hydroxylysine and Arthritis--Rheumatoid

In inflammatory granuloma, synovial sclerosis or inflammation and in Dupuytren's contracture, the neocollagen contains chains and/or transverse links that are characteristic of rapidly growing immature tissues. In arthrosis, a conversion of collagen synthesis towards a cutaneous type may occur. The destruction of cartilage in rheumatoid arthritis is brought about by a specific collagenase that originates from the inflamed synovial membrane. Finally, certain forms of osteoporosis may be due to alterations of the osseous collagen which impair the mechanism of calcification.

Topics: Animals; Arthritis, Rheumatoid; Bone Diseases; Cartilage, Articular; Collagen; Collagen Diseases; Dupuytren Contracture; Fibroblasts; Granulation Tissue; Granuloma; Humans; Hydroxylysine; Microbial Collagenase; Osteitis Deformans; Osteoarthritis; Osteoporosis; Protein Conformation; Rheumatic Diseases; Sclerosis; Synovial Membrane; Synovitis

Two protected derivatives of beta-D-galactopyranosyl-5-hydroxy-L-lysine, in which HO-4 of galactose has been O-methylated or replaced by fluorine, have been prepared. The building blocks were incorporated at position 264 of the peptide fragment CII259-273 from type II collagen by solid-phase synthesis. The ability of these two glycopeptides, and two CII259-273 glycopeptides in which HO-4 of galactose was either unmodified or deoxygenated, to elicit responses from T-cell hybridomas obtained in a mouse model for rheumatoid arthritis was then determined. The hybridomas were all highly sensitive towards modifications at C-4 of the beta-D-galactosyl residue of CII259-273, highlighting the role of HO-4 as an important contact point for the T-cell receptor. Most likely, this glycopeptide hydroxyl group is involved in hydrogen bonding with the T-cell receptor.

Topics: Animals; Arthritis, Rheumatoid; Collagen Type II; Disease Models, Animal; Dose-Response Relationship, Immunologic; Galactose; Glycopeptides; Hybridomas; Hydroxylysine; Magnetic Resonance Spectroscopy; Mice; Peptide Fragments; Receptors, Antigen, T-Cell; T-Lymphocytes

Five protected analogues of beta-D-galactosyl-(5R)-5-hydroxy-L-lysine were prepared, in which the galactosyl moiety was modified by monodeoxygenation or inversion of stereochemistry at C-4. The building blocks were used in the solid-phase synthesis of a set of glycopeptides related to the peptide fragment CII256-273 from type II collagen. Evaluation of the glycopeptides revealed that T-cell hybridomas obtained in collagen-induced arthritis (CIA), which is a common mouse model for rheumatoid arthritis, recognized the galactosyl moiety with high specificity for individual hydroxy groups. Moreover, T-cell hybridomas obtained in a humanized variant of CIA were also found to recognize the glycopeptides in an equally carbohydrate-specific manner. The results allowed the generation of models of the complexes formed between the appropriate class II major histocompatibility complex (MHC) molecule, glycopeptide, and the T-cell receptor, that is, of an interaction that is critical for the stimulation of T cells in the arthritis models. In the structural models, peptide side chains anchor the glycopeptide in pockets in the class II MHC molecule, whereas the galactosylated hydroxylysine residue forms the key contacts with the T-cell receptor. Importantly, the results also suggest that a T-cell response towards glycopeptide fragments from type II collagen could play an important role in the development of rheumatoid arthritis in humans.

Topics: Animals; Arthritis, Rheumatoid; Binding Sites; Collagen Type II; Disease Models, Animal; Glycopeptides; Histocompatibility Antigens Class II; Humans; Hybridomas; Hydroxylysine; Mice; Mice, Transgenic; Peptide Fragments; Structure-Activity Relationship; T-Lymphocytes, Helper-Inducer