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The MHC-glycopeptide-T cell interaction in collagen induced arthritis: a study using glycopeptides, isosteres and statistical molecular design in a mouse model for rheumatoid arthritis
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population in the western world. It is characterised by a tissue specific attack of cartilage in peripheral joints. Collagen induced arthritis (CIA) is one of the most commonly used animal models for (RA), with similar symptoms and histopathology. CIA is induced by immunisation of mice with type II collagen (CII), and the immunodominant part was previously found to be located between residues 256-270. This thesis describes the interaction between the MHC molecule, glycopeptide antigens from CII and the T cells that is essential in development of CIA. The glycopeptide properties for binding to the mouse MHC molecule Aq have been studied, as well as interaction points in the glycopeptide that are critical for stimulation of a T-cell response.

The thesis is based on five studies. In the first paper the minimal glycopeptide core, that is required for binding to the Aq molecule while still giving a full T cell response was determined. The second paper studied the roles of amino acid side-chains and a backbone amide bond as T-cell contact points. In the third paper the hydrogen bond donor-acceptor characteristics of the 4-OH galactose hydroxyl group of the glycopeptide was studied in detail. In the fourth paper we established a structure activity relationship (QSAR model) for (glyco)peptide binding to the Aq molecule. Finally, the stereochemical requirements for glycopeptide binding to the Aq molecule and for T-cell recognition was studied in the fifth paper.

The study was performed using collagen glycopeptide analogues, which were synthesised on solid phase. Amide bond and hydroxyl group isosteres were introduced for study of hydrogen bond donor-acceptor characteristics. Statistical methods were used to design a representative peptide test set and in establishing a QSAR model.

The results give a deeper understanding of the interactions involved in the ternary MHC-glycopeptide-T cell complex. This information contributes to research directed towards finding new treatments for RA.

Place, publisher, year, edition, pages
Umeå: Kemi , 2006. , 73 p.
Keyword [en]
Rheumatoid arthritis, collagen, T-cell, class II MHC, solid phase peptide synthesis, glycopeptide, peptide isostere, PCA, statistical molecular design, PLS, QSAR, sequence binding motif
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-899ISBN: 91-72-64-193-2 OAI: oai:DiVA.org:umu-899DiVA: diva2:144957
Public defence
2006-11-11, KB3B1, KBC, Linneus väg 6, Umeå, 10:00
Opponent
Supervisors
Available from: 2006-10-20 Created: 2006-10-20 Last updated: 2011-04-01Bibliographically approved
List of papers
1. Identification of the minimal glycopeptide core recognized by T cells in a model for rheumatoid arthritis
Open this publication in new window or tab >>Identification of the minimal glycopeptide core recognized by T cells in a model for rheumatoid arthritis
2005 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 13, no 2, 473-482 p.Article in journal (Refereed) Published
Abstract [en]

Collagen induced arthritis (CIA) is a common mouse model for rheumatoid arthritis. Two sets of truncated peptides derived from type II collagen have been prepared and tested for binding to Aq, a MHC-II molecule associated with development of CIA. Binding to Aq correlated well with predictions from a computer-based model. T-cell hybridomas, obtained in CIA, were also used to study the ability of Aq bound peptides to trigger a T-cell response. The minimal peptide epitope required for binding, as well as for giving a T-cell response, was determined to be CII260–267. In collagen this epitope is often glycosylated at hydroxylysine 264 and glycosylation has been shown to be an immunodominant feature in CIA. Synthesis and evaluation of CII260–267 carrying a β-d-galactosyl moiety at position 264 revealed that this glycopeptide stimulated representative members from a panel of carbohydrate-specific T-cell hybridomas obtained in CIA.

Place, publisher, year, edition, pages
Oxford: Pergamon Press, 2005
Keyword
Glycopeptide, Collagen, T cell, Rheumatoid arthritis
Identifiers
urn:nbn:se:umu:diva-5438 (URN)10.1016/j.bmc.2004.10.011 (DOI)
Available from: 2006-10-20 Created: 2006-10-20 Last updated: 2011-03-23Bibliographically approved
2. Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis
Open this publication in new window or tab >>Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis
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2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 17, 5921-5932 p.Article in journal (Refereed) Published
Abstract [en]

Collagen induced arthritis (CIA) is the most studied animal model for rheumatoid arthritis and is associated with the MHC class II molecule Aq. T-cell recognition of a peptide from type II collagen, CII256–270, bound to Aq is a requirement for development of CIA. Lysine 264 is the major T-cell recognition site of CII256–270 and CIA is in particular associated with recognition of lysine 264 after posttranslational hydroxylation and subsequent attachment of a β-d-galactopyranosyl moiety. In this paper we have studied the structural requirements of collagenous glycopeptides required for T-cell stimulation, as an extension of earlier studies of the recognition of the galactose moiety. Synthesis and evaluation of alanine substituted glycopeptides revealed that there are T-cells that only recognise the galactosylated hydroxylysine 264, and no other amino acid side chains in the peptide. Other T-cells also require glutamic acid 266 as a T-cell contact point. Introduction of a methylene ether isostere instead of the amide bond between residues 260 and 261 allowed weaker recognition by some, but not all, of the T-cells. Altogether, these results allowed us to propose a model for glycopeptide recognition by the T-cells, where recognition from one or the other side of the galactose moiety could explain the different binding patterns of the T-cells.

Place, publisher, year, edition, pages
Oxford: Pergamon Press, 2006
Keyword
Glycopeptide; Collagen, T-cell, Rheumatoid arthritis, Amide bond isostere, Peptide mimetics
Identifiers
urn:nbn:se:umu:diva-16105 (URN)doi:10.1016/j.bmc.2006.05.023 (DOI)
Available from: 2007-08-17 Created: 2007-08-17 Last updated: 2011-04-01Bibliographically approved
3. Role of galactosyl moiety of collagen glycopeptides for T-cell stimulation in a model for rheumatoid arthritis
Open this publication in new window or tab >>Role of galactosyl moiety of collagen glycopeptides for T-cell stimulation in a model for rheumatoid arthritis
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2003 In: Bioorganic and medicinal chemistry, Vol. 11, no 18, 3981-3987 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-5440 (URN)
Available from: 2006-10-20 Created: 2006-10-20Bibliographically approved
4. Multivariate design synthesis and biological evaluation of peptides binding to Aq class II MHC molecules: a QSAR model for peptide binding in a mouse model for rheumatoid arthritis
Open this publication in new window or tab >>Multivariate design synthesis and biological evaluation of peptides binding to Aq class II MHC molecules: a QSAR model for peptide binding in a mouse model for rheumatoid arthritis
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-5441 (URN)
Available from: 2006-10-20 Created: 2006-10-20 Last updated: 2017-10-16
5. Stereo-chemical requirements for collagen glycopeptide binding to Aq class II MHC molecules and stimulation of T-cells obtained in a mouse model for rheumatoid arthritis
Open this publication in new window or tab >>Stereo-chemical requirements for collagen glycopeptide binding to Aq class II MHC molecules and stimulation of T-cells obtained in a mouse model for rheumatoid arthritis
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-5442 (URN)
Available from: 2006-10-20 Created: 2006-10-20 Last updated: 2010-01-13Bibliographically approved

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