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.

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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