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MCD Immunology > 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. Caused by? (2) 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 result in immune-mediated inflammatory diseases? by? (2)

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: What can mediate an allergy? (2) 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/non infectious proteins/agents 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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10
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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11
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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12
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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13
Q

Q: How does the response against pathogens decline as the infection is eliminated? (2) Driven by? how?

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 (antigens), 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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14
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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15
Q

Q: Why is immunological tolerance important?

A

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

Therapeutic Potential - inducing tolerance by regular exposure

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16
Q

Q: What does breakdown of self tolerance lead to?

A

A: autoimmunity

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17
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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18
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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19
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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20
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

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21
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

22
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

23
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

24
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

25
Q

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

A

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

26
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

27
Q

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

A

A: central tolerance

28
Q

Q: What does peripheral tolerance control?

A

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

29
Q

Q: What are the 4 mechanisms for peripheral tolerance?

A

A: Anergy
Ignorence
Deletion
Regulation

30
Q

Q: Explain anergy as a mechanism for peripheral tolerance. (3) Result? 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)

31
Q

Q: Explain ignorance as a mechanism for peripheral tolerance. Where does it occur? why?

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

32
Q

Q: Explain deletion as a mechanism for peripheral tolerance. Often caused by? when?

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

33
Q

Q: Explain regulation as a mechanism for peripheral tolerance. (2)

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

34
Q

Q: What transcription factor is expressed by Treg? What do mutations of this lead to? examples (3).

A

A: FoxP3

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

35
Q

Q: What are regulatory T cells? Phenotype. (3)

A

A: type of CD4 T helper cell

Phenotype: CD4, IL-2 receptor, FoxP3

36
Q

Q: What’s a T regulatory cell’s mechanism of action? (4) What happens to individuals who can’t make Treg? (2)

A

A: 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’

have broad spectrum autoimmune conditions - it is a failure of peripheral tolerance

37
Q

Q: What are the 2 types of Treg? Describe (2,1).

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

38
Q

Q: What is peripheral tolerance largely driven by? reason?

A

A: Tregs

Tregs produce IL-10 which shuts down other immune responses

39
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

40
Q

Q: Define resolution. What’s involved?

A

A: NO tissue damage, returns to normal.

Phagocytosis of debris by macrophages.

41
Q

Q: Define repair. What’s involved?

A

A: healing with scar tissue and regeneration

Fibroblasts and collagen synthesis

42
Q

Q: What is chronic inflammation? due to? characterised by? (4)

A

A: long lasting inflammation (weeks or months) due to persistent aggressive stimuli and is characterised by: active inflammation with mononuclear cells, tissue destruction and repair

43
Q

Q: Explain breaking tolerance. (2) Example.

A

A: Exposure to environmental/self antigens in the context of infection/Inflammation = can alter the outcome and trigger a lack of tolerance

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

44
Q

Q: What is self limitation? (3)

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

45
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

46
Q

Q: What family do cytokines belong to?

A

A: inflammatory mediators

47
Q

Q: What is IL-10? Function? (3) Which cell does it act on?

A

A: key inflammatory cytokine

multifunctional

  • blocks pro inflammatory cytokine synthesis including TNF, IL-6, IL-8
  • downregulates macrophages
  • viral mimics

acts on a range of cells

48
Q

Q: What induces regulatory macrophage phenotype?

A

A: Interaction of resident macrophages with Tregs or with a B cell subset

49
Q

Q: What is a regulatory macrophage’s function? therefore? What do they produce? level?

A

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

Produce high levels of IL-10

50
Q

Q: What can suppress T cells? explain. Where has this been seen? (3)

A

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

cancer, pregnancy, infectious disease- HIV

51
Q

Q: Summarise T and B lymphocyte collaboration. What interaction has bidirectional effects? What are T cells induced to do? result? (2) What do T cell derived cytokines drive? What do cytokines direct?

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

MCD Immunology (10 decks)

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