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PATH30001 - Mechanisms of Disease > Lecture 12 - Autoimmunity > Flashcards

Lecture 12 - Autoimmunity Flashcards

1
Q

What is the key discrimination in the immune response?

A

Self vs. non-self

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2
Q

What is the definition of tolerance?

A

Specific unresponsiveness to an antigen through prior exposure to that antigen

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3
Q

Who discovered tolerance, and how were they recognised?

A

Macfarlane Burnet and Peter Medawar.

Nobel Prize for Medicine, 1960

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4
Q

Describe the first demonstration of induced tolerance

A

Two mice of strain A

  1. One of the mice exposed to spleen cells from strain B during neonatal period
  2. Both mice given strain B graft as adults
  3. Graft only accepted in the strain that saw the spleen cells from strain B as a neonate

This tells us that tolerance is set up during the neonatal period

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5
Q

Why is tolerance important?

A
  • Critical part of the adaptive immune response
  • 10^11 different B and T cell specificities thanks to recombination, which potentially contain auto-reactive specificities
  • auto-reactivity can cause major pathology in the host
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6
Q

Which factors determine whether a given lymphocyte becomes tolerant or responsive to an antigen?

A

• Avidity

also:
• timing
• duration
• costimuli

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7
Q

Compare location and cell type in central and peripheral tolerance

A

Central:
• Occurs in the thymus or bone marrow
• positive / negative selection of immature lymphocytes

Peripheral:
• occurs in 2° lymphoid organs
• ‘regulatory’ responses of mature lymphocytes

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8
Q

What are the mechanisms of T cell tolerance?

A

Central:
• Deletion (through apoptosis)
• Receptor editing, change of the specificity
• Development of Tregs

Peripheral:
• Anergy
• Apoptosis
• Suppression by Tregs

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9
Q

What is anergy?

A

Lack of co-stimulation

Lymphocyte won’t be activated

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10
Q

Which T cells are positively selected in the thymus?

Which are negatively selected?

A

Positive selection: those with an intermediate affinity for self-HLA

Negative selection: those with TCRs with a high affinity for self-HLA or any Ag in the thymus

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11
Q

Describe T cell peripheral tolerance

What are the mechanisms?

A 
Mechanisms:
 • Ignorance
 • Deletion
 • Anergy
 • Negative regulation
 • Suppression
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12
Q

Describe the mechanism of suppression

A

Through Tregs

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13
Q

Which is more important, B or T cell tolerance?

A

T cell tolerance is more critical, because B cells must be first activated by T cells.

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14
Q

What happens when immunological tolerance breaks down?

What can cause this ‘breaking down’?

A

Activation of:
• Self-reactive T cells
• Auto-reactive antibodies

Caused by:
• Molecular mimicry
• Failure of regulatory networks
• Failure of tolerance (central or peripheral)

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15
Q

What are the key factors leading to autoimmunity

A
  1. Genetic predisposition
  2. Environmental exposure
  3. Loss of self-tolerance
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16
Q

Describe Molecular mimicry bringing about autoimmunity

A

Host and foreign antigen share a similar epitope (may be linear or conformational)

  1. S. pneumoniae infection and immune response against a specific antigen
  2. S. pneumoniae antigen resembles antigen on heart valves
  3. Immune response directed against heart valves
  4. Rheumatic heart fever
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17
Q

What are the important suppressive cytokines? Where do these come from?

A

Come from Treg
• IL-10
• TGF-β

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18
Q

Describe the role of Treg in autoimmunity

A

Suppresses APCs and T cells through:
• cell-cell contact
• release of suppressive cytokines (IL-10, TGF-β)

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19
Q

What are Milgrom and Witebsky’s criteria for autoimmunity?

A

• lymphocyte infiltrate in target organ
• circulating auto-antibody / auto reactive T cells against target organ
• identification of the auto antigen
etc.

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20
Q

What is the classic organ specific autoimmune disease?

A

Hashimoto thyroiditis

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21
Q

What is the classic non-organ specific autoimmune disease?

A

SLE: systemic lupus erythematosus

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22
Q

Which sort of antibodies are commonly seen in non-organ specific autoimmune diseases?
What about organ specific autoimmune diseases?

A

Non-organ specific:
• anti-DNA Ab (in SLE)
• anti-cytoskeleton Ab

Organ specific:
• anti-thyroglobulin antibodies (in Thyroiditis)
• anti-myeline basic protein (in MS)
etc.

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23
Q

Describe ‘ignorance’ in T cell peripheral tolerance

A

The lymphocyte is sequestered from antigen, and never encounters it

24
Q

Describe suppression in T cell peripheral tolerance

A

The lymphocyte is downregulated by Treg and suppressive cytokines release by the Treg

25
Q

Describe the mechanism of apoptosis in T cell peripheral tolerance

A
  1. T cell adheres to the APC
  2. Engagement of Fas by FasL on the APC
  3. Death receptor pathway to apoptosis
26
Q

What are the mechanisms for B cell tolerance?

A
  • Deletion
  • Anergy
  • Ignorance
27
Q

Does the presence of auto reactive lymphocytes categorically mean that there is autoimmunity?

A

No, there are autoantibodies present in the body.

For example, B cells involved in mopping up cellular debris after apoptosis

28
Q

What are some environmental factors that can lead to the production of auto antigen?

A
  • Smoking
  • Infection
  • Drugs
29
Q

What is the spectrum of autoimmune disease?

Where does Type I diabetes sit on this spectrum?

A

Organ specific to non-organ specific

Diabetes is organ specific

30
Q

What is the auto-antigen in SLE?

A
  • DNA histones
  • DNA nucleotides
  • Sm-RNP (Smith protein, Ribonucleoprotein)
31
Q

Is Rheumatoid arthritis organ specific?

A

No, it’s non-organ specific

32
Q

How are autoimmune disorders tested for in the lab?

A

Staining patterns

  1. Suspected autoimmune disorder
  2. Patient’s cells are taken and grown up in the lab
  3. Patient’s serum is taken and added to the cell culture
  4. If Ab in the serum reacts with their own cells, there will be specific staining pattern observed
33
Q

What is ‘Diabetes’?

A

A group of disorders affect insulin production and / or function

34
Q

What are some general features of Type I Diabetes?

Secondary disorders?

When is the onset?

A
  1. Break down in tolerance for β cells in the islets of Langerhans in the pancreas
  2. β cells destroyed
  3. No insulin production
2° damage:
 • Kidneys
 • Eyes
 • Nerves
etc.

Onset:
• first year of life → adulthood

35
Q

How does glucose get into cells?

A

Through the Glut 4 receptor

36
Q

Outline the various types of diabetes

A

Type I:
• Autoimmune disorder

Type II:
• Lifestyle disorder; insulin resistance

Various other types:
• Type 1.5
• Gestational diabetes
• CFRDM

37
Q

What is LADA?

A

Latent autoimmune diabetes in adults

‘Type 1.5 diabetes’
• Masquerades as ‘non-obese type II diabetes’
• Late onset of type I diabetes

38
Q

Describe the pathogenesis of type II diabetes

A

Insulin is present and binds to IR (unlike in IDDM), but there is a defect in signalling through to Glut 4

→ Diminished glucose uptake through Glut 4

39
Q

Describe in detail the pathogenesis of Type I diabetes

A

Insulitis → overt diabetes

Aetiology:
• Genetic (certain HLA alleles, CTLA4 polymorphism)
• Environmental (viral infections)

  1. Underlying genetic predisposition
  2. Environmental trigger → break down in tolerance (central & peripheral)
  3. CTL and Th1 infiltration into islets → Insulitis, appearance of auto-antibodies
  4. Decrease in β cell mass in islets
  5. Loss of insulin; glucose intolerance
  6. Loss of C peptide
40
Q

Which auto antigens have a role in Type I diabetes?

A

Many different enzymes in the β cells that are responsible for insulin production and metabolism

e.g. 
 • GADA (Glutamic acid decarboxylase)
 • ICA512
 • Zinc transporter (ZnT8)
 • Insulin (IAA)
41
Q

What is C peptide?

A
  • part of proinsulin

* holds together the A- and B-chains in proinsulin

42
Q

Describe histological features of Type I diabetes

A
  • Progressive infiltration of inflammatory cells into the β cell islets in pancreas
  • These cells are predominantly CTLs and Th1

• Infiltration of these cells leads to the destruction of the islet

43
Q

Which specific things might be happening in break down of T cell tolerance in Type I diabetes?

A
  • Defective deletion in central tolerance

* Defective regulation of T cells (peripheral)

44
Q

At which point are clinical symptoms seen in Type I diabetes?

A

Can be years after the β cells have started to be destroyed.

Symptoms only seen when there are very few β cells left

45
Q

What is ICA?

A

Islet cell antigen

46
Q

Which autoantibodies are present in Type I diabetes?

Describe their presence and importance

A

Four main ones, called ICA

  • Anti-GAD (Glutamic acid decarboxylase)
  • Anti-ICA512
  • Anti-Zinc transporter (ZnT8)
  • Anti-Insulin (IAA)

Levels of these auto-Ab increase over time up to the onset at around age 15

Their role in pathogenesis is unclear

47
Q

Which genetic factors are linked to Type I diabetes?

A

HLA DR3-DQ2
HLA DR4-DQ8

Certain CTLA alleles

48
Q

How is the onset of SLE described?

A

• Remitting and relapsing
(goes away, then comes back)
• acute or insidious

49
Q

Which organs are affected in SLE?

A
  • Skin
  • Kidneys (Glomerulonephritis)

These are the main ones, but most tissues in the body are affected

50
Q

What are some of the criteria of SLE?

What is the diagnostic feature?

A

• Malar rash
(+ loads of other rashes)
• Antinuclear antibody (diagnostic feature!)

51
Q

What components of the nucleus are targeted by antibodies in SLE?

A
  • DNA
  • Sm protein
  • RNA
  • histones
52
Q

What are Sm-proteins?

A
  • RNA binding proteins

* found in the nucleus

53
Q

Describe the pathogenesis of SLE

A
  1. Cause:
    • Breakdown in tolerance
    • Environmental trigger (UV) → increased apoptosis → increased nuclear elements present
  2. Anti-nuclear antibody forms complexes with the nuclear antigen
  3. Endocytosis of immune complexes
  4. Engagement of TLRs by the DNA
  5. B cells activated (through TLR activation)
  6. Production of high level anti-nuclear IgG
  7. More formation of immune complexes
  8. Type III sensitivity
54
Q

What type of hypersensitivity is SLE?

Describe this

A

Type III (immune complex)
• Complex between Ab and nuclear antigen
• Complexes get deposited in places where blood is filtered (kidneys, joints)
• Complement activation (from IgG and IgM of immune complexes)
• Inflammation and infiltration of phagocytes

55
Q

What is the main cause of death in SLE?

A

Renal failure

56
Q

What is the treatment for SLE?

A
  • Corticosteroids

* Immunosuppressants

PATH30001 - Mechanisms of Disease (34 decks)

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