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Endocrine System > Thyroid: Autoimmune Diseases > Flashcards

Thyroid: Autoimmune Diseases Flashcards

1
Q

What is Hashimotos’ thyroiditis?

A

T-cell-mediated autoimmune disease where the immune system destroys thyroid tissue –> chronic inflammation –> eventual hypothyroidism

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2
Q

What is the genetic association of Hashimoto thyrioditis?

A

Strongly associated with HLA-DR3, predisposes individuals to inappropriate immune responses targeting the thyroid

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3
Q

What are the clinical symptoms of Hashimoto thyroiditis?

A

Hypothyroidism with symptoms like bradycardia, fatigue, weight gain and cold intolerance

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4
Q

What is the mechanism behind Grave’s disease?

A

Production of autoantibodies (TSH receptor antibodies) that stimulate the thyroid-stimulating hormone receptor –> hyperthyroidism

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5
Q

What is the genetic association of Grave’s disease?

A

HLA-B8 and HLA-DR3

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6
Q

What are the clinical symptoms of hyperthyroidism?

A

Weight loss, heat intolerance, tachycardia, and exophthalmos.

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7
Q

How is autoimmunity classified?

A

Clusters that are either organ-specific or systemic

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8
Q

Under which autoimmunity classification are thyroid diseases found?

A

Organ-specific autoimmune diseases

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9
Q

What are the key differences between the categories of autoimmunity?

A

Systemic –> autoimmune cells targeting antigens present all over the body (the target is a common antigen found on many cell types)

Organ-specific autoimmune disorder –> autoimmune response targeting very specific antigens found on those particular organs only

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10
Q

What are the different mechanisms of loss of tolerance?

A
  1. Bystander activation
  2. Adjuvant based/vaccine based activation
  3. Molecular mimicry
  4. Epitope spreading
    5.. Superantigen activation
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11
Q

What is the mechanism of Bystander activation?

A
  1. Infection or tissue damage –> activation of APC
  2. Once APC is activated, apart from presenting antigen, it will also upregulate their surface molecules
  3. APC is now focused on putting the antigen on their surface that they got from the viral infection and primarily activate a virus-specific T cell.
  4. But during the activation, it is not limiting other T cells to come next to it
  5. In this case, it is also going to express some amount of self-antigen, and if it expresses some degree of self-antigen with enough co-stimulation that it has –>it gives a bystander activation
  6. The APC is trying to activate a virus-specific T cell, but just because it is carrying all the things needed to activate a T cell –>, it will end up activating an auto-reactive T cell
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12
Q

What is Bystader activation?

A

A Tcell that just happens to be in that anatomical proximity and just tries to see the antigen on the surface

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13
Q

What happens if the bystander activation is there for extracellular pathogens? Why?

A

It will not really start an autoimmune process as efficiently as a virus-specific immune response because the cytokines that are generated by this APC to activate viral Tcell are the Th1 cytokines, and some will help kick an autoreactive T cell

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14
Q

What happens if an APC is activated as a result of helminthic or parasitic infection (bystander activation)?

A

It will make cytokines that will be of Th2 subclass, and these Th2 will not initiate an immune response.
–> Since B cells need to recognize the antigen to get help from Th2, while a Th1 response will pile up a strong response due to the CD8+

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15
Q

What is the mechanism of adjuvant/vaccine in terms of loss of tolerance?

A
  1. The same bystander activation that we see in case of infection can also be mimicked in cases of vaccines
  2. Vaccines can cause autoimmunity because vaccines, particularly those that we try to use with some adjuvant, are again primarily trying to activate the immune system against the pathogenic peptide
  3. At the same time, you can have the possibility of the vaccine triggering an autoreactive T-cell
  4. The adjuvant of the vaccine is the one responsible for activating the costimulation of APC
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16
Q

What is the result of Pattern recognition receptors enlargement?

A

Costimulation and expression of proinflammatory mediators

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17
Q

What is the mechanism of molecular mimcry in terms of loss of tolerance?

A
  1. A virus or pathogen presents antigens that structurally mimic self-antigens.
  2. These antigens are processed and presented by activated antigen-presenting cells (APCs) to virus-specific T cells.
  3. Once these T cells are activated, they also recognize and attack self-tissues expressing similar antigens, resulting in tissue damage and autoimmunity, in this case, the thyroid.
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18
Q

What is an example of molecular mimicry when it comes to loss of tolerance?

A

Coxsackie virus:
–> Known to mimic antigens found in the endocrine system.
1. Implicated in triggering Type 1 Diabetes Mellitus (T1DM) and Hashimoto’s thyroiditis through molecular mimicry.
2. In the case of Hashimoto’s thyroiditis, the immune system mistakenly attacks the thyroid gland, leading to hypothyroidism.

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19
Q

What is epitope spreading?

A

A process where an initial autoimmune response against a specific self-antigen expands to target additional self-antigens during the progression of the disease

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20
Q

What is the mechanism of epitope spreading in terms of loss of tolerance?

A
  1. Inflammation triggers tissue damage, which leads to an increase in apoptotic cells.
  2. These apoptotic cells release more self-antigens into the environment.
  3. The greater the tissue damage, the greater the amount of self-antigen released. (immune response is directly proportional to the amount of antigen)
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21
Q

What is the role of APCs in epitope spreading?

A

Take up these new self-antigens and present them to autoreactive T cells

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22
Q

Does epitope spreading itself initiate autoimmunity?

A

No, it does not start autoimmunity but worsens it by increasing the range of self-antigens targeted.

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23
Q

How is SLE an example of epitope spreading?

A
  1. In SLE, DNA or nuclear antigens from apoptotic cells act as self-antigens.
  2. APCs present these antigens to T cells, triggering a vicious cycle of inflammation and increased antigen release, worsening the disease.
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24
Q

What are superantigens?

A

Microbial toxins, such as those produced by certain bacteria (Staph. aerus)

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25
Q

Where do superantigens act? What is their effect?

A

They act outside the antigen-binding site of T cell receptors (TCRs) and major histocompatibility complex (MHC) molecules to cause nonspecific activation of T cells.

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26
Q

How do superantigens work? (3)

A
  1. Bridge TCR and MHC II: they link the TCR β-chain on T cells and MHC Class II molecules on antigen-presenting cells (APCs), bypassing the normal antigen-recognition process.
  2. Massive Polyclonal T-Cell Activation: usually only T cells with specific TCRs are activated, but superantigens activate many T cells simultaneously, leading to polyclonal expansion
  3. Prolonged engagement: prolonged binding of superantigens to TCRs and MHC molecules prevents normal immune regulation, which can create an autoimmune potential.
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27
Q

What is the effect of forming a bridge between TCR and MHC Class II (superantigen activation)?

A

Activates T cells regardless of their specificity for the antigen being presented.

28
Q

What is the result of massive polyclonal T-cell activation?

A

Cytokine storm, characterized by the overproduction of pro-inflammatory cytokines like IL-1, IL-2, and TNF-α.

29
Q

How does superantigen activation lead to loss of tolerance? (3)

A
  1. Breach of Specificity: override the specificity of TCRs, allowing autoreactive T cells to become activated
  2. Tissue damage: massive immune activation damages tissues, releasing self-antigens into the environment. Fuel epitope spreading and thus further loss of tolerance
  3. Autoimmunity activation: autoreactive T cells attacking the body’s own tissues, contributing to autoimmune diseases.
30
Q

What can cytokine storm lead to?

A

Toxic shock syndrome

31
Q

What are examples of superantigen-driven autoimmune diseases?

A

Rheumatoid arthritis
Psoriasis

32
Q

What is the gland function?

A
  1. Thyroid epithelial cells –> thyroglobulin
  2. Thyroglobulin is iodinated by peroxidase
  3. TSH from anterior pituitary –> acts on the TSH receptor –> increased synthesis and release of thyroid hormones: T4 and T3 into the bloodstream
  4. Serum T4 and T3 negatively regulate THS secretion by the anterior pituitary
33
Q

Which proteins unique to the thyroid are a target for autoimmune response?

A

Thyroglobulin
Thyroid peroxidase
TSH receptor
Thyroid iodide transporter

34
Q

What are the outcomes of thyroid autoimmune response?

A

Loss of thyroid hormones –> Hypothyroidism
Increase in thyroid hormone production –> Hyperthyroidism

35
Q

What is Grave’s disease / Thyrotoxicosis?

A

Endogenous hyperthyroidism
Anti-receptor antibodies

36
Q

Which age group is targeted by Grave’s disease?

A

20 to 40 years of age
Female: Male –> 10:1

37
Q

What is the immunology behind Grave’s disease?

A

Normal: 1. The pituitary gland secretes TSH which acts on the thyroid to induce the release of thyroid hormones
2. Thyroid hormones then act on the pituitary to shut down the production of TSH, suppressing further hormone synthesis

Grave’s: 1. Autoimmune B cells make antibodies against the TSH receptor that also stimulate thyroid production
2. Thyroid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production
3. The immune system recognizes the TSH receptor as foreign and that is why autoantibodies are formed in the first place

38
Q

Which kind of autoantibodies made against TSH have a pathological effect?

A

The ones that go and bind in the groove where TSH comes in, they bind on the binding of the ligand and they are AGONISTIC

39
Q

What happens of the TSH autoantibodies in Grave’s disease bind to other sites other than the TSH groove?

A

They are not signaling any outcome through the adenylate cclase these antiboides do not have any ptahological outcome

40
Q

Why are there rare cases in which Grave’s patient suffer from HYPOthyroidism?

A

An antibody comes and binds to the TSH receptor at a site other than the active binding site, but it tends to block the ligand (TSH) from approaching and signal through the receptor –> patient will have hypothyroidism withered elevated antibodies against the TSH receptor

41
Q

What is the effect of the auto-antibodies produced that mimic TSH (Grave’s disease)?

A
  1. Receptor-bound IgG antibodies culminate in chronic overproduction of thyroid hormones independent of feedback control
  2. Thyroid growth stimulating Ig leads to the proliferation of the follicular epithelium
42
Q

What is Grave’s disease like in pregannacy?

A
  1. During pregnancy, there is already a generalized immunosuppression throughout the body,
  2. Women suffering from any autoimmune disease such as Grave’s disease” also have remission of symptoms when they get pregnant,
  3. Post-pregnancy, though, the immune system again recalibrates to normal, and flare-ups & relapses are often seen
43
Q

How does neonatal thyrotoxicosis occur?

A

This happens in pregnant women because IgG1 can cross the placenta and reach the neonate

44
Q

What is neonatal thyrotoxicosis?

A
  1. Passive autoreactive antibody to neonatal e
45
Q

What kind of receptors are present on the orbital fibroblast?

A

Thyrotropin receptors

46
Q

How are the thyrotropin receptor activated?

A

TSI binds to TSH on fibroblasts and activates them

47
Q

How does smoking increase the risk of opthalmopathy in Grave’s disease?

A

One of the mechanisms is that smoking gives rise to stronger TNF-a and INF-gamma responses –> smoking is not a condition that may kick start an autoimmune response but aggravate it

48
Q

What is the immunology behind exopthalmos in Grave’s disease?

A
  1. Retro-orbital T cell infiltration
  2. Th1 cytokines –> IFN gamma and TNF alpha –> activation of fibroblasts
  3. Secreteion of extracellular matric: hyaluronic acid, glycosaminoglycans, chondroitin sulfate
  4. Edema and inflammation
  5. Increase in adipocytes
49
Q

Which CD is important for activation of T-cells?

A

CD28, but once T cells are activated, they start expressing CTLA4

CD28 gets displaced because of the high affinity of CTLA4

50
Q

What happens if a person has single nucleotide polymorphisms of CTLA4?

A

CTLA4 is not good at displacing CD28 and it will allow binding of CD28 to CD80/86

51
Q

Wha is the function of protein PTPN22?

A

Responsible for tyrosine kinase activity

52
Q

What happens if there is a mutation in the PTPN22 protein?

A

It helps stimulate T cells much faster than it would normally –> individuals have stronger and faster responses against viral infection, but it could also be that if autoreactive response kicks in, it will be stronger in nature

53
Q

What is chronic thyroiditis/ Hashimoto’s thyroiditis?

A

The most common cause of hypothyroidism with NORMAL iodine levels is gradual thyroid failure

54
Q

Why is there gradual thyroid failure with Hashimoto’s thyroiditis?

A

Thyroid gland is unable to make thyroid hormones, highly localized lesion

55
Q

What is the female to male ratio for chronic thyroiditis / Hashimoto’s thyroiditis?

A

Female: Male
10:1

56
Q

What kind of disorder is Hashimoto’s?

A

T-cell mediated disorder, not B-cell

57
Q

What is Hashimoto’s thyroiditis?

A

A condition in which you have the lysis of the thyroid with a Th1 response, and following lysis, there iscells and phagocytosis. This is initiated by macrophages and stimula a breakdown of ted by Th1

58
Q

What kind of cells are found by the time of diagnosis in Hashimoto’s thyroiditis?

A

Giant cells known as Hürthle cells

59
Q

What are the cells present in Hashimoto’s thyroiditis?

A

Th1
CT2
MØ –> form giant cells
NK
B-cells –> form germinal centers

60
Q

What is the immunological mechanism behind Hashimoto’s?

A
  1. Th1 secrete IFN-gamma and TNF-alpha to activate macrophages
  2. These MØ will engage through:
    –> TCR-MHC
    –> CD40L-DC40
  3. These MØ, in response to this T-cell stimulation, will carry out phagolysosomal fusion more efficiently
  4. If you have chronically increased IFN-gamma and TNF-alpha, it keeps the MØ in a stimulated state
  5. During the stimulated state of phagocytosis activity MØ can become frustrated & reduce functionality
  6. In such conditions, one MØ fuses with another so that the first one can rely on the cytoplasmic contents of the 2nd
  7. That is why they appear as multinucleated giant cells
61
Q

In which thyroid pathology are there massive lymphocytic infiltartes seen?

A

Hashimoto’s NOT in Grave’s

62
Q

Why may MØ become frustrated and lose functionality in stimulated states of phagocytosis (Hashimoto’s)?

A

The storage of product and enzymes for phagocytosis are deplated

63
Q

The B-cells activated in Hashimoto’s disease target what exactly?

A

Target surface proteins of the thyroid follicle, in this case the antibodies come and get deposited and these are IgG, and IgG3 mainly.
Once deposited, they stimulate another cell type –> NK cells

64
Q

What is the effect of IgG antibodies deposited n the thyroid follicular cell?

A

It will engage the CD16, and then when multiple CD16 molecules are engaged, the NK cells will release perforins & granzymes –> killing follicle

65
Q

What are patients with Hashimoto’s like?

A

They will have hyperthyroidism followed by hypo, which will keep on going back and forth because, with each follicle killed and destroyed, the substances from the colloid will give rise to a short spike of hyperthyroidism but over time once the thyroid is damaged enough it will go back to its original hypothyroidism state

66
Q
A

Endocrine System (25 decks)

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