Autoimmune thyroid disease: new models of cell death in autoimmunity

Autoimmunity against the thyroid gland generates two opposite pathogenic processes: thyroid hyperplasia in Graves' disease and thyroid destruction in Hashimoto's thyroiditis. Three different mechanisms have been sequentially proposed to be responsible for autoimmune thyrocyte depletion: first, antibody-mediated destruction through immune-complex deposition; second, T-cell-mediated destruction through the release of cytotoxic granules after specific target recognition; and third, death-receptor-mediated induction of apoptosis. The rate of thyrocyte apoptosis dictates the clinical outcome of thyroid autoimmunity. Thyrocyte apoptosis is extremely rare in normal thyroid. It markedly increases during Hashimoto's thyroiditis, but not in Graves' disease. Therefore, regulation of thyrocyte survival is a crucial pathogenic determinant. During Hashimoto's thyroiditis, thyrocytes express death-receptor ligands that might trigger apoptosis of both thyrocytes and infiltrating lymphocytes. So, it is not clear whether lymphocytes kill thyrocytes or vice versa. T-helper lymphocytes produce cytokines that influence both immune and target cells at several levels. The predominance of T-helper type 1 (TH1) or TH2 cytokines might regulate thyrocyte survival through the induction of pro-apoptotic and anti-apoptotic proteins. So, the ability of T-helper cytokines to modify the pattern of apoptotic-related proteins could have a remarkable effect in various immune-mediated conditions.