The structural basis of MHC control of collagen-induced arthritis; binding of the immunodominant type II collagen 256 – 270 glycopeptide to H-2Aq and H-2Ap molecules
| Autor: | Ianeric Ivarsson, Rikard Holmdahl, Ulrica Brunsberg, Mikael Vestberg, Johan Broddefalk, Arne Svejgaard, Lars Fugger, Åke Engström, Bjarke E. Hansen, Peter Kjellén, Jan Kihlberg |
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| Rok vydání: | 1998 |
| Předmět: |
Models
Molecular Glycosylation Molecular Sequence Data Immunology Mice Transgenic chemical and pharmacologic phenomena Peptide binding Peptide Major histocompatibility complex Mice Structure-Activity Relationship chemistry.chemical_compound MHC class I Animals Immunology and Allergy Amino Acid Sequence Amino Acids chemistry.chemical_classification Antigen Presentation Mice Inbred C3H MHC class II biology Immunodominant Epitopes Arthritis T-cell receptor Glycopeptides H-2 Antigens MHC restriction Molecular biology Rats Mice Inbred C57BL chemistry Biochemistry Mice Inbred DBA biology.protein Collagen Protein Processing Post-Translational Spleen Protein Binding |
| Zdroj: | European Journal of Immunology. 28:755-766 |
| ISSN: | 1521-4141 0014-2980 |
| DOI: | 10.1002/(sici)1521-4141(199802)28:02<755::aid-immu755>3.0.co;2-2 |
| Popis: | The Aq major histocompatibility complex (MHC) class II molecule is associated with susceptibility to murine collagen-induced arthritis (CIA), whereas the closely related H-2Ap molecule is not. To understand the molecular basis for this difference, we have analyzed the ability of H-2Aq and H-2Ap molecules (referred to as Aq and Ap) to bind and present collagen type II (CII)-derived glycosylated and non-glycosylated peptides. T cell clones specific for the immunodominant CII 256-270 peptide and restricted to both Aq and Ap molecules were identified. When these clones were incubated with CII protein and either Aq- or Ap-expressing antigen-presenting cells (APC), only Aq-expressing APC were able to induce stimulation. With the use of A(beta) transgenic mice this could be shown to be solely dependent on the MHC class II molecule itself and to be independent of other MHC- or non-MHC genes. Peptide binding studies were performed using affinity-purified MHC class II molecules. The CII 256-270 peptide bound with lower affinity to the Ap molecule than to the Aq molecule. Using a set of alanine-substituted CII 256-270 peptides, MHC class II and T cell receptor (TCR) contacts were identified. Mainly the side chains of isoleucine 260 and phenylalanine 263 were used for binding both the Aq and Ap molecule, i.e. the peptide was orientated similarly in the binding clefts. The major TCR contact amino acids were lysine 264, which can be posttranslationally modified, and glutamic acid 266, which is the only amino acid in the heterologous peptide which differs from the mouse sequence. Glycosylation at positions 264 and 270 of the CII 256-270 peptide did not change the anchor positions used for binding to the Aq or Ap molecules. The autologous form of the peptide (with aspartic acid at position 266) bound with lower affinity to the Aq molecule as compared with the heterologous peptide. The variable affinity displayed by the immunodominant CII 256-270 peptide for different MHC class II molecules, the identification of MHC and TCR contacts and the significance of glycosylation of these have important implications for the understanding of the molecular basis for inherited MHC class II-associated susceptibility to CIA and in turn, for development of novel treatment strategies in this disease. |
| Databáze: | OpenAIRE |
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