Predominant selection of T cells specific for the glycosylated collagen type II epitope (263–270) in humanized transgenic mice and in rheumatoid arthritis
- Johan Bäcklund†,‡,
- Stefan Carlsen†,‡,
- Torsten Höger§,
- Björn Holm¶,
- Lars Fugger‖,
- Jan Kihlberg¶,
- Harald Burkhardt§, and
- Rikard Holmdahl†,**
- †Section of Medical Inflammation Research, Sölvegatan 19, I11 BMC, Lund University, SE-221 84 Lund, Sweden; §Department of Internal Medicine III and Institute of Clinical Immunology, Friedrich-Alexander-University Erlangen-Nürnberg, D-91054 Erlangen, Germany; ¶Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden; and ‖Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, 8200N Aarhus, Denmark
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Communicated by N. Avrion Mitchison, University College London, London, United Kingdom (received for review February 25, 2002)
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.
Footnotes
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↵ ‡ J.B. and S.C. contributed equally to the present work.
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↵ ** To whom reprint requests should be addressed. E-mail: rikard.holmdahl{at}inflam.lu.se.
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See commentary on page 9611.
- Abbreviations:
- CII,
- type II collagen;
- CIA,
- collagen-induced arthritis;
- huCII,
- human type II collagen;
- PBMC,
- peripheral blood mononucleated cells;
- RA,
- rheumatoid arthritis;
- mDR,
- T cell clones from mouse CII and DR4;
- hDR,
- T cell clones from huCII/DR4
- Copyright © 2002, The National Academy of Sciences
