title: Synthesis of glycopeptides from type II collagen-incorporating galactosylated hydroxylysine mimetics and their use in studying the fine specificity of arthritogenic T cells.
abstract: Five analogues of the bovine type II collagen (bCII) immunodominant glycopeptide [beta-D-Gal-(5R)-5-Hyl264]CII(256-270) (1) carrying diverse modifications at the critical hydroxylysine (Hyl) 264 side chain were designed and synthesised, to explore the fine specificity of bCII-reactive T cells involved in the initiation and/or regulation of collagen-induced arthritis (CIA), a mouse model for rheumatoid arthritis (RA). Beta-D-galactosyl-(5R)-5-hydroxy-L-lysine (19) and corresponding mimetics (22-25), conveniently protected for solid-phase synthesis, were all obtained by a divergent route involving enantiopure 5-hydroxylated 6-oxo-1,2-piperidinedicarboxylates as the key intermediates. All three bCII-specific T hybridomas used, as well as a recurrent pathogenic CD4+ T-cell clone isolated from bCII-immunised DBA/1 mice, recognised the galactosylated form 1 of the immunodominant bCII (256-270) epitope. These cells were extremely sensitive to changes at the epsilon-amino group of Hyl264, but differed in their pattern of recognition of analogues with a Hyl264 side chain modified at C-5 (i.e. inversion of stereochemistry, methylation). These data further document the importance of collagen post-translational modifications in autoimmunity and in the CIA model in particular, and provide a new insight into the molecular interaction between glycopeptide 1 and the TCR of pathogenic T cells.
authors.affiliation: UPR 9021 CNRS-Immunologie et Chimie Thérapeutiques, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, 67084 Strasbourg Cedex, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Marin
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Blaton
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Briand
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.forename: Catherine
authors.initials: C
authors.lastname: Fournier
authors.forename: Gilles
authors.initials: G
authors.lastname: Guichard
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D040761:Biomimetic Materials / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D024043:Collagen Type II / Q000737:chemistry* / Q000276:immunology; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000276:immunology; D006901:Hydroxylysine / Q000031:analogs & derivatives* / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008811:Mice, Inbred DBA
chemical_list: D024043:Collagen Type II; D006020:Glycopeptides; D016056:Immunodominant Epitopes; D006901:Hydroxylysine