Transcript gravesx
Graves Disease By Ursula Corbett and Tori Sanders Immunology Dr. Steve Spilatro http://www.endocrinesurgery.net.au/graves-disease/ What is Graves Disease?4 An autoimmune disorder involving the overproduction of thyroid hormones (hyperthyroidism) Leading cause of hyperthyroidism in developed countries (70-80% of cases) https://embryology.med.unsw.edu.au/embryology/images/thumb/0/02/Thyroxine.jpg/300pxThyroxine.jpg Epidemiology4 Annual incidence in developed countries is 14/100,100 More common in females (5:1 ratio) http://p-fst1.pixstatic.com/506ad86bdbd0cb306c0018aa._w.1500_s.fit_.jpg Risk Factors and Triggers4,7 Non-Genetic Triggers Infections ex: Yersinia enterocolitica Iodine intake Genetic Susceptibility HLA-DR3 HLA-DR4 HLA-DR9 Smoking HLA-DQ2 Psychic stress HLA-DQ3 Vaccines HLA-A2 ex: NY-ESO-1 Symptoms of Hyperthyroidism4 Nervousness Palpitations Heat Intolerance Increased appetite Weight loss Tremor of hands http://cdn1.medicalnewstoday.com/content/images/articles/170/170005/symptoms-of-gravesdisease.jpg Detecting GD in a Clinical Setting4 *Hyperthyroidism* Ophthalmopathy Evidence of bruit Goiter Acropachy Pretibial myxedema http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2011/nejm_2 011.364.issue-7/nejmicm1008597/production/images/medium/nejmicm1008597_f1.gif http://intranet.tdmu.edu.ua/data/kafedra/internal/meds/classes_stud/en/nurse/en/BSN(4y)/3%20year/Spring%20semester/Health%20Alteration%201%20Practicum/21.%20Assessme nt%20and%20Management%20of%20Patients%20With%20Disorders%20of%20Thyroid%20and Pretibial Myxedema5 Endocrinology of GD Hyperthyroidism http://classes.midlandstech.edu/carterp/Courses/bio211/chap16/chap16.htm Stimulating Auto-Antibodies in Graves Disease Auto-antibody bound to TSHR Pituitary gland TSH TSH receptor (TSHR) Negative feedback control Stimulates hormone synthesis Stimulates hormone synthesis Thyroid cell Regulated production of thyroid hormones Unregulated overproduction of thyroid hormones http://www.ihealthblogger.com/2013/06/graves-disease-symptoms-causesdiet-treatment.html Infection-Induced Molecular Mimicry8,9 ABs produced against Yersinia enterocolitica share similar AA sequences as TSHR, causing the immune system to mistake the TSHR as foreign. Autoimmune Disease Graves Disease Yersinia enterocolitica Cross-reacting Sequences DAFGGVYS DALGNVTS Origin of Peptide Human thyroid stimulating hormone receptor Yersinia enterocolitica outer membrane protein http://www.sekisuidiagnostics.com/writable/products/images/320x/bacteria_copy2.jpg https://books.google.com/books?id=d4l81P7ODcIC&pg=PA522&lpg=PA522&dq=Graves+Disease+molecular+mimicry+amino+acid+sequences&source=bl&ots=xGZpPskdCL&sig=gVj5KlQTntecgvRpEtNK8nP_VA&hl=en&sa=X&ved=0CDYQ6AEwA2oVChMIyP3CdGVyQIVD_JjCh0gBQUq#v=onepage&q=Graves%20Disease%20molecular%20mimicry%20amino%20acid%20sequences&f=false Vaccine-Induced Molecular Mimicry7 NY-ESO-1 vaccination used in immunotherapy for cancer patients Shares 5 homologous epitopes with the TSHR Genetic susceptibility is key http://discovermagazine.com/~/media/impor t/images/2/3/1/vaccine.jpg Additional Manifestation of Molecular Mimicry for GO & PM2,5 TSHR is expressed in specific fibroblast cells of the orbital/tibial regions Same auto-ABs bind Causes an inflammatory response that sensitizes T-cells and launches an additional immune response Induces swelling in muscle and connective tissue Primary Treatment Focused on treating hyperthyroidism by: 1. Medication 2. Surgery 3. Radioactive Iodine Why don’t we target the auto-ABs? http://www.lifeextension.com/~/media/lef/images/magazine/mag2012/images/aug2012_thyroid 8.ashx Medication3,6 Beta blockers- symptoms unrelated to the thyroid gland PTU (propylthiouracil)- interferes with synthesis of thyroid hormones and inhibits peripheral conversion of T4 to T3 MMI (methimazol)- interferes with the synthesis of thyroid hormones http://www.progressivehealth.com/downloads/headerImages/THYROID%20MEDICATIONS.png Surgery3,6 Thyroidectomysurgical removal of the thyroid Followed by hormone replacement therapy https://mdmedicine.files.wordpress.com/2011/05/4185-16-thyroidgland.jpg Radioactive Iodine3,6 Preferred treatment in the U.S. Exposed to radioactive iodine that is taken up by the thyroid gland. Radioactivity destroys the function of the gland. At one year follow ups, 90% of patients are at an euthyroid or hypothyroid state. Followed by hormone replacement therapy. https://edc2.healthtap.com/htstaging/user_answer/reference_image/7544/l arge/Radioactive.jpeg?1386669668 Treatments for GO1 Steroids (Prednisone) Antibiotics with antiinflammatory/immunom odularity features (Doxycycline) Orbital decompression surgery http://iovs.arvojournals.org/article.aspx?articleid=2188086 References 1. Hiromastu Y, Wall JR, Kahaly GJ, Kakizaki H. 2015. Graves’ orbitopathy. International Journal of Endocrinology 2015: 1-2. 2. Khalilzadeh O, Noshad S, Rashidi A, Amirzargar A. 2011. Graves’ ophthalmopathy: a review of immunogenetics. Current Genomics 12: 564-575. 3. Klein I, Becker DV, Levey GS. 1994. Treatment of hyperthyroid disorders. Annals of Internal Medicine 121(3): 281-288. 4. Menconi F, Marcocci C, Marino M. 2014. Diagnosis and classification of graves’ disease. Autoimmunity Reviews 13(2014): 398-402. 5. Prabhakar BS, Bahn RS, Smith TJ. 2003. Current perspective on the pathogenesis of graves’ disease and ophthalmopathy. Endocrine Reviews 24(6): 802-835. References Continued 6. Streetman DD, Khanderia U. 2003. Diagnosis and treatment of graves’ disease. The Annuals of Pharmacotherapy 37: 1100-1109. 7. Vita R, Guarneri F, Agah R, Benvenga S. 2014. Autoimmune thyroid disease elicited by ny-eso-1 vaccination. THYROID 24(2): 390-394. 8. Wang Z, Zhang Q, Lu J, Jiang F, Zhang H, Gao L, Zhao J. 2010. Identification of outer membrane porin f protein of Yersinia enterocolitica recognized by antithyrotropin receptor antibodies in graves’ disease and determination of its epitope using mass spectrometry and bioinformatics tools. Journal of Clinical Endocrinology and Metabolism 95(8): 4012-4020. 9. Zhang H, Kaur I, Niesel DW, Seethamaiah GS, Peterson JW, Justement LB, Prabhakar BS, Klimpel GR. 1996. Yersinia enterocolitica envelope proteins that are crossreactive with the thyrotropin receptor (TSHR) also have b-cell mitogenic activity. Journal of Autoimmunity 9:509-516. Special Acknowledgements A special thanks to Dr. Jane Cases, M.D., Dr. Douglas Virostko, M.D., and Drs. David and Brenda Lozowski, D.O., for their valuable feedback and input for “Detecting GD in a Clinical Setting”. Study Questions: Essay A) Describe the negative feedback control loop that normally occurs for TRH, TSH, and thyroid hormones. B) In GD, how do thyroid auto-antibodies interfere with the production of hormones and the feedback control loop? Multiple Choice 1. Why would being infected by Yersinia enterocolitica increase a person’s risk for developing Graves Disease? a) Extracellular domains of the bacterium bind to the TSHR. b) The infection stimulates the synthesis of T3 and T4. c) The antibodies produced against this bacterium have crossreactive AA sequences with the TSHR. d) The infection causes increased blood flow to the thyroid gland, creating an excess of TSHR receptors. Multiple Choice 2a. Treatment of Graves Disease focuses on the symptoms of the disease rather than targeting the antibodies causing the overproduction of thyroid hormones. Which of the following scenarios make it difficult to target the auto-ABs? a) Targeting the constant region of the auto-ABs could lead to systemic immunodeficiency by inactivating all ABs of that isotype. b) Targeting B cells creates the risk of diminishing the entire humoral response. c) Targeting the variable region of the auto-ABs is too difficult due to great diversity. d) All of the above are true. \ 2b. What is the preferred treatment for Graves Disease in the United States? a) Thyroidectomy b) The drug, MMI c) Radioiodine therapy d) The drug, PTU Multiple Choice 3. Which element is essential to the synthesis of thyroid hormones? a) Chloride b) Iodine c) Nitrogen d) Carbon Multiple Choice 4. When testing for GD hyperthyroidism, a blood test would check for low levels of _____ and/or high levels of _____. a) thyroid stimulating hormone; T3 and T4 b) thyrotropin-releasing hormone; thyroid stimulating hormone c) T3 and T4; thyroid stimulating hormone d) thyroid stimulating hormone; thyrotropin-releasing hormone