Abstract
Accumulation of hyaluronic acid within the orbital tissues represents a histological hallmark of Graves' ophthalmopathy. The hyaluronic acid/CD44-receptor plays a key role in the binding and metabolism of hyaluronic acid, and affects numerous cellular functions of potential relevance to the pathogenesis of Graves' ophthalmopathy, including cell proliferation, migration, and adhesive interactions between connective tissue components and immunocompetent cells. Using a highly sensitive immunoperoxidase technique and monoclonal antibodies directed against the standard CD44 molecule, we examined the expression and modulation of hyaluronic acid/CD44 receptors in cryostat sections of orbital biopsy specimens derived from patients with severe Graves' ophthalmopathy and normal individuals. Modulation of CD44 by cytokines and affinity-purified IgGs derived from patients with Graves' ophthalmopathy was studied in extracts of fibroblast monolayers following stimulation in vitro, using SDS-polyacrylamid gel electrophoresis and immunoblotting. Strong immunoreactivity for CD44 was present in all specimens derived from patients with Graves' ophthalmopathy and was detected in fibroblasts residing in retroorbital connective tissue, in extracellular matrix components and in mononuclear cell infiltrates. By contrast, in normal orbital specimens, CD44 immunoreactivity was faint and present only in occasional connective tissue cells. Recombinant IL-1 alpha, TNF alpha, IGF-1 and GO-IgGs significantly stimulated CD44 expression in Graves' retroocular fibroblasts (range: 168 to 588%; all p < 0.05). By contrast, EGF, IL-6, control IgGs and 15% fetal calf serum failed to alter CD44 expression. Treatment of monolayers with IFN gamma resulted in weak inhibition of CD44 expression. In conclusion, the hyaluronic acid/CD44 receptor is expressed at elevated levels in Graves' orbital connective tissue in situ.(ABSTRACT TRUNCATED AT 250 WORDS)
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