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Pom > Immune Tolerance > Flashcards

Immune Tolerance Flashcards

1
Q

Immune regulation

A

Control of immune response to prevent inappropriate reactions

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2
Q

Why do we have immune regulation

A

Avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
Prevents inappropriate reactions against self antigens

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3
Q

3 failures of immune regulation

A

Autoimmunity-immune repose against self antigens. Can be systemic or organ specific reuksting from responses against self antigens or microbial antigens(crowns).Pathological
Allergy-Harmful immune responses to non-infectious antigens that cause tissue damage and disease. Mediated by igE and mast cells causing anaphylactic shock or T cells causing delayed hypersensitivity

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4
Q

Hypercytokinemia and sepsis

A

Too much immune response
Often in a positive feedback loop
Triggered by pathogens entering wrong compartment (sepsis) or failure to regulate response to correct level

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5
Q

3 phases of cell mediated immunity

A

Induction
Cell infected. Dc presents antigen to T cells
Peptide tcr interaction

Effector
Naive T cell becomes effector
Effector cell sees MHC peptide on infected cell and performs function

Memory
Effector pool contracts to memory

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6
Q

How is immune response self limiting

A

The immune response shuts down/declines once it eliminates the antigen that initiated the response.

~ Apoptosis of lymphocytes as they lose their survival signals (antigen)

~ Memory cells survive

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7
Q

What are three signals needed to license and immune response

A

1) Antigen recognition

2) Co-stimulation → protein interactions on cell surface of APC, T cells and B cells

3) Cytokine release → cytokines are soluble signalling molecules

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8
Q

How do responses against pathogens decline as infection clears

A
  • Apoptosis of lymphocytes that lose their survival signals (antigen etc)
  • Memory cells are the survivors
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9
Q

How are responses to persistent antigens limited

A
  • Active control mechanisms limit response to persistent antigens (self-antigens, possibly tumours and some chronic infections)
  • This is tolerance and is the basis of cancer immunotherapy
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10
Q

3 outcomes of infection

A

Resolution-no tissue damage,phagocytosis of debris by macrophages
Repaire-healing with scar tissue,fibroblasts and collagen synthesis
Chronic inflammation-active inflammation that attempts to repair damage

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11
Q

Immunological tolerance

A

Specific unresponsiveness to an antigen that’s induced by exposure of lymphocytes to that antigen
Autoimmunity occurs when there’s a lack of it

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12
Q

Why is immunological tolerance significant

A
  • All individuals are tolerant of their own antigens (self-tolerance) → breakdown of self-tolerance leads to autoimmunity
  • Therapeutic potential- restoring tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases
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13
Q

Central tolerance

A

Destroy self reactive T or B cells before they enter circulation

10^15 possible TCR and antibodies randomly generated, and some of these will be self-reactive so need to be removed

If immature B cells encounter antigen in a form which can crosslink their IgM, apoptosis is triggered

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14
Q

T cell central tolerance

A

T cell selection occurs in thymus and is more complex than B cells because of need for MHC:TCR interaction. We need to select for TCR which are capable of binding self-MHC or self-peptide

  • If T cell receptors don’t bind any self-MHC at all, death by neglect occurs (apoptosis)
  • If TCRs bind self-MHC weakly it gets a signal to survive- positive selection
  • If TCRs bind self-MHC too strongly, apoptosis is triggered- negative selectionNOTE: this is mediated by AIRE
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15
Q

AIRE

A

Autoimmune regulator
A transcription factor which allows thymic exprression of genes that are expressed in peripheral tissues so developing T cells in thymus can encounter NHC bearing peptides
Promotes self tolerance
If mutation present multi organ autoimmunity occurs

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16
Q

Peripheral tolerance

A

Destroy self reactive T or B cells once in circulation
Undergoes antibody production,memory cell,affinity maturation (change shape of antibody to better bind it

17
Q

How can affinity maturation cause autoimmunity

A

Exposure to self antigens can alter outcome if antigen in pathogen is similar to self cell
Eg Anti-streptococcus pyogenes antibodies can cross react with heart muscle since antigens on the bacteria and heart muscle are similar
Where antibody changes shape to better bind it

18
Q

What 4 mechanisms occur through peripheral tolerance

A

Regulation
Anergy
Ignorance
Antigen induced cell death

19
Q

Anergy

A
  • Naive T cells need co-stimulatory signals in order to become activated
  • Most cells lack co-stimulatory proteins AND MHC II
  • If naive T cell sees its MHC/peptide ligand (self-antigen on APC) without costimulatory signal protein, the T cell becomes anergic (becomes unresponsive)
  • Less likely to be stimulated in future even if co-stimulation is present.
20
Q

Ignorance

A

Antigen present in too low concentration to reach threshold for T cell receptor to become triggered

T cells become anergic or no longer reactive
Occurs in immunologically privileged sites eg eyes or brain

21
Q

Antigen induced cell death

A
  • Activation of T cell through TCR induces expression of the death ligand, which results in apoptosis of T cell
  • T cells that bind to self-cells die in circulation due to Fas- Fasl linkages. Here, T cells are activated to be killed
    Fas receptors found on T cells and fasl ligands are produce by the T cell itself or other cells. They cause death preventing T cells that react too strongly from entering circulation
22
Q

Treg cells

A

A subset of T helper cells called T regulatory cells inhibit other T cells and other cells through production of cytokines

23
Q

Phenotypic markers of treg cells

A

CD4
High IL-2 receptors
Foxp3 transcription factor

24
Q

Mechanism of action for treg cell so

A
  • Secretion of immune-suppressive cytokines (TGFbeta, IL-10, IL-35)
  • Inactivation of dendritic cells or responding lymphocytes
25
Q

Foxp3

A

FoxP3 transcription factor needed for Treg development

  • Severe and fatal autoimmune disorder → Immune dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) syndrome
    Occurs when there a mutation in Foxp3
26
Q

IL-10

A
  • Key anti-inflammatory cytokine
  • Multi-functional (pleiotropic)- acts on a range of cells
  • Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFNγ
  • Downregulates macrophage functions
  • Viral mimics e.g. EBV so it hides from immune system by making a protein that looks like IL-10 → shuts down immune response
27
Q

Why do treg only exist in mammals

A

Critical in pregnancy when mother is exposed to new antigens often expressed in context of MHC I from baby (half of baby’s MHC is from dad which could be foreign to mum and could lead to attack by T cells)

28
Q

Different types of tregs

A

Natural tregs-developed in thymus and resides in peripheral tissues
Inducibke tregs-develop from mature cd4 T cells that are exposed to antigen in periphery,made to limit collateral damage

29
Q

Cytokines

A
  • Program the immune response and can focus it for the right kind of response
  • Can be inflammatory (increase response) or anti-inflammatory (decrease response)
  • e.g. interferon gamma (inflammatory), IL-2 (inflammatory), IL-10 (anti-inflammatory)
30
Q

Chemokines

A
  • Drive movement around body
  • chemoattractant cytokines which that recruit cells to move towards areas of inflammation
  • Act like address labels sending things to the right place
  • Chemokine receptor profiles change with activation state of the cells
31
Q

Cross regulation in T cells

A

Where cytokine response from 1 type of Th cell will shutdown response of other Th cell types

32
Q

How do T cells boost B cell response

A

CD4 T cells release a certain type of cytokine

This cytokine is detected by the B cell

The antibody that the B cell will produce will now have its constant region altered which determines its class

  • T cell produce cytokines which programme B cells to activate gene factors to switch Ig classes

This way, the class of antibody produced is dependent on the cytokine triggered

33
Q

Communication signals
Antigen
Costimulation
Cytokine

A

T cells:MHC peptide on DC/Bcell,expresses CD40L to activate B and expresses CD28 to be activated,IL-21
B cells:soluble antigen,expresses CD40 to be activated by T and expresses B7

34
Q

Cytokine types and function

A

Tfh- pro antibody
Th1:boosts immune response
Th2:anti multicellular organism
Th17-controls bacterial and fungal infection
Treg(Th0)-Anti inflammatory

35
Q

Cross regulation

A

Where cytokine response from 1 type of Th cell will shut down response of other Th cell types

36
Q

What three pathways can be cell undergo after activation by T cell

A

Antibody production
Memory cell
Affinity maturation where antibody changes shape to better bind via somatic hypermutation

Pom (44 decks)

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