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CMB2004 > L7 - Regulation of the immune response > Flashcards

L7 - Regulation of the immune response Flashcards

1
Q

Why do we need immunological tolerance?

A

Random generation of repertoire of BCR & TCR

Self-reactive specificities will be produced

If no tolerance, could be a serious problem – self-destruction

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2
Q

How do lymphocytes become tolerant?

A

If:

  1. They encounter Ag in central lymphoid organs (BM/thymus) when they are immature: central tolerance
  2. They encounter Ag in the peripheral tissues in the absence of other necessary signals: peripheral tolerance
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3
Q

Tolerance through clonal deletion

A

Engagement of receptors on immature B or T cells leads to their deletion

Occurs in thymus & bone marrow

Death occurs by apoptosis

Only works for Ag to which developing lymphocytes are exposed

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4
Q

Random TCR gene rearrangement leads to T cells expressing TCR that…

A

a) Fail to recognise self-MHC
b) Recognise self-MHC + peptide generated from ‘self’ Ag present in the thymus
c) Recognise self-MHC + ‘any other’ peptide

a die by neglect – no positive selection survival signals
b & c expanded by positive selection
b then eliminated by negative selection – binds self MHC too well
c are they only ones that survive – have medium affinity for self-MHC

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5
Q

Why are TCRs that have a medium affinity for self-MHC the only ones that survive?

A

Shouldn’t give an autoimmune response, but includes cells that are capable of responding to self MHC when it contains peptides derived from pathogens

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6
Q

Not all self-Ag are expressed in the thymus

Why?

A

eg. insulin

Insulin is very tissue specific (beta cells in the pancreas) so you would never predict it to be expressed in the thymus as it doesn’t work there

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7
Q

What is AIRE?

A

Autoimmune regulator protein

Transcription factor

Key role in tolerance induction

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8
Q

What does AIRE do?

A

Allows the expression of normally tissue-specific Ag in the thymus & hence deletion of T cells that recognise these Ag

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9
Q

What happens if you get a deficiency or mutation in AIRE?

A

Causes major autoimmune syndrome

Causes autoimmune T cells

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10
Q

BCR generation/bone marrow selection & tolerance

A

Random Ig gene rearrangement leads to B cells expressing self-reactive BCR

Similar to T cells, autoreactive B cells are negatively selected in bone marrow

Unlike T cells, B cells get a second chance to re-arrange any self-reactive BCR – receptor editing

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11
Q

What is receptor editing?

A

Immature B cells that bind self-antigens may undergo further light chain gene rearrangements – possibility of expressing a receptor that is not self-reactive

Similarly immature T cells that fail positive selection can also undergo further rearrangements of the TCR-alpha locus to produce a different receptor

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12
Q

Tolerance through clonal anergy

A

Lymphocytes that recognise self Ag are rendered unresponsive – anergic

Immature B cells: when receptors encounter Ag that is NOT multivalent – downregulate BCR

Anergy is important in peripheral tolerance: T cells that encounter Ag in the absence of co-stimulation become anergic – signal 1 without signal 2

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13
Q

What does anergy mean?

A

Anergy is defined as the lack of responsiveness to an antigen despite the presence of antigen-specific lymphocytes

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14
Q

Other mechanisms of tolerance

A

Immunological ignorance

Privileged sites

Many B cell responses are T cell dependent

Regulatory T cells

Regulatory B cells

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15
Q

Other mechanisms of tolerance:

Immunological ignorance

A

Many Ag are not presented at sufficient levels to activate (or tolerise) T cells

Needs to be a threshold of antigen

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16
Q

Other mechanisms of tolerance:

Privileged sites

A

Ag sequestered from immune system (suppressive cytokines also prevalent)

Eg. eye, testis, CNS (barriers in place)

If you damage your eye & immune system cells get in – you may get autoimmunity in your eye as you’ve broken the barrier

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17
Q

Other mechanisms of tolerance:

Many B cell responses are T cell dependent

A

If Ag-specific T cells are absent/tolerant no help is available  no antibody response

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18
Q

Other mechanisms of tolerance:

Regulatory T cells

A

CD4+ T cell subset that suppress immune responses – turn off IR

Crucial for tolerance & suppressing autoimmune responses

Arise in thymus from T cells with high affinity receptors for self-antigen n(atural)Treg – can also be induced in the periphery (iTreg)

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19
Q

nT-regs & iT-regs

A

nTreg controls the cells that escape negative selection that aren’t Treg

If an autoreactive cell in the periphery is causing an issue, it can be induced into an iTreg to escape natural selection

Multiple layers of control

20
Q

What happens if you get a deficiency in Treg?

A

Leads to a severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome)

21
Q

Other mechanisms of tolerance:

Regulatory B cells

A

Specific B cells to dampen down the immune response

B cells recently described that secrete IL-10 are crucial in preventing autoimmunity

22
Q

Why do we need to regulate immune responses?

A

To ensure responses continue only for as long as they are needed

To minimise collateral (tissue) damage

To ensure responses are qualitatively appropriate – ie. Right for the specific pathogen

23
Q

What happens once naive CD4 T cells are activated?

A

naïve CD4 T cells differentiate into effector T cells – do not require co-stimulation anymore

24
Q

What are effector T cells?

A 
TH-1
TH-2
TH-17
T(reg)
T-FH
25
Q

What are CD4+ cells?

A

T helper cells

26
Q

What are CD8+ cells?

A

Cytotoxic T cells

27
Q

What do CD4 TH-1 cells do?

A

Activation of macrophages, NK cells, cytotoxic T cells

28
Q

What do CD4 TH-2 cells do?

A

Promote responses mediated by eosinophils & mast cells

Role in antibody responses, especially IgE

29
Q

What do CD4 TH-17 cells do?

A

Promote responses against fungi

30
Q

What do CD4 T(reg) cells do?

A

Suppress unwanted responses

31
Q

What do CD4 T-FH cells do?

A

Specialised TH found in GC to help B cells

Can produce TH1, TH2 & TH17 cytokines

32
Q

How do CD4 TH-1 cells activate macrophages?

A

Via secretion of cytokines: eg. IFN-gamma, GMCSF, TNF-alpha

CD40L binding to macrophage CD40

33
Q

How do CD4 TH-1 cells increase the efficiency of macrophages?

A

Macrophages eats & destroy pathogens

Puts a peptide on its class II MHC on the surface which is recognised by TH1 cells – makes the macrophage eat things a lot more effectively

34
Q

How do CD4 TH-1 cells increase microbicidal activity of macrophages?

A

Increased fusion of phagosomes with lysosomes

Increased synthesis of oxygen radicals, NO, proteases

35
Q

How do CD4 TH-1 cells kill chronically infected macrophages?

A

Fas ligand/ Fas induce apoptosis

Released bacteria destroyed by healthy macrophage

Other cells can then kill the pathogens

36
Q

How do CD4 TH-17 cells act against fungi?

A

Secrete IL-17

Function to recruit neutrophils early in (fungal) infections

Implicated in autoimmune disease

Suggested to be the evolutionarily ‘oldest’ form of acquired immunity

37
Q

Why are CD4 T-reg cells different from the other types of T cells?

A

Not a single population
Mixed bag of cells – CD4+, CD25+, CD8+
Double negative

Arise in the thymus (nTreg) or from circulating T cells in the peripheral tissues (iTreg)

38
Q

What is the type of TH response influenced by?

A

The cytokines that are present when T cells are activated (signal 3)

39
Q

What is signal 3?

A

The cytokines that are present when T cells are activated

40
Q

What are the key cytokines involved in signal 3?

A

IL-12 & IFN-gamma play a key role in induction of TH1 responses

IL-4 important for induction of TH2 responses

Cytokines present when a naïve T cell is activated determine the effector T cell it becomes as a consequence of key transcription factor activity

41
Q

What do TH-1 cytokines do?

A

Promote commitment to TH1

Inhibit development of TH2 & TH17

42
Q

What do TH-2 cytokines do?

A

Promote commitment to TH2

Inhibit development of TH1 & TH17

43
Q

What do TH-17 cytokines do?

A

Promote commitment to TH17 cytokines

Inhibit development of Treg

44
Q

What do T-reg cytokines do?

A

Inhibit TH1, TH2 & TH17 responses

45
Q

What is the importance of polarised responses?

A

Ensures correct responses for different types of pathogens

Infection – one route may be better for the host

Allergy – excessive TH2

Autoimmune disease

CMB2004 (12 decks)

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