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Y1 Fwong MCD Immunology (A) > 8 Regulation Of Lymphocyte Responses > Flashcards

8 Regulation Of Lymphocyte Responses Flashcards

1
Q

Q: Why is immune regulation important? (2)

A

A: protection from infection by pathogenic microorganisms

survival of an infected mammalian organisms

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2
Q

Q: What is immune regulation required to do? Failure to do this leads to?

A

A: avoid excessive lymphocyte activation and tissue damage
prevent inappropriate reactions to self antigens

immune-mediated inflammatory diseases

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3
Q

Q: What are the two types of autoimmunity on either side of the spectrum?

A

A: organ-specific to systemic

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4
Q

Q: What is autoimmunity?

A

A: immune response against self antigen

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5
Q

Q: What is pathogenesis based on?

A

A: genetic predisposition + environmental triggers

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6
Q

Q: Define immune-mediated inflammatory diseases IMID. What are the 2 types?

A

A: chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation

Can be systemic or organ-specific

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7
Q

Q: What can cause immune-mediated inflammatory diseases?

A

A: May result from pathogens expressing antigens that are very similar to self antigens hence causing autoimmune disease

Can be caused by T cells and antibodies

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8
Q

Q: What are 3 examples for immune regulation failure?

A

A: autoimmunity
allergy
hypercytokinemia and sepsis

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9
Q

Q: Define allergy.

A

A: harmful immune response to non-infectious agents that cause damage and disease

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10
Q

Q: What can mediate an allergy? What is allergy? What causes the symptoms?

A

A: Can be mediated by IgE and mast cells
Can be mediated by T cells - DELAYED TYPE HYPERSENSITIVITY

Allergy is, in effect, recognising benign proteins and responding to them as if they were pathogens.

When exposed to their antigen, mast cells degranulate and release their histamines causing local inflammation

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11
Q

Q: What are hypercytokinemia and sepsis? What causes them? Define hypercytokinemia. Define sepsis. What is their relationship?

A

A: TOO MUCH IMMUNE RESPONSE

Positive Feedback - by triggering inflammation you cause damage to local cells leading to the release of more inflammatory mediators

Hypercytokinemia - too many cytokines in the blood - this happens when the response isn’t properly controlled and you get too much immune response

Sepsis - when bacteria crosses from the mucosa into the blood stream - pathogens entering the wrong compartment

Sepsis can cause hypercytokinemia

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12
Q

Q: What are the 3 signals that licence a cell to respond (in immune system)?

A

A: antigen recognition
co stimulation
cytokine release

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13
Q

Q: What are the 2 general principles that control immune responses?

A

A: Responses against pathogens decline as the infection is eliminated

Active control mechanisms may function to limit responses to persistent antigens (self antigens, possibly tumours and some chronic infections)
-Often grouped under ‘tolerance’

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14
Q

Q: How does the response against pathogens decline as the infection is eliminated?

A

A:

  • If there are lots of bugs, you get lots of T cells dealing with it
  • As the amount of pathogen starts to decline, you start switching off your immune response to the pathogen
  • This is driven by apoptosis of the lymphocytes - once they stop having antigens to bind to they lose their survival signals
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15
Q

Q: Define immunological tolerance.

A

A: specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)

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16
Q

Q: Why is immunological tolerance important?

A

A: This is important in self-tolerance - you are tolerant against your own antigens

Therapeutic Potential -

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17
Q

Q: What does breakdown of self tolerance lead to?

A

A: autoimmunity

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18
Q

Q: What is therapeutic potential?

A

A: it may be possible to turn T cells from being activated to being tolerogenic - inducing tolerance by regular exposure

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19
Q

Q: What are the 2 types of tolerance?

A

A: Central Tolerance - destroy self-reactive T or B cells before they enter the circulation

Peripheral Tolerance - destroy any self-reactive T or B cells which do enter the circulation

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20
Q

Q: What if immature B cells in the bone marrow recognise an antigen in a form which can crosslink their IgM?

A

A: apoptosis is triggered (central tolerance of B cells)

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21
Q

Q: What can B cells do if they react with self antigens? (2)

A

A: may change their specificity (affinity hypermutation) and some T cells will turn into regulatory T cells

22
Q

Q: What can happen if T cell receptors TCR bind too weakly to MHC during the selection process?

A

A: may not be enough to allow signalling when binding to MHC presenting a foreign antigen

23
Q

Q: What can happen if T cell receptors TCR bind too strongly to MHC during the selection process?

A

A: may allow signalling irrespective of whether a self antigen or foreign peptide is found in the groove

24
Q

Q: What do you consider with T cell selection in the thymus? (3)

A

A: Is it USELESS?
Doesn’t bind to MHC
-> Death by neglect (apoptosis)

Is it DANGEROUS?
Binds to self MHC too strongly
-> Apoptosis is triggered - negative selection

Is it USEFUL?
Binds self MHC weakly
-> Signal to survive - positive selection

25
Q

Q: What is the problem with the thymus being the only organ that allows the development of T cells?

How do we get round this?

What does it promote?

A

A: The problem with the thymus is that it’s just one organ - the cells in the thymus won’t normally produce all 25,000 gene products that your body can produce.
This means that there would be some self-peptides that aren’t made by the thymus cells and so when the T cells get out of the thymus, they discover a whole range of self-peptides which leads to autoimmunity.

They get around this using a specialised transcription factor - AIRE

If all the proteins are processed and presented on MHC to the developing T cells, you are negatively selecting against the entire peptide library - thus PROMOTING SELF-TOLERANCE

26
Q

Q: What do mutations or absence of AIRE lead to?

A

A: multi-organ autoimmunity (autoimmune polyendocrinopathy syndrome type 1)

27
Q

Q: What does AIRE allow?

A

A: the thymic expression of genes that are expressed in peripheral tissues - so the thymus can express all the proteins in the human body

28
Q

Q: Which tolerance is a way of screening the newly developed T cells?

A

A: central tolerance

29
Q

Q: What does peripheral tolerance control?

A

A: controls the lymphocytes which might start to react with self-antigens

30
Q

Q: What are the 4 mechanisms for peripheral tolerance?

A

A: Anergy
Ignorence
Deletion
Regulation

31
Q

Q: Explain anergy as a mechanism for peripheral tolerance. Definition.

A

A:
Naïve T cells need COSTIMULATORY SIGNALS (CD) to become activated

Most cells lack costimulatory proteins and MHC class II

If a naïve T cell sees its MHC/peptide ligand without appropriate costimulatory protein = becomes anergic

ie = less likely to be stimulated in future even if co stimulation is then present

Anergy = unresponsiveness (sort of like increasing the activation energy)

32
Q

Q: Explain ignorance as a mechanism for peripheral tolerance.

A

A: antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering

immunologically privileged sites eg eye, brain

At these sites, T cells CANNOT become activated because there are NO APCs

33
Q

Q: Explain deletion as a mechanism for peripheral tolerance.

A

A: = Antigen Induced Cell Death

Activation through the TCR can lead to APOPTOSIS of the T cell

In peripheral T cells this is often caused by the expression of the death ligand - Fas ligand

34
Q

Q: Explain regulation as a mechanism for peripheral tolerance.

A

A: Regulated by T regulatory cells (Treg) - subset of helper T cells

Treg produces cytokines (IL-10) which inhibits other self-reactive T cells

35
Q

Q: What transcription factor is expressed by Treg? What do mutations of this lead to?

A

A: FoxP3

mutations lead to severe and fatal autoimmune disorder: IPEX = immune dysregulation, Polyendocrinopathy, Enteropathy X-linked syndrome)

36
Q

Q: What are regulatory T cells? Phenotype.

A

A: type of CD4 T helper cell

Phenotype: CD4, IL-2 receptor, FoxP3

37
Q

Q: What’s a T regulatory cell’s mechanism of action?

A

A: Mechanism of action:

Secrete immunosuppressive cytokines (TGFb, IL-10 and IL-35)
They engage other effector T cells and turn them off
IL-10 also has a role in shutting down dendritic cells
It switches the DCs from saying ‘this is dangerous’ to ‘this is safe’

Individuals who can’t make Treg have broad spectrum autoimmune conditions - it is a failure of peripheral tolerance

38
Q

Q: What are the 2 types of Treg? What does the type reflect?

A

A: Natural (nTreg)
Develop in the Thymus
Reside in peripheral tissues to prevent harmful reactions against self

Inducible (iTreg)
When they are exposed to APCs they turn from being a T helper activator function to a Treg function

Tregs reflect the Th subsets seen in T effectors

In summary…peripheral tolerance is largely driven by

39
Q

Q: What is peripheral tolerance largely driven by?

A

A: Tregs

Tregs produce IL-10 which shuts down other immune responses

40
Q

Q: Why is immune regulation key in pregnancy?

A

A: Pregnancy is like a parasitic infection

To allow successful pregnancies, the body needs to immunosuppress

41
Q

Q: Define resolution.

A

A: NO tissue damage, returns to normal. Phagocytosis of debris by macrophages.

42
Q

Q: Define repair.

A

A: healing with scar tissue and regeneration. Fibroblasts and collagen synthesis

43
Q

Q: What is chronic inflammation?

A

A: active inflammation and attempts to repair damage ongoing

44
Q

Q: Explain breaking tolerance.

A

A: Exposure to environmental antigens or self antigens in the context of infection can alter the outcome.

EXAMPLE: Streptococcus pyogenes can produce an antigen which looks like heart muscle antigen

Exposure + Inflammation may trigger a lack of tolerance

45
Q

Q: What is self limitation?

A

A: Self-Limitation = a feature of all immune responses

PRINCIPLE MECHANISM: the immune response eliminates the antigen that initiated the response

So, the first signal for lymphocyte action was eliminated

The immune response shuts down

46
Q

Q: Describe cross regulation by T cell cytokines.

A

A: T helper cells produce cytokines= have a diverse actions on a wide range of cells -> influence the outcome of the immune response

47
Q

Q: What family do cytokines belong to?

A

A: inflammatory mediators

48
Q

Q: What is IL-10? (6)

A

A: key inflammatory cytokine

multifunctional

acts on a range of cells

blocks pro inflammatory cytokine synthesis including TNF, IL-6, IL-8

downregulates macrophages

viral mimics

49
Q

Q: What induces regulatory macrophage phenotype?

A

A: Interaction of resident macrophages with Tregs or with a B cell subset induces regulatory macrophage phenotype

50
Q

Q: What is a regulatory macrophage’s function? What do they produce high levels of?

A

A: Produce high levels of IL-10

NORMAL FUNCTION: reduce inflammatory immune response and thereby limit tissue damage

51
Q

Q: What can suppress T cells? Where has this been seen?

A

A: amino acid starvation-
removing essential amino acids which leads to downregulation of responses

cancer, pregnancy, infectious disease- HIV

52
Q

Q: Summarise T and B lymphocyte collaboration. What interaction has bidirectional effects? What induces T cells? What do T cell derived cytokines drive? What do cytokines drive?

A

A: Specific interaction of antigen-binding B cell with the T cell has bidirectional effects

T cells are induced to express B cell costimulatory molecule CD40 which binds to CD40 on B cells, and secrete cytokines.

T cell derived cytokines drive proliferation and differentiation of B cells into antibody secreting plasma cells

The cytokines direct immunoglobulin class-switching

Y1 Fwong MCD Immunology (A) (9 decks)

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