Download Stimulating Auto-Antibodies in Graves Disease

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