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Immunology > 2. Tolerance and autoimmunity > Flashcards

2. Tolerance and autoimmunity Flashcards

1
Q

What are the genetic and environmental risk factors of autoimmune diseases?

A
  • Genes - runs in family
  • Sex - women more susceptible
  • Infections
  • Diet
  • Stress
  • Microbiome
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2
Q

What happens to T cell tolerance in autoimmune disease?

A

T cell tolerance is broken

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3
Q

Which antibodies almost always mediate autoimmune diseases?

A

IgG (need class switching - T cell involvement)

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4
Q

Are autoimmune diseases acute, chronic or can they be both?

A

Chronic

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5
Q

Which hypersensitivity reactions do autoimmune diseases resemble?

A

Types II, III and IV

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6
Q

How are mechanisms different in adaptive immune reactions against self?

A

The same

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7
Q

Which hypothesis potentially explains the rising incidence of autoimmune disease?

A

Hygiene hypothesis

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8
Q

How is a baby affected in a pregnant woman with Grave’s disease?

A
  • IgG involved can cross the placenta
  • Developing foetus can acquires the antibodies
  • Is born with neonatal Grave’s disease
  • Symptoms stop as the maternal antibodies are removed
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9
Q

What is Goodpasture’s syndrome?

A
  • Type II hypersensitivity
  • Antibodies against type IV collagen
  • Complement activation, inflammatory cell recruitment etc.
  • Particularly affects kidney => glomerulonephritis
  • Pulmonary haemorrhage is another consequence
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10
Q

What causes Grave’s disease?

A
  • Type II hypersensitivity
  • Antibodies stimulate the TSH receptor (agonistic)
  • Excessive release of thyroid hormones
  • Negative feedback lost due to stimulation
  • Hyperthyroidism
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11
Q

What causes SLE?

A
  • Type III hypersensitivity
  • Immune complexes formed and deposited around the body
  • Affect DNA, histones, ribosomes, snRNP, scRNP
  • Particularly affects the kidney, joints and skin
  • Results in glomerulonephritis, vasculitis and arthritis
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12
Q

How are the effector mechanisms different in type II and III hypersensitivities?

A

They are the same i.e. complement activation, inflammatory cell recruitment etc.

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13
Q

What directly destroys beta cells in T1DM?

A

T cells - CD4+ and CD8+ (type IV)

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14
Q

What presents antigens to T cells in type IV hypersensitivity?

A

MHC on APC

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15
Q

Which MHC molecules do CD4+ and CD8+ recognise?

A
  • CD4+ = MHC class II

* CD8+ = MHC class I

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16
Q

Which MHC is the dominant genetic factor affecting susceptibility to autoimmune disease?

A

Human MHC (HLA) class II

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17
Q

What are the most polymorphic genes in the body?

A

HLA genes

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18
Q

Can B cells be involved in autoimmunity?

A

Yes

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19
Q

How does the Freemartin Cattle experiment provide evidence for the concept of self tolerance?

A
  • Cattle have fused placentas and exchange cells and antigens when in utero
  • They are non-identical - have different sets of blood group antigens
  • When adults, they can tolerate blood transfusions and skin grafts from each other
  • This suggests that exposure to foreign antigens in utero makes them tolerant to them
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20
Q

If you inject some spleen and bone marrow cells from an adult to a newborn mouse of different strains, will the newborn be able to accept skin grafts from the other strain when older?

A

Yes, as long as the skin graft is from the same strain as the bone marrow cells (but this doesn’t work if you inject the cells into an adult mouse)

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21
Q

What is tolerance?

A

Acquired inability to respond to an antigenic stimulus

22
Q

When does tolerance occur in life?

A

Early in life, and maintained throughout life (active process in neonates)

23
Q

What are the 2 types of tolerance?

A
  • Central

* Peripheral

24
Q

When does central tolerance occur and what does it involve?

A
  • During lymphocyte development

* Mechanism of deletion of autoreactive T and B lymphocyte in primary lymphoid organs

25
Q

What does peripheral tolerance involve and what are the 3 types?

A

Mechanisms to develop tolerance once we’ve generated mature lymphocytes
• Anergy
• Immune privilege
• Regulation

26
Q

Where do all lymphocyte originate?

A

Stem cells in the bone marrow

27
Q

Where do precursors of lymphocytes migrate to?

A

Thymus

28
Q

Where do B cells develop to become a antibody-secreting plasma cells when activated?

A

Bone marrow

29
Q

Why do lymphocytes need to be carefully selected?

A
  • T cell receptors are derived from the random rearrangement of gene segments
  • Potential for development of receptors reactive against self
30
Q

Where exactly are lymphocytes selected?

A

On thymic epithelial cells and dendritic cells in the thymus

31
Q

What do the thymus cells, involved in selection, express?

A

MHC molecules with self peptides, which are presented to the developing T lymphocytes

32
Q

What are the 3 possible outcomes for maturing T cells?

A

Based on how strongly they bind to self MHC
• Don’t recognise MHC, useless => apoptosis
• Weakly associate with MHC, useful => signal to survive (positive selection)
• Associate with MHC too strongly => apoptosis (negative selection)

33
Q

What is B cell selection based on?

A
  • Interaction between BCR and antigens in bone marrow
  • No self reaction => become mature B lymphocytes
  • Reaction => apoptosis
34
Q

What antibodies do mature b cells express?

A

IgD and IgM

35
Q

What happens if mature B cells recognise soluble autoantigens?

A

Receptor editing
• Still migrate to the periphery
• However, they express low levels of IgM => anergic (not very response)
• Prevents autoimmunity

36
Q

When can receptor editing sometimes not work?

A
  • If the B cell has a weak interaction with the soluble autoantigen
  • It can then develop fine and have the potential to cause autoimmune disease
37
Q

What is APECED and the cause?

A

• Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy
• Failure to delete T cells in the thymus
• Caused by mutations in the transcription factor AIRE
- important for expression of tissue-specific genes in the thymus
• Developing T cells aren’t exposed, so can become self-reactive

38
Q

What do the gene products of AIRE do?

A
  • Peptides derived from the genes are presented on cells in the thymus
  • Developing T cells are exposed to the peptides and selected for
39
Q

What is APECED also known as, and what tissues does it affect/conditions does it cause?

A

• Autoimmune poly-glandular disease (APD)

  • Thyroid
  • Kidneys
  • Chronic mucocutaneous candidiasis
  • Gonadal failure
  • Diabetes mellitus
  • Pernicious anaemia
40
Q

What happens to mature the T cell apart from the MHC-TCR reaction, for full activation?

A
  • Co-stimulation e.g. by CD80, 86 expressed on APCs (only when activated)
  • These interact with e.g. CD28 on the T cell
  • CD4 on T cell interacts with MHC II on APC
  • Cell proliferation doesn’t proceed with co-stimulation
  • T cell becomes anergic - harder to activate
  • Only specialised APCs can express and activate it, most cells can’t do this
41
Q

What does immunological ignorance refer to?

A
  • Antigen concentration is too low in the periphery for lymphocytes to recognise it
  • May also occur by physical barrier e.g. in immunological privileged sites, where immune cells normally cannot penetrate e.g. eye, CNS, PNS and testes
  • Cells don’t become tolerised against autoantigens
42
Q

What is sympathetic opthalmia?

A
  • Damage to immune privileged site in the eye
  • Physical trauma can release proteins (antigens) which can enter lymph nodes
  • These antigens can be presented to re-circulating T cells
  • T cells can become activated and go to the eyes
  • Both eyes can show symptoms, even if one eye is affected
  • Can lead to blindness
43
Q

Auto-reactive T cells may still be present but don’t respond to autoantigens, so how are they controlled?

A

Regulatory T cells with:
• CD4
• CD25 - high affinity IL-2 receptor
• CTLA-4 - binds to B7 and sends a negative signal
• FOX P3 - transcription factor required for Treg development

44
Q

What is IPEX, it’s cause and symptoms?

A
  • Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome
  • Genetic condition - recessive
  • Mutation in FOXP3 gene
  • Treg cells don’t develop + work properly
  • Onset of autoimmune symptoms and accumulation of auto-reactive T cells
  • Early onset insulin dependent diabetes mellitus
  • Severe enteropathy
  • Eczema
  • Variable autoimmune phenomena
  • Severe infections
45
Q

Which viruses are linked to T1DM?

A

Coxsackie virus B4, rubella, CMV, mumps

46
Q

Which viruses are linked to Lupus Erythematosus?

A

EBV

47
Q

Why can streptococci cause myocarditis?

A

Antibodies against streptococci can also target the heart muscle

48
Q

What is molecular mimicry?

A

• Microbe has similar structure to self molecules
• Cross-activation of autoreactive lymphocytes:
- infection can induce co-stimulatory molecules or inappropriate MHC class II expression
- pro-inflammatory environment
• Immune response against microbe will cause response against self molecules
• Immune deviation e.g. Th1 => Th2

49
Q

Which structure on microbes help the activation of APCs?

A

PAMPs (pathogen associated molecular patterns)

50
Q

Can activating an APC be enough to activate a naïve, self-reactive T cell?

A

Yes

Immunology (5 decks)

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