-patients (n = 14). Thus, RA T cells predominantly recognize the immunodominant CII peptide in its glycosylated form and may explain why previously it has been difficult to detect T cell responses to CII in RA patients.
Bäcklund
Johan
J
Section of Medical Inflammation Research, Sölvegatan 19, I11 BMC, Lund University, SE-221 84 Lund, Sweden.
Carlsen
Stefan
S
Höger
Torsten
T
Holm
Björn
B
Fugger
Lars
L
Kihlberg
Jan
J
Burkhardt
Harald
H
Holmdahl
Rikard
R
D000818:Animals; D000918:Antibody Specificity; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D024043:Collagen Type II / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D006020:Glycopeptides / Q000276:immunology; D006031:Glycosylation; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D024043:Collagen Type II; D000939:Epitopes; D006020:Glycopeptides; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D010446:Peptide Fragments