Study on the pathogenesis and mechanism of the development of thyroid-associated ophthalmopathy

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We have studied the pathogenesis and mechanism of the development of ophthalmopathy in Graves' disease.1) Susceptibility genes to thyroid-associated ophthalmmopathy (TAO)There are much evidence that cytokines, immunomodulators, transcription factors play important roles in the development of TAO.In association studies we have shown that the polymorphisms of the IL-18, ICAM-1 and NFkB1 genes were significantly associated with the development of ophthalmopathy. On the other hand, CTLA-4 gene and CD40 gene polymorphisms were associated with Graves' disease, but not with TAO.2) TSH receptor expression on the orbital fibroblasts and its modulation by nicotinamideA recent randomized controlled trail showed the usefulness of nicotinamide on TAO. We investigated the effect of nicotinamide on cultured orbital fibroblasts (preadipocytes) in adipogenesis and expressions of TSH receptor on the fibroblasts.We confirmed the expression of TSH receptor on orbital fibroblasts derived from patients with TAO. Pioglitazone, a PPARγ agonist, induced adiopogenesis and the expression of TSH receptor mRNA. Nicotinamide did not affect the expression of TSH receptor mRNA, but suppressed the proliferation of the fibroblasts.