• Credits

  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

• Q. Which organs have TSH receptors and hence are affected by TSH receptor antibodies in Graves’ disease?

  • Thyroid
  • Fibroblasts – including orbital fibroblasts
  • Adipocytes – including orbital adipocytes
  • Bone cells

• Q. What is the histopathological feature in Graves’ disease?

  • Patchy lymphocytic infiltration
  • Follicular hyperplasia
  • Reduction of follicular colloid

• Q. What is the nature of the lymphocytes?

  • They are mainly T cells
  • Some B cells may be present

• Q. Which antibody is associated with Graves’ disease?

  • TRAb
    • TSH receptor antibody – which is stimulating TSI (TSI- TRAb)

• Q. What is the class of TRAb?

  • It is an IgG1 antibody
  • It is oligoclonal, unlike TPO and Anti Tg, which are polyclonal

• Q. Does TRAb values help in the follow-up of a patient on ATD treatment?

  • Yes it does
  • At the time of discontinuation of ATD  if TRAb is high- chances of recurrence are hight

• Q. What happens to TRAb after radioactive iodine therapy?

  • Transient increase of TRAb- that’s why orbitopathy worsens
  • It normalizes in 3-5 months
  • Then slowly declines over years

• Q. What happens to TRAb after thyroid surgery?

  • The rapid decline in levels are seen
  • By 18 months- 80% of TRAb disappear after surgery

• Q. What are the types of TRAb antibodies?

  • Stimulating
  • Blocking
  • Neutral

• Q. What subtype of TRAb is seen in Graves’ disease?

  • A mixture of stimulating and blocking antibody- mainly stimulating antibody

• Q. Which are the specific T cells which are pathogenic in Graves’?

  • CD4+ Th1 cells – predominate
  • They produce IL2, TNF alpha, and Interferon-gamma
  • They activate CD8 T cell
  • CD4 Th2 are also present
  • Graves is a mixture of CD4 Th1 + Th2
  • Hashimoto’s is a predominantly Th1 disease

• Q. Which of these cytokines increases the production of TRAb antibodies?

  • Interferon-gamma is the main culprit here

• Q. Which are the costimulatory molecule for T Cell activation by APC in Graves, and which is it in type 1 diabetes?

  • Type 1 diabetes- costimulatory molecules are CD28 interacting with CD80 and 86
  • In Graves', it is CD40

• Q. Why does Graves’ disease become milder in pregnancy?

  • Because of the  increase of Treg – regulatory T cells

• Q. Which are the possible immune mechanisms which activate the autoimmunity in Graves’?

  • Three possible problems:
    • Molecular mimicry – bacterial heat shock protein, Yersinia, Retroviral sequences
    • Thyroid cell HLA expression
    • Bystander activation

• **Precipitating factors **

• Q. Which HLA subtypes are associated with Graves’ disease?

  • HLA-DR8 is associated
  • However, the association is weak, and hence typing is not useful

• Q. Can infections predispose to thyroid autoimmune disease?

  • Yes
  • Some have been implicated, like retrovirus and hepatitis C
  • However, none have been proven

• Q. Can stress precipitate Graves’?

  • Yes
  • Stress  increase cortisol → suppression of immunity → rebound hyperimmune response once cortisol is relived

• Q. Why do females have more Graves’ disease?

  • It is not exactly known
  • However, the moderate amount of estrogen stimulate autoimmunity – neither high nor low amounts

• Q. What is the relation of pregnancy with graves’?

  • Graves’ becomes milder in pregnancy
  • However, many new cases of Graves are precipitated in the postpartum period
  • The presence of fetal cells in the mother may be responsible- this is called Fetal microchimerism

• Q. Which drugs can precipitate Graves’ disease?

  • Iodine
  • Amiodarone
  • Almetezumab used in Multiple sclerosis
  • Interferon alpha- used in hepatitis C

• Q. Summarize the precipitating factors which can predispose to graves’ disease?

  • HLA subtypes and genes- HLA DR8
  • Female sex – moderate estrogen influence
  • Postpartum status – Fetal micromimicry
  • Infection- Yersinia, Retrovirus, hepatitis C
  • Drugs
  • Smoking
  • Stress

• Q. Summarize the pathogenesis of Graves’ disease?

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