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Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis.

Bäcklund, Johan LU ; Carlsén, Stefan LU ; Höger, Torsten; Holm, Björn; Fugger, Lars; Kihlberg, Jan; Burkhardt, Harald and Holmdahl, Rikard LU (2002) In Proceedings of the National Academy of Sciences 99(15). p.9960-9965
Abstract
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... (More)
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. (Less)
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published
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Proceedings of the National Academy of Sciences
volume
99
issue
15
pages
9960 - 9965
publisher
National Acad Sciences
external identifiers
  • wos:000177042400066
  • scopus:0037162490
ISSN
1091-6490
DOI
10.1073/pnas.132254199
language
English
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yes
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c1ef0410-e01c-4cfa-bb75-574682487c1b (old id 109597)
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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12089323&dopt=Abstract
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2007-07-11 09:17:29
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@article{c1ef0410-e01c-4cfa-bb75-574682487c1b,
  abstract     = {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.},
  author       = {Bäcklund, Johan and Carlsén, Stefan and Höger, Torsten and Holm, Björn and Fugger, Lars and Kihlberg, Jan and Burkhardt, Harald and Holmdahl, Rikard},
  issn         = {1091-6490},
  language     = {eng},
  number       = {15},
  pages        = {9960--9965},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis.},
  url          = {http://dx.doi.org/10.1073/pnas.132254199},
  volume       = {99},
  year         = {2002},
}