Differential regulation of Fas-mediated apoptosis in both thyrocyte and lymphocyte cellular compartments correlates with opposite phenotypic manifestations of autoimmune thyroid disease

Several mechanisms are probably involved in determining the evolution of au toimmune thyroid disease (AITD) towards either hypothyroidism and the clini cal syndrome known as Hashimoto's thyroiditis (HT) or toward hyperthyroidis m and the symptoms of Graves' disease (GD). To gain further insight into su ch mechanisms we performed an exhaustive comparative analysis of the expres sion of key molecules regulating cell death (Fas, Fas ligand [FasL], Bcl-2) and apoptosis in both thyrocytes and thyroid infiltrating lymphocytes (TIL s) from patients with either GD or HT. GD thyrocytes expressed less Fas/Fas L than HT thyrocytes, whereas GD TILs had higher levels of Fas/FasL than HT TILs. GD thyrocytes expressed increased levels of the antiapoptotic molecu le Bcl-2 compared to the low levels detected in HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT thigh Bcl-2) TILs. The patte rns of apoptosis observed were consistent with the regulation of Fas, FasL, and Bcl-2 described above. Our findings suggest that in GD thyroid the reg ulation of Fas/FasL/Bcl2 favors apoptosis of infiltrating lymphocytes, poss ibly limiting their autoreactive potential and impairing their ability to m ediate tissue damage. Moreover, the reduced levels of Fas/FasL and increase d levels of Bcl-2 should favor thyrocyte survival and favor the thyrocyte h ypertrophy associated with immunoglobulins stimulating the thyrotropin (TSH ) receptor. In contrast, the regulation of Fas/FasL/Bcl2 expression in HT p romotes thyrocyte apoptosis, tissue damage, and a gradual reduction in thyr ocyte numbers leading to hypothyroidism. These findings help define key mol ecular mechanisms contributing to the clinical outcome of thyroid autoimmun ity.