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BIOL2022 > Autoimmunity > Flashcards

Autoimmunity Flashcards

1
Q

Give some examples of autoimmune diseases?

A
  • Multiple sclerosis (MS)
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
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2
Q

LO

A
  • Describe how breakdown of the normal functioning of the immune system leads to autoimmune diseases
  • Explain why plasticity of the immune system in pathogen recognition comes at a price

Key POINTS:

  • effectors of acquired immunity: antibodies, T-cells
  • antigen presentation by professional APCs
  • mechanisms of tolerance
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3
Q

Statistics of autoimmune diseases

A

Prevalence of autoimmune diseases:

  • 4 million in the UK (2018)
  • 1 in 5 persons (2018)
  • 75% of autoimmune occur in women (2018)
  • 4th largest cause of disability among women
  • Rheumatoid Arthritis affects 1 in 100 people
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4
Q

Tell me the stages to a normal CD4 T cell response

A
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5
Q

What causes autoimmunity?

When does it occur?

A

The immune system normally can distinguish “self” from “non-self.

Autoimmune diseases occur when:

  • the usual control process is interrupted, allowing lymphocytes to avoid suppression
  • when there is an ‘alteration’ in cells/tissue so that it is no longer recognized as “self” and is thus attacked.
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6
Q

Why may bacteria, viruses, toxins and some drugs play a role in triggering an autoimmune process?

A

Bacteria, viruses, toxins, and some drugs may play a role in triggering an autoimmune process in someone who already has a genetic (inherited) predisposition to develop such a disorder

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7
Q

How does the immune system discriminate between proteins from self and foreign proteins?

A

Tolerance is the prevention of an immune response against a particular antigen. For instance, the immune system is generally tolerant of self-antigens, so it does not usually attack the body’s own cells, tissues, and organs

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8
Q

When this ‘tolerance’ to self breaks down, what does it give rise to?

A

Autoimmune diseases

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9
Q

What did Rete C Doherty and Rolf M Zinkernagel win the nobel prize for?

Tell me about their experiment and what they found out?

A
  • Win the Nobel Prize in 1996 for their discoveries concerning “the specificity of the cell mediated immune defence”.
  • In 1970 immunologist learned to generate cytotoxic T cell for virus infected cells
  • Mice infected with lymphocyte choriomeninges virus (LCM) produce CTLs that could lyse LCM-infected target cells in vivo
  • These CTLs fail to bind to free virus or viral antigens:
  • DIFFERENT FROM B CELLS
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10
Q

Tell me the evidence for the role of the thymus in T cell development and the experiment used in this idea

A
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11
Q

What are the two types of tolerance?

A

Central and peripheral tolerance

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12
Q

What is Central tolerance?

A

Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides.

When T cell mature in the thymus, they are checked for their reactivity against self. T cells which react against self are destroyed.

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13
Q

Whats Peripheral tolerance?

A

Peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery (after T and B cells egress from primary lymphoid organs). Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease.

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14
Q

Whats needed for T cell activation?

A

T cell activation: recognition of self MHC + foreign antigen

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15
Q

What is tolerance?

A

The lack of an immune response to self

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16
Q

Tell me the selection stages that a T-cell precursor goes through before maturing into CD4+ or CD8+ T lymphocytes

A
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17
Q

Tell me the stages of central tolerance?

A

Steps of T cell tolerance

  1. During positive selection, T cells are checked for their ability to bind peptide-MHC complexes with affinity. If the T cell cannot bind the MHC class I or MHC class II complex, it does not receive survival signals, so it dies via apoptosis. T cell receptors with sufficient affinity for peptide-MHC complexes are selected for survival.
  2. Depending on whether the T cell binds MHC I or II, it will become a CD8+ or CD4+ T cell, respectively.
  3. Positive selection occurs in the thymic cortex with the help of thymic epithelial cells that contain surface MHC I and MHC II molecules..
  4. During negative selection, T cells are tested for their affinity to self. If they bind a self peptide, then they are signaled to apoptose (process of clonal deletion).
  5. The thymic epithelial cells display self antigen to the T cells to test their affinity for self.
  6. Transcriptional regulators AIRE and Fezf2 play important roles in the expression of self tissue antigens on the thymic epithelial cells in the thymus.
  7. Negative selection occurs in the cortico-medullary junction and in the thymic medulla.
  8. The T cells that do not bind self, but do recognize antigen/MHC complexes, and are either CD4+ or CD8+, migrate to secondary lymphoid organs as mature naïve T cells.
  9. Regulatory T cells are another type of T cell that mature in the thymus. Selection of T reg cells occurs in the thymic medulla and is accompanied by the transcription of Foxp3. T reg cells are important for regulating autoimmunity by suppressing the immune system when it should not be active
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18
Q

T cells in the circulation recieve their signals from where in order to survive?

What happens when these control systems fail?

A

T cells in the circulation must receive signals from normal cellular tissue to survive. When these control systems fail, the immune system can react against our own molecules

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19
Q

Tell me about peripheral tolerance

A

Peripheral tolerance: deletion or anergy (absence of the normal immune response to a particular antigen or allergen) of lymphocytes that recognize self-antigens in peripheral tissue

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20
Q

What can lead to anergy or inactivation of T cells?

A

Lack of accessory signals in presence of TCR engagement with MHC-peptide may lead to anergy or inactivation.

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21
Q

What do T reg cells respond to?

A

T reg cells will respond to Ag but induce an inhibitory response (regulation)

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22
Q

Tell me about escape tolerance?

A

Some lymphocytes with low affinity for self-antigens make no response to the antigen: escape tolerance= ignorant to self.

If stimulus is strong enough these cells can be activated (infection)

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23
Q

Tell me the three mechanisms by which self-tolerance is maintained, and how this distinguishes self from non-self?

A
  1. Encounter the ligand when still immature

(Central and peripheral tolerance)

  1. High and constant concentration of ligand
  2. Binding of ligand without co-stimulation
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24
Q

Tell me the light and heavy chain subunits that define the antibody isotopes

A
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25
Q

Diagram showing where central tolerance occurs

A
  • Clonal selection and immunological memory
  • Each B cell has a specific antibody as a cell surface receptor.
  • The arrangement and generation of antibody genes occurs prior to any exposure to antigen.
  • When a soluble antigen is present, it binds to the antibody on the surface of B cells that have the correct specificity.
  • These B cells develop into antibody-producing plasma cells or memory cells
  • Only B cells which are antigen specific, are capable of secreting antibodies
  • Following initial expose to antigen, the plasma cell stops producing antibody and die
  • Memory cells remain in greater number than the initial B cells, allowing the body to quickly respond to a second exposure of that antigen
  • Second immune response is faster and produces more Ab with higher affinity
  • The higher affinity comes from a mechanism that alters the variable region of light and heavy chains of the memory cells by specific somatic mutations
  • This is a random process that by chance can improve antigen binding
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26
Q

What can cross linking of IgM on immature B cells cause?

A

Cross linking of IgM on immature B cells can cause cell death

  • Binding of self-reactive IgM to self-antigen
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27
Q

What did Nemazee and Burki do experiments on/about?

Tell me the three scenarios they came across

A

Transgenic mouse expressing heavy and light chain for Kk (this is an antigen) into H-2d and H-2d/kmice (MHC class molecules which are strain d and k)

1. H-2d/k transgenics

2. H-2d transgenics

3. H-2d/k transgenics with RAG expression

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28
Q

Tell me about H-2d/k transgenics

A
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29
Q

Tell me about H-2d transgenics

A
30
Q

Tell me about H-2d/k transgenics with RAG still expressed

A
31
Q

What are the two types of transgenics?

A
  1. Expressing antigen
  2. Expressing antibodies against this antigen (re-arranged genes for heavy and light chains)
32
Q

Tell me about the experiment on transgenic mice to double transgenic mice

A
33
Q

The concentration of HEL and IgM occupancy appears to determine whether the peripheral HEL-reactive B cells become anergic or not, describe the 4 different outcomes of immature B cells in the bone marrow

A
34
Q

What are the two types of autoimmune diseases that can occur?

A

Organ specific autoimmunity (target antigen is unique to a single organ or gland, manifestations largely limited to that organ: cellular damage, over-stimulation, or blockade)

Systemic autoimmunity

35
Q

Some autoimmune diseases in humans

A
36
Q

Tell me about Pernicious anaemia?

What is it due to?

Symptoms?

Treatment?

A
  • Auto-antibodies against membrane bound intestinal proteins on gastric parietal cells (intrinsic factor)
  • Blocks B12 absorption which is needed for haematopoiesis
  • Number of red cells down regulated
  • Weakness, fatigue, peripheral nerve damage, jaundice…
  • B12 replacement therapy at treatment
37
Q

Tell me about the history for the treatment for pernicious anaemia?

A
  • In 1907: first report of pernicious anaemia: survival between 1-3 years
  • Hamburger meat: first demonstration of an ‘intrinsic factor; from gastric juice
  • In 1920: make dogs anaemia, different food as treatment: liver!
  • In 1926: raw liver juice as treatment
  • 1934: Nobel prize in medicine
  • In 1928: liver extract more potent, and injectable into muscle (Cohn)
  • In 1948: active ingredient discovered: vitamin B12
38
Q

Tell me the following about the thyroid gland?

location/ appearance?

Synthesises?

Regulates?

TSH location?

A
39
Q

Tell me about an autoimmune disease that can occur at the thyroid gland?

A
40
Q

Comparison in thyroid glands between those with normal and Hashimoto’s disease

A
41
Q

What is Hashimoto thyroiditis disease due to?

A
  • First disease to be recognised as an autoimmune disease
  • Autoreactive antibodies and T cells that attack the thyroid
42
Q

Tell me some phenotype symptoms of Hashimoto’s disease?

A

Inflammation

enlargement of thyroid

gradual destruction of follicles in thyroid

43
Q

Tell me the tyroid blocking antibodies involved with Hashimoto’s disease

A
  • thyroid-stimulating hormone (TSH) receptor,
  • thyroid peroxidase and or thyroglobulin

….. inadequate iodine uptake

……inadequate thyroid hormone production and secretion

44
Q

Tell me the genetics of middle ages females with Hashimoto’s disease and the symptoms they could experience

A

Genetics: HLA-DR5, CTLA4

Symptoms: weight gain, depression, mania, sensitivity to cold, fatigue, panic attacks, tachycardia

45
Q

What is Hashimoto disease often misdiagnosed for and how it this diagnostic difficulty dealt with?

A

Hashimoto’s thyroiditis is often misdiagnosed as depression

Testing for-thyroid antibodies can resolve any diagnostic difficulty.

46
Q

Tell me about another autoimmune disease involved with the thyroid?

Tell me a phenotype often associated with this disease?

A

Grave’s disease

Bulging eyes is a typical symptom of patients with graves disease

47
Q

Tell me about the stimulating autoantibodies associated with Graves’ disease

A
48
Q

Tell me about Graves’ disease…

Most common form of what?

Overproduction of…?

Long-acting…?

Increases…?

A
  • Most common form of hyperthyroidism -overproduction of thyroxine
  • Long-acting thyroid-stimulating antibodies (LATS).
  • Increases metabolic rate by 60-100%.
49
Q

Symptoms of Graves’ disease?

A

anxiety

irregular heartbeat

fatigue

tremor

exophthalmos (bulging of eye out of socket)

50
Q

Are men or women more commonly affected by Graves’ disease?

A

Women more commonly affected than men 8:1.

51
Q

What is the cause of Graves’ disease

A

Causes not known but factors include genetics (HLA DR3), sex, age, stress

52
Q

This is what should happen normally…

Compare this to Graves’ disease

A
53
Q

Is Lupus a systemic or organ-specific immune disease?

A

systemic disease that attacks many tissues

54
Q

Is Lupus more common in men or women?

A

More common in women than men (9:1) as immune system in females is different to men and women may have a greater humoral response in women than men

55
Q

What are the symptoms of Lupus?

A

Symptoms include fever, arthritis, skin rash, pleurisy, kidney dysfunction

56
Q

What are the auto-antibodies to in Lupus?

A

Auto-antibodies to DNA, histones, RBCs etc

57
Q

What leads to Vasculitis (Vasculitis means inflammation of the blood vessels) in those with lupus?

A

Immune complex formation and complement activation leading to vasculitis.

58
Q

Auto-antibodies bind to basement membrane in the glomerulus of the kidney resulting in immune-complex driven inflammation

A
59
Q

Nucleic acid containing immune complexes from dying cells acticate dendritic cells

A
60
Q

Name an autoimmune disease of the brain?

A

Multiple sclerosis

61
Q

Tell me about the pathogenesis of MS?

What does it cause?

Tell me the steps?

A
  • Pathogenesis of MS: MS is currently classified as an autoimmune disease of the CNS. The diseases attacks myelin causing inflammation and damages the myelin.
  • Causes activation of B cells and production of Antibodies

1. BBB becomes permeable to leukocytes and blood proteins

2a. T cells interact with B cells

2b. T cells interact with microglia

3. Antibodies and cytokines are released

4. Demyelination of neurons

62
Q

Evidence that MS is a T cell driven autoimmune disease

A
63
Q

What are the possible causes of autoimmune diseases?

A
  • Release of sequestered antigen (CNS, eye)
  • Molecular mimicry (infectious agents, neoplasms)
  • Inappropriate activation of MHC Class II
  • Polyclonal activation of B-cell e.g., by infectious agent
  • Unlikely to be a single cause
  • Complex interplay between genetic and environmental factors
64
Q

Table showing the molecular mimicry between proteins of infectious organisms and human host proteins

A
65
Q

Compare the production differences in the pancreas between those who are healthy and those who are diabetic

A
66
Q

Tell me the stages to the immune response to those with type 1 diabetes

A
67
Q

Autoimmunity and inappropriate MHC II expression

A
68
Q

Tell me some therapeutic interventions to autoimmune diseases

A
  • Immunosuppression - corticosteroids, azathioprine, cyclophosphamide - cyclosporin
  • Immunomodulation - beta-interferon.
  • Anti-inflammatory drugs - alpha4beta1, TNF-alpha blockade.
  • Selective blockade of TCR or MHC
  • Re-establish tolerance -oral antigens, mucosal antigens
69
Q

Autoimmune diseases are…?

  • Rare?
  • Transmittable, infectious?
  • Genetically determined?
  • Caused by changes in the environment (climate change, diet)?
  • Caused by infections?
  • More common in women than men?
A
  • Rare (no)
  • Transmittable, infectious (no)
  • Genetically determined (yes, MHC haplotype, cytokine receptors: but an additional trigger is needed)
  • Caused by changes in the environment (climate change, diet). Yes: sun, drugs
  • Caused by infections (yes, bacteria, molecular mimicry)
  • More common in women than men (yes, Pregnancy)
70
Q
A

1b and 2a?

BIOL2022 (8 decks)

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