This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
Disease OverviewGrave’s disease is an autoimmune thyroid disease that specifically induces hyperthyroidism. In an autoimmune disorder, the immune system is reactive to the body’s own cells and organs. With Grave’s disease, the immune system mistakenly produces antibodies directed against the thyroid stimulating hormone (thyrotropin) receptors. The result is excessive production of the thyroid hormones which circulate in the body to cause pathology. [1]
The thyroid gland is a hormone secreting organ located in the front of the neck that synthesizes triiodothyronine (T3) and thyroxine (T4), which circulate through the blood stream and function to control metabolism. The regulation of metabolism has direct effects on mood, weight, mental and physical energy levels. Hyperthyroidism results when the body produces excessive thyroid hormones. [2] Grave’s disease is the leading cause of hyperthyroidism in the United States, occurring in women seven times more frequently than in men. About 0.5% of people in western populations suffer from the disorder. Common symptoms of Grave’s disease hyperthryoidism are fatigue, irritability, heat intolerance, increased sweating, increased appetite, trouble sleeping, hand tremors, weight loss, rapid or irregular heartbeat, and goiter [2]. About 35% of individuals also develop Grave’s ophthalmopathy which is an inflammatory disease of the orbital tissues [1]. An individual’s aberrant immune system attacks the muscle and tissue behind the eye resulting in a buildup of adipocytes (fat) and fibroblasts (tissue) [3]. The condition results in the commonly observed bulging eyes and vision complications [2]. |
Treatment
Grave’s disease can be diagnosed and treated using several different methods. Blood tests that measure TSH and T3/T4 are diagnostic for hyperthyroidism. Low TSH and high T3/T4 occur with thyroid dysfunction. A radioactive iodine uptake test can indicate Grave’s disease. Grave’s disease can also be distinguished by identifying TSH receptor antibody in the blood stream. Treatment of Grave’s disease involves three options: radioiodine therapy, medications, or surgical removal. Radioiodine therapy gradually destroys the thyroid gland so hormone replacement therapy will be necessary. Antithyroid medications interfere with thyroid hormone production, but this method requires frequent health care monitoring. Surgical removal of the thyroid also requires hormone replacement therapy. Grave’s disease normally responds well to treatment, however hypothryroidism is commonly observed. [1]
CTLA4: Grave's Disease
Autoimmune thyroid disorders display a multifactor pattern of inheritance, with environmental and genetic factors [5]. A major susceptibility locus has been identified as cytotoxic T-lymphocyte associated antigen 4 (CTLA4). The CTLA4 locus encodes an immunoregulatory molecule that is expressed on the surface of activated T cells. The molecule has been shown to provide an inhibitory signal to T cells, limiting the immune response by modulating tolerance and down regulating proliferation. The genes involvement in the immune response makes it susceptible to autoimmune thyroid disorders. When the surface expression of the protein is decreased, negative modulation of the immune response is lost, leading to Grave's Disease.[4]
The human CTLA4 gene spans 6.2kb located at the q-terminus of chromosome 2, consisting of four exons. The fist exon encodes a leader sequence, the second an immunoglobulin V-like domain, the third a hydrophobic trans-membrane region, and the fourth a cytoplasmic domain. [3] There are several polymorphisms of the gene that can affect the T-effector activity of the gene. In particular, the A49G dimorphism resulting in a threonine/alanine peptide exchange has been linked to Grave’s disease in the majority of populations. This polymorphism leads to the expression of a defective receptor, so the inhibitory effect of the receptor on T cell activation is impaired [5].
The human CTLA4 gene spans 6.2kb located at the q-terminus of chromosome 2, consisting of four exons. The fist exon encodes a leader sequence, the second an immunoglobulin V-like domain, the third a hydrophobic trans-membrane region, and the fourth a cytoplasmic domain. [3] There are several polymorphisms of the gene that can affect the T-effector activity of the gene. In particular, the A49G dimorphism resulting in a threonine/alanine peptide exchange has been linked to Grave’s disease in the majority of populations. This polymorphism leads to the expression of a defective receptor, so the inhibitory effect of the receptor on T cell activation is impaired [5].
[1] National Endocrine and Metabolic Diseases Information Service. (2012). Grave’s Disease. Retrieved February 7, 2013 from http://www.endocrine.niddk.nih.gov/pubs/graves/
[2] AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8(6). Retrieved Februrary 7, 2013 from https://www.aace.com/files/hypo-hyper.pdf
[3] Chistiakov D., Turakulov R., (2003). CTLA-4 and its role in autoimmune thyroid disease. J Mol Endocrinol, 31, doi: 10.1677/jme.0.0310021
[4] Vaidya, B., Oakes, E. J. C., Imrie, H., Dickinson, A. J., Perros, P., Kendall-Taylor, P. and Pearce, S. H. S. (2003), CTLA4 gene and Graves’ disease: association of Graves’ disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism. Clinical Endocrinology, 58: 732–735. doi: 10.1046/j.1365-2265.2003.01778.x
[5] Pastuszak-Lewandoska D., Sewerynek E., Domańska D., Gładyś A., Skrzypczak R., Brzeziańska E. (2012) CTLA-4 gene polymorphisms and their influence on predisposition to autoimmune thyroid diseases (Graves’ disease and Hashimoto's thyroiditis). Arch Med Sci, 8(3). doi: 10.5114/aoms.2012.28593
[6] U.S National Library of Medicine: Genetics Home Reference. CTLA4. February 7, 2013. Retrieved from: http://ghr.nlm.nih.gov/gene/CTLA4
[2] AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8(6). Retrieved Februrary 7, 2013 from https://www.aace.com/files/hypo-hyper.pdf
[3] Chistiakov D., Turakulov R., (2003). CTLA-4 and its role in autoimmune thyroid disease. J Mol Endocrinol, 31, doi: 10.1677/jme.0.0310021
[4] Vaidya, B., Oakes, E. J. C., Imrie, H., Dickinson, A. J., Perros, P., Kendall-Taylor, P. and Pearce, S. H. S. (2003), CTLA4 gene and Graves’ disease: association of Graves’ disease with the CTLA4 exon 1 and intron 1 polymorphisms, but not with the promoter polymorphism. Clinical Endocrinology, 58: 732–735. doi: 10.1046/j.1365-2265.2003.01778.x
[5] Pastuszak-Lewandoska D., Sewerynek E., Domańska D., Gładyś A., Skrzypczak R., Brzeziańska E. (2012) CTLA-4 gene polymorphisms and their influence on predisposition to autoimmune thyroid diseases (Graves’ disease and Hashimoto's thyroiditis). Arch Med Sci, 8(3). doi: 10.5114/aoms.2012.28593
[6] U.S National Library of Medicine: Genetics Home Reference. CTLA4. February 7, 2013. Retrieved from: http://ghr.nlm.nih.gov/gene/CTLA4