YAMASHITA Shunichi NAGASAKI UNIVERSITY SCHOOL OF MEDICINE, DEPARTMENT OF CELL PHYSIOLOGY, ATOMIC DI, 医学部, 教授 (30200679)
IZUMI Motomori NAGASAKI UNIVERSITY SCHOOL OF MEDICINE, THE FIRST DEPARTMENT OF INTERNAL MEDICIN, 医学部, 助教授 (80039552)
|Budget Amount *help
¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 1992: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1991: ¥3,900,000 (Direct Cost: ¥3,900,000)
To clarify the pathogenesis of autoimmune thyroid disease - Graves' disease and Hashimoto's disease, we first investigated the role of cytokines and adhesion molecules in thyroid glands of patients with Graves' disease. Thyroid epithelial cells are characterized by strong expression of HLA-I and -II, generation of new blood vessels, infiltration of mononuclear cells and also expression of the adhesion molecule, ICAM-1. HLA-I expression on thyroid cells can be in vitro induced by interferon (IFN) -alpha, beta and gamma and tumor necrosis factor (TNF) -alpha, HLA-II expression by IFN-gamma and ICAM-1 expression by interleukin-1, IFN-gamma and TNF-alpha. Analysis of intrathyroidal lymphocytes reveals an increase in activated helper and memory T cells and enhanced expression of various adhesion molecules (LFA-1, CD2, VLA-4 and VLA-5). Furthermore, vascular endothelial cells in thyroid glands also strongly express ICAM-1. These data suggest the migration of circulating lymphocytes into thyroid glands and the perpetuation of autoimmune process in thyroid glands by interaction of memory T cells with thyroid cells and endothelial cells through adhesion molecules (extracellular matrix). Then, we studied the antigenicity of one of the thyroid specific proteins - TSH receptor. in order to elucidate how autoantigens are involved in such intgrathyroidal autoimmune reactions. Taq I restriction enzyme is found to identify a restriction fragment length polymorphism in the human TSH receptor gene, implying TSH receptor protein abnormality. Finally, we cloned the truncated TSH receptor cDNA of 1 kb in length (the full length TSH receptor cDNA is 4 kb in length), suggesting the involvement of the secreted, truncated TSH receptor protein in autoimmune process as an autoantigen.