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Graves Disease

By Ursula Corbett and Tori Sanders


Immunology
Dr. Steve Spilatro

http://www.endocrinesurgery.net.au/graves-disease/

What is Graves Disease?


An autoimmune disorder
involving the
overproduction of thyroid
hormones
(hyperthyroidism)

Leading cause of
hyperthyroidism in
developed countries (7080% of cases)

https://embryology.med.unsw.edu.au/embryology/images/thumb/0/02/Thyroxine.jpg/3
00px-Thyroxine.jpg

Epidemiology

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.f
t_.

Risk Factors and Triggers4,7


Non-Genetic Triggers Genetic Susceptibility
Infections
ex: Yersinia
enterocolitica

Iodine intake
Smoking
Psychic stress
Vaccines
ex: NY-ESO-1

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/symptomsof-graves-disease.jpg

Detecting GD in a Clinical
Setting4
*Hyperthyroidism*
Ophthalmopathy
Evidence of bruit
Goiter
Acropachy
Pretibial
myxedema
http://intranet.tdmu.edu.ua/data/kafedra/internal/meds/classes_stud/en/nurse/en/BS
http://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nej
m/2011/nejm_2011.364.issue-7/nejmicm1008597/production/images/medium/nejmic N-(4y)/3%20year/Spring%20semester/Health%20Alteration
%201%20Practicum/21.%20Assessment%20and%20Management%20of%20Patients
m1008597_f1.gif

Pretibial Myxedema

Endocrinology of GD Hyperthyroidism

AutoABS

Normal

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-ca
uses-diet-treatment.html

Infection-Induced Molecular Mimicry 8,9


ABs produced against
Yersinia enterocolitica
share similar AA
sequences as TSHR,
causing the immune
system to mistake the
TSHR as foreign.
AutoimmuneDisease

Yersinia enterocolitica

Cross-reactingSequences
DAFGGVYS

Graves Disease
DALGNVTS

Origin of Peptide
Human thyroid stimulating
hormonereceptor
Yersinia enterocolitica outer
membraneprotein

http://www.sekisuidiagnostics.com/writable/products/images/320x/bacteria_copy2.jp
g
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=0CDYQ6AEwA2oVChMIyP3C-dGVyQIVD_JjCh0gBQUq#v=onepage&q=Graves%20Disease%20molecular%20mimicry%20amino

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 specifc fbroblast 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 dont we target


the auto-ABs?

http://www.lifeextension.com/~/media/lef/images/magazine/mag2012/images/aug2
12_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

Surgery

3,6

Thyroidectomysurgical removal of
the thyroid

Followed by
hormone
replacement
therapy
https://mdmedicine.fles.wordpress.com/2011/05/418516-thyroid-gland.jpg

Radioactive Iodine

3,6

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 antiinflammatory/immun
omodularity 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


classifcation 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.


Identifcation 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 persons 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 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?

2b. What is the preferred treatment


for Graves Disease in the United
States?

a) Targeting the constant region of the


auto-ABs could lead to systemic
immunodefciency by inactivating all
ABs of that isotype.

c) Radioiodine therapy

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.
\

a) Thyroidectomy
b) The drug, MMI

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