graves disease by ursula corbett and tori sanders immunology dr. steve spilatro
TRANSCRIPT
Graves DiseaseBy Ursula Corbett and Tori Sanders
ImmunologyDr. 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/300px-Thyroxine.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
Infectionsex: Yersinia enterocolitica
Iodine intake
Smoking
Psychic stress
Vaccinesex: NY-ESO-1
Genetic Susceptibility
HLA-DR3
HLA-DR4
HLA-DR9
HLA-DQ2
HLA-DQ3
HLA-A2
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-graves-disease.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_2011.364.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.%20Assessment%20and%20Management%20of%20Patients%20With%20Disorders%20of%20Thyroid%20and%20Parathyroid%20Glands.files/image007.jpg
Pretibial Myxedema5
Endocrinology of GD Hyperthyroidism
http://classes.midlandstech.edu/carterp/Courses/bio211/chap16/chap16.htm
Normal Hyperthyroidism
http://www.ihealthblogger.com/2013/06/graves-disease-symptoms-causes-diet-treatment.html
Thyroid cell
TSH
Auto-antibody bound to TSHR
Stimulating Auto-Antibodies in Graves Disease
TSH receptor (TSHR)
Pituitary gland
Negative feedback control
Unregulated overproduction of thyroid hormones
Regulated production of thyroid hormones
Stimulates hormone synthesis
Stimulates hormone synthesis
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.
http://www.sekisuidiagnostics.com/writable/products/images/320x/bacteria_copy2.jpg
Yersinia enterocolitica
https://books.google.com/books?id=d4l81P7ODcIC&pg=PA522&lpg=PA522&dq=Graves+Disease+molecular+mimicry+amino+acid+sequences&source=bl&ots=xGZpPskdCL&sig=gVj5KlQ-
TntecgvRpEtNK8nP_VA&hl=en&sa=X&ved=0CDYQ6AEwA2oVChMIyP3C-dGVyQIVD_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/import/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 TreatmentFocused 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_08.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
Thyroidectomy- surgical removal of the thyroid
Followed by hormone replacement therapy
https://mdmedicine.files.wordpress.com/2011/05/4185-16-thyroid-gland.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/ht-staging/user_answer/reference_image/7544/large/Radioactive.jpeg?1386669668
Treatments for GO1
Steroids (Prednisone)
Antibiotics with anti-inflammatory/immunomodularity 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: EssayA)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 Choice1. 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 cross-reactive AA sequences with the TSHR.
d) The infection causes increased blood flow to the thyroid gland, creating an excess of TSHR receptors.
Multiple Choice2a. 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 Choice3. Which element is essential to the synthesis of thyroid hormones?
a) Chloride
b) Iodine
c) Nitrogen
d) Carbon
Multiple Choice4. 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