Role of apoptosis in pathogenesis of thyroiditis

Abstract

Apoptosis is a highly regulated mechanism of cell death that differs from necrosis and plays an important role in normal tissue development, homeostasis and immune regulation. Apoptosis is involved in many diseases. Defective apoptosis can cause systemic autoimmunity by allowing the survival of autoreactive lymphocytes. It may also be involved in the pathogenesis of organ-specific autoimmune diseases such as Hashimoto's thyroiditis and in the pathogenesis of tumors. Apoptosis is regulated at multiple levels, including death receptor and ligand expression, adapter protein, cascades of caspases, mitochondria and the expression of anti apoptotic and pro apoptotic proteins. Apoptotic cell death can occur by two different pathways. Type I is initiated by the activation of death receptors (Fas, TNF-receptor-family) on the plasma membrane followed by activation of caspase 8. Type II involves changes in mitochondrial integrity initiated by various effectors, leading to the release of cytochrome c and activation of caspase 9. The thyroid cell destruction characteristic of autoimmune thyroiditis can be seen as the consequence of inappropriate expression of Fas or TRAIL death pathway molecules and down-regulation of the apoptosis controlling protein Bcl-2, which may be induced by cytokines released locally by infiltrating lymphocytes. Thyroid cell destruction in autoimmune hypothyroidism is dependent on T cell-mediated cytotoxicity with the likely additional effect of death receptor-mediated apoptosis. Modulation of apoptosis-related proteins by T helper 1 and T helper 2 cytokines controls thyrocyte survival in thyroid autoimmunity.