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Principles of Medicine (POM) - Block 2 > Lecture 16: Immune Tolerance > Flashcards

Lecture 16: Immune Tolerance Flashcards

1
Q

What is immune regulation?

A

Control of immune response to prevent inappropriate reactions

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2
Q

What is the underlying cause of immune-mediated inflammatory diseases?

A

Failure of control mechanisms

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3
Q

What is the definition of autoimmunity?

A

Immune response against self (auto-) antigen = pathologic

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4
Q

What are the general features of autoimmunity diseases?

A
  • Fundamental problem = imbalance between immune activation and control
  • Pathogenesis: susceptibility genes and environmental triggers
  • Systemic or organ specific
  • immune system is inappropriately directed or controlled: effector mechanisms of injury same as in normal responses to microbes
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5
Q

What are the general features of allergy?

A
  • harmful immune responses to non-infectious antigens that cause tissue damage and disease
  • can be mediated by IgE and mast cells –> acute anaphylactic shock
  • wheal and flare reactions
  • or by T cells –> delayed type hypersensitivity
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6
Q

What are the general features of hypercytokinemia and sepsis?

A
  • too much immune response
  • often positive feedback loop
  • triggered by pathogens entering wrong compartment (sepsis) or failure to regulate response to correct level
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7
Q

What 3 signals are required to licence the cell to respond?

A
  1. antigen recognition
  2. co-stimulation
  3. cytokine release
    NOTE: all 3 things must happen for cell to respond
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8
Q

Describe how self-limitation of the immune system works.

A

The immune system starts clearing away the pathogen so the antigen is being eliminated, which means the first signal for lymphocyte activation is eliminated so there is a decline of immune responses.

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9
Q

What are the 3 phases of cell mediated immunity?

A

INDUCTION - cell infected, dendritic cell collects antigen fragments
EFFECTOR - MHC:peptide TCR interaction, naïve T cell becomes effector, effector cell sees MHC:peptide on infected cell + performs function
MEMORY - effector pool contracts to memory

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10
Q

What is meant by resolution at the end of a immune response?

A

No tissue damage
Returns to normal
Phagocytosis of debris by macrophages

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11
Q

What is meant by repair at the end of a immune response?

A

Healing with scar tissue and regeneration

Fibroblasts and collagen synthesis

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12
Q

What is meant by chronic inflammation at the end of a immune response?

A

Active inflammation and attempts to repair damage ongoing

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13
Q

Define immunological tolerance.

A

Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen

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14
Q

What does a breakdown of self-tolerance result in?

A

Autoimmunity

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15
Q

What is the significance of immunological tolerance?

A
  • all individuals tolerant of own antigens

- therapeutic potential –> exploited to prevent graft rejection, treat autoimmune and allergic diseases

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16
Q

What is the difference between central tolerance and peripheral tolerance?

A

Central tolerance destroys self-reactive T or B cells before they enter circulation, whilst Peripheral tolerance destroys the ones which enter the circulation

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17
Q

How does central tolerance control self-reactive B cells?

A

If immature B cells in bone marrow encounter self-antigen in form which can crosslink their IgM, apoptosis is triggered

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18
Q

How does central tolerance control self-reactive T cells?

A

It selects for T cell receptors which are capable of binding self MHC to a certain extent:

  • Can’t bind to any self-MHC at all = death by neglect (apoptosis)
  • NEGATIVE SELECTION: Binds self MHC too strongly (dangerous) = apoptosis triggered
  • POSITIVE SELECTION: Binds self MHC weakly = signal to survive
19
Q

What is the role of autoimmune regulator (AIRE)?

A

Transcription factor that allows developing T cells in thymus to be exposed to self-antigens/ MHC bearing peptides expressed in other parts of body by allowing thymic expression of genes from other tissues.

20
Q

What can mutations in AIRE result in?

A

Multi-organ autoimmunity

21
Q

How does anergy work in peripheral tolerance?

A
  • naïve T cells need co-stimulatory signals to become activated
  • most cells lack co-stimulatory proteins and MHC class II
  • if naïve T cell sees it’s MHC/peptide ligand without appropriate co-stimulatory protein it becomes ANERGIC i.e. less likely to be stimulated in future even with co-simulation present
22
Q

How does ignorance work in peripheral tolerance?

A

Antigen present in too low concentration to reach threshold for T cell receptor triggering - achieved by compartmentalisation of cells and fact antigen controls interactions

23
Q

Where is ignorance often seen in the body?

A

Immunologically privileged sites e.g. eye, brain

24
Q

How does antigen induced cell death work in peripheral tolerance?

A
  • activation through T cell receptor can result in apoptosis
  • influenced by nature of initial T cell activation events
  • often caused by induction of expression of death ligand, Fas ligand (CD95, FasL)
  • leads to apoptosis
25
Q

What are the 5 T helper (CD4) subsets?

A
  • T helper 1 cells (Th1)
  • T helper 2 cells (Th2)
  • Follicular helper T cells (TfH)
  • Th17 cells
  • Treg
26
Q

What do Th1 cells do?

A

Produce interferon gamma

boost intracellular immune response

27
Q

What do Th2 cells do?

A

Produce IL-4, IL-5, and IL-13

boost anti-multicellular organism response

28
Q

What do TfH cells do?

A

Produce IL-21, reside in B cell follicles

Essential for generation of isotype-switched antibodies

29
Q

What do Th17 cells do?

A

secrete IL-17 in autoimmune diseases like arthritis

important for control of bacteria

30
Q

What do Treg cells do?

A

T cells that regulate activation of effector functions of other T cells
Natural and induced regulatory T cells
Necessary to maintain tolerance to self-antigens
NOTE: Treg = T regulatory cells so inhibit other T cells

31
Q

What are T helpers defined by?

A

The cytokines they produce and the transcription factors they use

32
Q

Where have defective Treg cells been observed in?

A

Multiple Sclerosis

33
Q

What are the mechanisms of action of regulatory T cells?

A
  • secretion of immune-suppressive cytokines (TGFB, IL-10, IL-35)
  • inactivation of dendritic cells or responding lymphocytes
34
Q

What is the phenotype of regulatory T cells?

A

CD4
High IL-2 receptor (CD25), low IL-7 receptor
Foxp3 transcription factor
other markers

35
Q

What can mutations in FoxP3 lead to?

A

Severe and fatal autoimmune disorder e.g.

  • immune dysregulation
  • polyendocrinopathy
  • enteropathy X-linked syndrome
36
Q

What are the different subsets of Treg?

A
  • natural regulatory T cells (nTreg)
  • inducible regulatory T cells (iTreg)
    Tregs reflect the Th subsets seen in T effectors
37
Q

How do nTreg cells develop and where do they reside?

A
  • development (in thymus) requires recognition of self-antigen during T cell maturation
  • reside in peripheral tissues to prevent harmful reactions against self
38
Q

How do iTreg cells develop and when may they be generated?

A
  • develop from mature CD4 T cells that are exposed to antigen in periphery; no role for thymus
  • may be generated in all immune responses, to limit collateral damage
39
Q

Why is regulation critical in pregnancy?

A

Exposure to new antigen, expressed in context of foreign MHCI - body needs to immunosuppress to allow successful pregnancies
T regs only exist in mammals

40
Q

What may trigger a lack of tolerance?

A

exposure (in wrong place e.g. peanut oil on broken skin) and inflammation

41
Q

What are some key features and roles of IL-10?

A
  • master regulator
  • key anti-inflammatory cytokine
  • multi-functional (pleiotropic)
  • acts on range of cells
  • blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFNy
  • down regulates macrophages
  • viral mimics
42
Q

Under what influence does Ig class switching occur?

A

Under T cell influence (cytokines)

43
Q

How do T and B cells collaborate?

A

They activate and are activated by each other by different signals

Principles of Medicine (POM) - Block 2 (12 decks)

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