Apoptosis and cell death in the endocrine system.

Inflammatory diseases of the endocrine system--such as thyroiditis, diabetes, and Graves' disease--are considered to be autoimmune in origin. More recently, these and other autoimmune diseases have been associated with defects in Fas apoptosis. The mutation of the Fas or Fas ligand (FasL) has been observed in a minority of patients with autoimmune disease. However, dysfunction of the Fas apoptosis signaling pathway or production of soluble factors, including sFas and sFasL, may be more prevalent. Certain endocrine tissues, such as the testes, are immune privilege sites. Defects in Fas and FasL expression in immune privilege sites can trigger an inflammatory response. Other factors that trigger inflammatory diseases of the thyroid or islets may be loss of self tolerance, leading to an autoimmune response. An infectious trigger or other environmental agent can initiate organ damage, leading to release of new antigens that initiate the autoreactive process. We have developed a murine cytomegalovirus model of Sjögren's syndrome in which defects in the Fas/FasL pathway are necessary to enable chronic inflammation, even after the initial virus has been cleared. Another interaction between the endocrine system and apoptosis is by direct hormone interaction. This is exemplified by the orphan steroid receptor Nur77. Nur77 is important for T cell apoptosis after signaling through CD3. We have demonstrated that a dominant-negative Nur77 transgenic mouse exhibits a defect in thymic selection of T cells. Therefore, there are many potential mechanisms by which endocrine glands or hormones can affect the Fas apoptosis pathway, resulting in either cell death or a chronic inflammatory disease in the endocrine system, leading to hypothyroidism and diabetes. This inflammatory dysfunction can be reversed by a dominant-negative I kappa B that prevents nuclear translocation of NF-kappa B. We have developed antigen-specific, antigen-presenting cells that express high levels of FasL that can prevent tissue-specific inflammatory disease. Treatment with these cells prevents development of diabetes in NOD mice. Further understanding of the role and regulation of apoptosis in diseases of the endocrine system (e.g., diabetes, thyroiditis) should lead to better methods of treatment and prevention of these diseases.