Worrall, Jennifer Garner; (1993) Carbohydrates in chronic inflammatory disease. A morphological study of N-acetylglucosamine, hyaluronan and chondroitin sulphates in rheumatoid arthritis. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The presence in rheumatoid arthritis of abnormally increased terminal N- acetylglucosamine (GlcNAc) on serum immunoglobulin G and of serum antibodies to GlcNAc-containing carbohydrates suggest a special role for GlcNAc in this disease. My hypothesis was that GlcNAc provides a specific driving force to the disease process in rheumatoid arthritis. The initial aim was to investigate histochemically the expression of terminal GlcNAc and the GlcNAc-containing carbohydrate, hyaluronan, in synovium. Terminal GlcNAc was identified using a specific monoclonal antibody, Mab GN7. A method was developed for localising hyaluronan in synovium using the hyaluronan-specific binding region of cartilage proteoglycan monomer. For both carbohydrates, greatly increased cellular and extracellular expression was found in rheumatoid synovium compared to normal. The appearances were, however, non-specific, being also present in osteoarthritic synovium and in a range of inflamed non-synovial tissues. Interest in the extracellular matrix led to a comparative morphological study of hyaluronan and the related glycosaminoglycans, chondroitin-4-sulphate/dermatan sulphate and chondroitin-6-sulphate, and of the cell-surface hyaluronan receptor, CD44. Each glycosaminoglycan showed a distinctive distribution in the matrix of synovium, skin and skeletal muscle, suggesting different roles in tissue matrix function. Normal synovial intima, for example, was found to contain more hyaluronan than subintima and to carry a discrete band of chondroitin-6-sulphate. Each showed profound alteration, indicating matrix disorganisation, in inflammatory disease. CD44-positive cytoplasmic processes were present on fibroblasts in hyaluronan-rich areas; they extended through the matrix and appeared to link with processes from distant cells. This study does not support a specific role for GlcNAc and GlcNAc-containing carbohydrates in rheumatoid arthritis but shows that carbohydrates, particularly those of the matrix, contribute to the marked heterogeneity of tissue structure and its modification in inflammatory disease.

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