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M1 Immunology > Immune Tolerance and Autoimmunity > Flashcards

Immune Tolerance and Autoimmunity Flashcards

1
Q

What is autoimmunity?

A

Adaptive immune response specific for self-Ags

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2
Q

What is an auto-antigen?

A

Ag targets in autoimmunity

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3
Q

What are auto-reactive cells?

A

Immune cells that respond to auto-Ags

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4
Q

What are auto-antibodies

A

Abs that target auto-Ags

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5
Q

What are the 2 hallmarks of autoimmunity?

A

1) Loss of immune tolerance to self-Ags
2) Tissue dmg/physiological dysf(x)

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6
Q

What are the 3 broad factors that cause a loss in self-tolerance?

A

1) Genes
a) single gene defects
- AIRE (-ve selection in thymus)
- Foxp3 (T regs)
b) multifactorial
- aetiology for majority of autoimmunity diseases
- environmental + genetics
c) MHC allele linked
- ankylosing spondylitis and HLA-B27

2) Sex bias
- 10x incidence of SLE in F

3) Infection
- microbial Ags similar to self-Ags

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7
Q

What is central tolerance?

A

The selection process through which surviving lymphocytes do not exert effector f(x) to self-Ags

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8
Q

Why is central tolerance needed?

A

VDJ recombination can produce lymphocytes that bind very strongly to self-MHC and self-Ag and hence have a high chance of eliciting autoimmunity (inducing apoptosis in normal cells)

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9
Q

How are T lymphocytes selected for central tolerance?

A

via negative selection where T cells with TCRs that bind to self-MHC-self-peptide with very high affinity under apoptosis

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10
Q

What is the role of Autoimmune Regulator (AIRE) in central tolerance?

A

They cause transient exp. of extra-thymic tissue specific Ags in the thymus.

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11
Q

Does central tolerance involve immature or mature lymphocyte?

A

Immature

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12
Q

What is peripheral tolerance?

A

The processes by which mature T cell activation is controlled to prevent autoimmunity.

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13
Q

What are 3 signals in T cell activation?

A

1) TCR binding to peptide MHC
2) Co-stimulation (eg. CD28-B7, CD40-CD40L, 4-1BB-4-1BBL)
3) Cytokines (eg. IL-2→CD8, IL-12→Th1, IL-4→Th2)

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14
Q

What are the 4 mechanisms of peripheral tolerance?

A

1) Ignorance (no signal 1)
2) Anergy (Signal 1, no signal 2)
3) Deletion (recognition of self-Ag → no co-stimulation)
4) Regulatory T cell inhibition

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15
Q

How does ignorance contribute to peripheral tolerance?

A

T cells with TCRs that have peptide-self-MHC interactions too weak don’t activate
(useless T cells → can never cause autoimmunity)

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16
Q

How does T cell anergy contribute to periphery tolerance?

A

It ensures that T cells that bind to immature APCs or Non-APCs do not receive co-stimulatory activation to be activated.

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17
Q

What happens in an anergised T cell?

A
  • It is an Ag-dependent process that causes anergy gene transcription
  • T cells don’t differentiate into effector cells
  • remain unresponsive (even w subsequent signal 1 & 2)
18
Q

What are the 3 mechanisms of T cell anergy?

A

1) Failure to activate IL-2 autocrine loop
2) Abnormal TCR-complex signaling
3) Ligation of inhibitory receptors

19
Q

What are the 2 major pathways in T cell deletion?

A

1) Mitochondrial (regulated by BCL-2)
2) Death receptor (meditated by Fas-FasL)

20
Q

How is a T cell deleted through mitochondrial and death receptor upon recognition of self-Ag?

A

Apoptosis

21
Q

T regs are ____ dependent T cells possessing TCRs that _____ recognise self-peptide-self-MHC and suppress self-reactive immune cell activation.

A

IL-2
strongly

22
Q

Which gene is crucial to Treg function?

A

FOXP3

23
Q

How do Treg cells inhibit immune cell activation?

A

1) Cell-cell contact (CTLA-4 exp.)
2) Soluble factors (inhibitory cytokines eg. TGF-ß)

24
Q

What are 2 immune checkpoint axes?

A

PD-1/PD-L1
CTLA-4/B7

25
Q

What are the 2 immune ligands that bind to B7 on APCs?

A

CTLA-4
CD28

26
Q

What are the similarities between CTLA-4 and CD28?

A

Both are expressed on T cells and bind to B7 on APCs

27
Q

What are the differences between CTLA-4 and CD28?

A

1) CTLA-4 is not constitutively expressed (it is only expressed 2-3 days after)
2) CTLA-4 > CD28 B7 affinity
3) CTLA-4 delivers inhibitory signalling

28
Q

Which cells express CTLA-4?

A

Activated T cells, Tregs, Cancer cells

29
Q

What is a possible outcome of CTLA-4 mutations?

A

Autoimmune diseases

30
Q

How do T cells express CTLA-4?

A

1) Naive T cells (CD28) interact with APC (B7) to release IL-2
2) IL-2 induces (i) clonal expansion (ii) differentiation
3) Activated T cells (aft. IL-2 exposure) ↑ CTLA-4 exp., outcompeting CD28 for B7
4) CTLA-4/B7 → ↓B7

31
Q

What does PD-1 bind to?

A

PD-L1/PD-L2

32
Q

How does PD-1/PD-L1 prevent autoimmunity?

A

It inhibits the activations signals from TCR and CD28 complexes esp. after increased PD-1 exp. in chronic T cell activation.

33
Q

When is PD-1 most highly expressed?

A

During chronic T cell activation

34
Q

How can inflammatory cytokines (eg. INF-y) lead to increased T cell suppression?

A

They increase PD-L1 on APCs

35
Q

Immune checkpoints put ____ on T-cell mediated autoimmune tissue damage

A

brakes

36
Q

What is “T cell exhaustion”?

A

When chronic TCR stimulation causes PD-1-mediated inhibition

37
Q

How can tumours lead to T cell exhaustion?

A

Tumour-infiltrating lymphocytes ↑PD-1 exp.
- persistent tumour-Ags → chronic TCR stimulation + T reg
→ PD-1/PDL-1 inhibition of T cell anti-tumour activity

38
Q

What are some ways to target the immune checkpoint blockade in anti-cancer treatment?

A

Abs that block CTLA-4, PD-1/PD-L1/2

39
Q

What are some issues with Immune checkpoint inhibitors used in cancer therapy?

A

1) non-Ag-specific
2) can reverse peripheral tolerance of T cells → autoimmune damage
3) Cost

40
Q

What are the 2 main indications for Anti-CTLA-4/PD-1/PD-L1 Ab cancer therapy?

A

1) PD-L1 upregulation on tumour cells
2) dMMR

(Both detected by IHC)

41
Q

What are 2 examples of autoAbs causing autoimmune disorders?

A

1) Myasthenia Gravis (anti-AChR Abs)
2) Graves Disease (anti-TSHR Abs)

M1 Immunology (9 decks)

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