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BIOL321 Clinical Immunology > Lecture 10: Autoimmune diseases and transplantation > Flashcards

Lecture 10: Autoimmune diseases and transplantation Flashcards

1
Q

What is the purpose of immune system toelrance?

A

To prevent our immune system from attacking our own cells and tissues

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2
Q

What is central tolerance?

A

The elimination of strongly self-reactive T-cells or B-cells before they are allowed to mature

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3
Q

How is central tolerance acheived?

A

Negative selection:

T-cells in thymus - T-cells with TCRs that bind strongly to self antigens are eliminated by apoptosis

B-cells in bone marrow - clonal deletion of B-cells with a self-reactive BCR and by receptor editing

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4
Q

Why might some self-reactive B and T-cells not be eliminated by central tolerance?

A

Not all antigens are expressed in the thymus or bone marrow

Some B or T-cells that bind weakly to self-antigens are not negatively selected

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5
Q

How does central tolerance in thymus and bone marrow prevent autoimmunity?

A

In thymus: mTEC stromal cells have transcription factors (AIRE, FEZF2) that allow them to express a range of self-antigens in order to test the reactivity of the TCRs

In bone marrow: receptor editing results in deletion of B-cells with autoreactivity

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6
Q

What factors can promote the development of autoimmunity?

A
  • predisposing genes (E.g. certain types of MHC genes)
  • Sex (autoimmunity more common in females)
  • Tissue damage
  • Inflammation
  • Infections
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7
Q

What is the role of peripheral tolerance?

A

To control the activity of escaped (from central tolerance) autoreactive T- and B-cells in the tissues this occurs by three main mechanisms:
- anergy and apoptosis
- ignorance
- Treg cells

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8
Q

Tolerance is favoured by antigens that what?

A
  1. are present at high doses (E.g. keratins)
  2. Show long-term persistence
  3. are introduced orally or intravenously
  4. are not accompanied by adjuvants (PAMPs) - no tissue damage or microbes present
  5. induce low levels of co-stimulation
  6. are presented by immature or unactivated APCs
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9
Q

What is one mechanism of peripheral tolerance?

A

Antigen sequestration
- retention of antigens in compartments without significant immune cell access that are immune privileged sites
- theses antigens cannot be accessed by B or T-cells leading to B and T-cell ignorance of these tissue-specific antigens

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10
Q

Give three examples of immune privileged sites

A

Eyes
Brain
Uterus
Testes

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11
Q

Explain how the peripheral tolerance mechanism of anergy and apoptosis prevent self-reactivity

A

When a T-cell recognises an antigen presented by an APC in the absence of co-stimulatory signals (CD80/86 - CD28, and CD40 - CD40L) this can lead to anergy or apoptosis of the T-cell

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12
Q

Explain how the peripheral tolerance mechanism of Treg cells prevent self-reactivity

A
  • Secrete anti-inflammatory cytokines IL-10 and TGF-beta
  • Inhibit the function of APCs when CTLA-4 on Treg binds CD80/86 on APC in place of the CD28 of T-cells sending an inhibitory signal into APC that inhibits release of proinflammatory cytokines and increases expression of IDO enzyme that promotes an immunosuppressive environment
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13
Q

What is bystander suppression in the context of APC inhibition by Tregs as part of peripheral tolerance?

A

Bystander suppression occurs when one APC engages several CD4+ T-cells of different specificities and the Treg cell bound to the same APC inhibits the activity of the other T-cells

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14
Q

What causes autoimmune diseases?

A

The failure of tolerance mechanisms which protect our tissues from destruction by our immune system
- can be caused by self-reactive autoantibodies or self-reactive T-cells (which can lead to cell lysis and organ damage)
- sometimes there are contributions also from innate immunity and complement

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15
Q

Give three examples of organ-specific autoimmune diseases? (give the name of disease, organ/cell/protein affected and the key immune mediators in the disease)

A

Disease: Type I diabetes mellitus
Affected: Beta cells
Immune mediator: Th1 cells and autoantibodies

Disease: Myasthenia gravis
Affected: acetylcholine receptors
Immune mediator: autoantibodies

Disease: Crohn’s disease
Affected: Gut mucosa
Immune mediator: innate immunity, Th17 cells

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16
Q

Give three examples of systemic autoimmune diseases? (give the name of disease, organ/cell/protein affected and the key immune mediators in the disease)

A

Disease: Multiple sclerosis
Affected: Brain, neurons
Immune mediator: Th1 cells, CTLs, autoantibodies

Disease: Rheumatoid arthritis
Affected: connective tissue, joint
Immune mediator: immune complexes, autoantibodies

Disease: Systemic Lupus Erythematosus (SLE)
Affected: RBCs, platelets, skin, kidneys
Immune mediator: interferons, autoantibodies, immune complexes

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17
Q

Which immune mediators contribute to the destruction of the beta cells in Type I DM?

A

Cytotoxic T-cells
Autoantibodies
Macrophages

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18
Q

What is myasthenia gravis?

A

an organ-specific autoimmune disease in which motor end plate cells of skeletal muscle are destroyed sue to autoantibodies against acetylcholine receptors that trigger complement-mediated lysis of these cells
(results in progressive loss of muscle function)

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19
Q

What are some potential treatments for myasthenia gravis?

A

Immunosuppressants (corticosteroids)

Cholinesterase inhibitors (prevent the breakdown of acetylcholine to increase chance of binding to receptor)

20
Q

What is Systemic Lupus Erythematosus
(SLE)?

A

SLE is a systemic autoimmune disease in which individuals produce autoantibodies against a wide range of tissue antigens
- common targets are proteins associated with self DNA and RNA (thought that the detection of self-nucleic acids by PRRs plays a role in the disease)

21
Q

What are some symptoms/characteristics of SLE?

A

Characteristic butterfly rash on face

other symptoms: fever, weakness, arthritis, kidney dysfunction

22
Q

What is the main cause of kidney dysfunction in SLE?

A

Deposition of immune complexes containing antibodies and complement that damage the glomerulus

23
Q

What causes the neurological symptoms seen in multiple sclerosis?

A

Due to the action of auto-reactive T-cells that attack the myelin sheath of nerve fibres and the spinal cord resulting in numbness, paralysis, loss of vision etc.

24
Q

What factors may be associated with the cause of multiple sclerosis?

A

genetic risk factors
associated infections - compromises the BBB so autoreactive T-cells can enter the immune privileged site and react with CNS antigens
- destruction of cells, mast cell activation, complement activation, antibodies and cytokines released
–> results in demyelination of neurons

25
Q

True or false: most autoimmune diseases are single gene disorders?

A

False: most are multifactorial diseases where many genes and environmental factors play a role

26
Q

What is an example of an autoimmune disease caused by a single gene mutation?

A

IPEX (Immune dysregulation Polyendocrinopathy, Enteropathy and X-linked syndrome)

mutation in FoxP3 transcription factor

27
Q

What genetic factors may increase susceptibility to autoimmune diseases?

A
  1. certain kinds of MHC variants
  2. genes for immune cell surface protein
  3. genes for innate immune signalling factors
28
Q

What is the MHS variant that predisposes an individual to ankylosing spondylitis?

A

HLA-B27

29
Q

Give examples of genes for immune cell surface proteins that increase susceptibility to T1DM and Crohn’s disease?

A

T1DM = IL-2 and CTLA-4

Crohn’s disease = IL-23

30
Q

Give examples of genes for innate immune signalling factors that increase susceptibility to SLE?

A

TLRs and RNA receptors

31
Q

Give 5 non-genetic factors that influence susceptibility to autoimmune diseases

A
  1. Hygiene hypothesis (early stimulation of the immune system prevents autoimmunity)
  2. Gut microbiome influences immune responses and tolerance
  3. Sex hormones (Oestrogen promotes inflammation)
  4. Injury - reveal antigens from immune privileged sites
  5. Molecular mimicry (infections containing antigens that are similar to self antigens)
32
Q

Give an example of molecular mimicry between human host proteins and proteins of an infectious agent

A

There is sequence similarity between the IE2 protein of the human cytomegalovirus and the human host HLA-DR molecule

33
Q

Hoe can microbiota dysbiosis promote autoimmunity?

A

change or absence of microbe produced factors can lead to a decrease in Treg cells and increase in Th17 and inflammation

34
Q

What are the three main challenges to transplantation?

A
  1. Availability of organs
  2. Surgical techniques
  3. Graft rejection
35
Q

What are the four types of graft used in transplantation?

A
  1. Autograft
    - tissue transported from one site of body to another
  2. Isograft
    - graft of tissue from one genetically identical individual to another (monozygotic twins)
  3. Allograft
    - graft of tissue from a donor to recipient (not genetically identical but need good genetic match and immunosuppression)
  4. Xenograft
    - transplantation of organs from animals to humans (aortic valve with pigs as donors) - cells and soluble proteins are removed to reduce immunogenicity
36
Q

What does autograft acceptance look like?

A

Revascularisation, healing and resolution (low neutrophil infiltration) within 14 days of graft

37
Q

What does autograft rejection look like?

A

revascularisation, much higher immune response (high neutrophil and other immune cells infiltration), thrombosis and necrosis of graft

38
Q

How does ‘first-set’ rejection differ from ‘second-set’ rejection of a autograft?

A

First set rejection takes place 12-14 days after graft

Since rejection displays specificity and memory, the ‘second set’ rejection takes places after a few days due to memory response
– this need to ensure second graft has different antigens to the original rejected graft

39
Q

What are the effector mechanisms of the immune system that lead to graft destruction?

A

activated CD4+ T-helper cells:
- produce IL-17 that activate neutrophils and lead to inflammation
- secrete INF-gamma which activates macrophages that result in movement of lytic enzymes into graft site
- secrete Lymphotoxin-alpha which causes cytotoxicity at the graft site

CTLs (CD4+ and CD8+) bind to MHC II and MHC I, respectively, alloantigen causing membrane damage

Activated B-cells produce antibodies against graft antigens that recruit complement that results in lysis
–> also NK cells of macrophages can bind to antibodies via Fc receptor, triggering ADCC

40
Q

Which type of graft is donor matching particular important for?

A

Allografts
- minimise the genetic differences between the donor and recipient
- match major antigens (ABO blood type and MHC molecules (HLAL))

41
Q

Why is it important to match MHC molecules between donor and recipient of allograft?

A

MHC proteins are very polymorphic so they often vary between individuals and can be recognised as foreign in the graft

42
Q

Who is commonly used as a good source of donor tissue in an allograft transplant?

A

family members

43
Q

What are the two types of ‘recognition’ of a graft as foreign?

A

Direct allorecognition and indirect allorecognition

44
Q

What is direct allorecognition?

A

When donor antigen presenting cells with intact donor MHC molecules presenting any peptide - the donor MHC molecules are recognised too strongly by the recipient T cells

45
Q

What is indirect allorecognition?

A

Recipient APC with recipient MHC presenting peptide from donor MHC - the recipient T cells recognise the donor MHC peptide presented by self cells

46
Q

Why are transplant recipients often more susceptible to infections and some cancers?

A

Transplant recipients often need to undergo immunosuppressive therapy for many years
- the treatments are not antigen-specific and cause general immunosuppression

47
Q
A

BIOL321 Clinical Immunology (10 decks)

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