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Immunoglobulins from Patients with Graves’ Disease Induce Hyaluronan Synthesis in Their Orbital Fibroblasts through the Self-Antigen, Insulin-Like Growth Factor-I Receptor

Division of Molecular Medicine (T.J.S.), Department of Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, California 90502; The Jules Stein Eye Institute (T.J.S.), David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095 (T.J.S.); and Long Beach Veterans Administration Healthcare System (T.J.S., N.H.), Long Beach, California 90822

Address all correspondence and requests for reprints to: Terry J. Smith, M.D., Division of Molecular Medicine, Building C-2, Harbor-University of California Los Angeles Medical Center, 1124 West Carson Street, Torrance, California 90502. E-mail: tjsmith{at}ucla.edu.

A distinctive histopathological feature associated with thyroid-associated ophthalmopathy is the disordered accumulation of the glycosaminoglycan, hyaluronan, in orbital connective tissues. This often occurs in the context of dramatic inflammation and tissue remodeling. Orbital fibroblasts exhibit a novel phenotype including exaggerated responses to cytokines. Here, we report for the first time the ability of IgG isolated from the sera of patients with Graves’ disease (GD-IgG) to provoke in orbital fibroblasts the synthesis of hyaluronan. The effect of GD-IgG can be reproduced by IGF-I, appears to be mediated through the IGF-I receptor, and is abolished with glucocorticoid treatment. TSH failed to influence the synthesis of hyaluronan. In contrast to the effects in GD fibroblasts, cultures derived from donors without known thyroid disease fail to respond to GD-IgG or IGF-I. The observation that hyaluronan production is induced by GD-IgG in fibroblasts suggests that the IGF-I receptor and its activating antibodies may represent a key pathway through which important pathogenic events in thyroid-associated ophthalmopathy are mediated.

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