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Thyroid Autoimmunity and Cancer

Project Title: Apoptosis in Thyroiditis
Performing Organization: The Regents of the University of Michigan

Primary Investigator: James R. Baker Jr., M.D., Professor of Internal Medicine, Chief, Division of Allergy and Clinical Immunology

Organization Address:
Division of Allergy and Clinical Immunology
Department of Internal Medicine
University of Michigan
1150 West Medical Center Drive
Ann Arbor, MI 48109-0648

Thyroiditis: An Important Clinical Problem:

Overall Program Objective:

The basis of autoimmune thyroid disease remains unclear. Most investigations into the pathogenesis of these disorders have focused on immune abnormalities that might lead to an autoimmune response. However, no unique genetic basis has been identified for the immune response to thyroid autoantigens, and many individuals who demonstrate autoimmune responses to thyroid antigens do not develop autoimmune disease. Recent work on programmed cell death, the mechanism most likely responsible for thyrocyte cytotoxicity in thyroiditis, has indicated that this is a highly regulated process.

Our work, funded by NIH-NIAID, indicates that programmed cell death is highly regulated in thyroid follicular cells and that a major mechanism for the induction of immune mediated apoptosis, the Fas pathway, is blocked by labile protein inhibitor(s) in a manner that could prevent cytotoxicity. These findings have led to the hypothesis that the regulation of programmed cell death pathways in the thyroid may prevent the development of thyroiditis by protecting thyroid cells from immune mediated apoptosis. Altered apoptosis could contribute to the pathogenesis of thyroiditis either by allowing initial cellular damage that leads to an immune response or allowing immune mediated apoptosis of thyroid follicular cells that results in hypothyroidism. Dr. James R. Baker is the Principal Investigator on this project in collaboration with Dr. Su He Wang.

The group has demonstrated the presence of receptors and specific pathway elements for FasL and TRAIL-mediated cell death. These studies strongly suggest a role for these proteins in thyroid pathophysiology. Our efforts focused on understanding the regulation of these receptor-mediated death pathways under different physiological conditions in the thyroid. We have characterized the effects of inflammatory cytokines on the regulation of TRAIL-induced apoptosis in thyroid cells. We have found that the conditions regulating receptor mediated death pathways differ between normal thyrocytes and those derived from thyroid goiters. Other intracellular inhibitors of apoptosis were investigated in detail in normal thyroid cells. We are currently investigating the mechanisms behind the differences in these responses between normal and thyroid cancers.

We have developed a mouse model for destructive experimental autoimmune thyroiditis (EAT) induced by immunization of CBA/J mice with porcine thyroglobulin (pTg) in the presence of IFN-g and TNFa. To model the effect of altered apoptosis on thyroid function we have constructed 2 different transgenic mouse lines capable of expressing different Fas regulatory proteins under the control of a thyroglobulin promoter.

Thyroiditis is an important clinical problem. Chronic (Hashimoto's) thyroiditis is a frequently observed disorder caused by the immune destruction of the thyroid gland. This disease is observed primarily in women (70-80% of cases) and affects 5% of all women by age 70. Patients usually develop a clinical syndrome of hypothyroidism from damaged thyroid follicles and goiter in the presence of serologic evidence of thyroid autoantibodies. As a result, thyroiditis is the most common cause of thyroid dysfunction in the United States and other areas with adequate dietary iodine intake.

It is often difficult to predict which patients will develop hypothyroidism, and this sometimes leads to a delay in appropriate treatment. Thyroiditis also occurs following up to 10% of pregnancies, and leads to a number of clinical problems in these patients. Thyroid hormone is perennially one of the top ten prescribed drugs in the United States, and aside from the cost of this therapy, thyroid hormone replacement may contribute to osteoporosis in women if not appropriately monitored. Thus, while often thought of as innocuous, thyroiditis is an important public health problem.