4.6 - Immune Tolerance Flashcards

1
Q

The importance of immune regulation

A
  • immune response required to protect from infection by pathogenic microorganisms and for survival of the infected mammalian organism
  • too much immune response is as bad as no response
  • immune regulation - control of the immune response to prevent inappropriate reactions
  • avoids excessive lymphocyte activation and tissue damage during normal protective responses against infections
  • prevents inappropriate reactions against self antigens (tolerance)
  • immune regulation achieved by a complex network of immune cells
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2
Q

Failure of immune regulation - autoimmunity

A
  • system of immune responses in an organism against its own cells and tissues
  • disorders often classified as ‘immune-mediated inflammatory diseases’
  • systemic (e.g. rheumatoid arthritis) or organ specific (e.g. Coeliac disease)
  • fundamental problem: imbalance between immune activation and control - failure of control mechanisms is the underlying cause of autoimmune diseases
  • underlying causative factors: susceptibility genes + environmental influences
  • may result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease)
  • immune response is inappropriately directed or controlled; effector mechanisms of injury are the same as in normal responses to microbes
  • may be caused by T cells and antibodies
  • many immunological diseases are chronic and self-perpetuating - it is attacking self antigens and there is always more antigen to attack
  • chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation
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3
Q

Failure of immune regulation - allergy

A
  • harmful immune responses to non-infectious antigens that cause tissue damage and disease
  • can be mediated by:
  • antibody (IgE) and mast cells - acute anaphylactic shock
  • or T cells - delayed type hypersensitivity
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4
Q

Failure of immune regulation - hypercytokinemia and sepsis

A
  • too much immune response
  • often in a positive feedback loop
  • triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate response to correct level
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5
Q

Phases of cell mediated immunity

A
  1. Induction
    - cell is infected, dendritic cell collects material
    - macrophages display foreign antigens on their surface in a form that can be recognised by antigen-specific Th1 lymphocytes
    - travels to lymph nodes
  2. Effector
    - MHC:peptide TCR interaction
    - naive T cell becomes effector
    - Th1 cells produce cytokines that promote the proliferation and differentiation of the T cells as well as other cells including macrophages
    - activated macrophages carry out phagocytosis and cytolysis
  3. Memory
    - effector pool contracts to memory
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6
Q

Self-limiting responses

A
  • fundamental feature of all immune responses: self-limitation
  • manifested by decline of all immune responses
  • principal mechanism: immune response eliminates antigen that initiated the response
    –> first signal for lymphocyte activation is eliminated
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7
Q

Licensing a response - the three signal model

A
  1. antigen recognition
  2. co-stimulation (cell to cell contact, through protein production)
  3. cytokine release
  • this licenses the cell to respond
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8
Q

Why does immunity require an antigen?

A
  • responses against pathogens decline as the infection is eliminated
  • apoptosis of lymphocytes that lose their survival signals (antigen etc)
  • memory cells are the survivors
  • active control mechanisms may function to limit responses to persistent antigens (self antigens, possibly tumours and some chronic infections)
  • often grouped under ‘tolerance’
  • basis of cancer immunotherapy
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9
Q

Possible outcomes at the end of the response

A
  • resolution - no tissue damage, returns to normal; phagocytosis of debris by macrophages
  • repair - healing with scar tissue and regeneration; fibroblasts and collagen synthesis
  • chronic inflammation - active inflammation and attempts to repair damage ongoing
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10
Q

Immunological tolerance

A
  • tolerance: specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen
    Significance:
  • all individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity
  • therapeutic potential - restoring tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases
  • tolerance occurs at two time points: before the T or B cells ever enter the circulation (central), or once in the circulation (peripheral)
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11
Q

Central tolerance

A
  • destroy self-reactive T or B cells before they enter the circulation
  • lymphocytes that recognise self antigens are eliminated (deletion) or made harmless in the generative organs as part of the maturation process
  • B cell down-selection of self reactive immature cells is simple - if immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered
  • T cell selection occurs in the thymus and is more complex due to MHC:TCR interactions - need to select for T cell receptors which are capable of binding self-MHC:
  • is T cell useless? doesn’t bind to any self-MHC at all = death by apoptosis
  • is T cell dangerous? binds self-MHC too strongly = apoptosis triggered (negative selection)
  • is T cell useful? binds self-MHC weakly = signal to survive (positive selection)
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12
Q

How can a T cell developing in the thymus encounter MHC bearing peptides expressed in other parts of the body?

A
  • AutoImmune REgulator (AIRE) and the self peptide conundrum
  • AIRE = a specialised transcription factor that promotes self tolerance - allows thymic expression of genes that are expressed in peripheral/other tissues
  • mutations in AIRE result in multi-organ autoimmunity
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13
Q

Peripheral tolerance

A
  • destroy or control any self reactive T or B cells which do enter the circulation
  • picks up on any escapees and also things that change
  • breaking tolerance: unlike T cells, B cells can change specificity after leaving the bone marrow (somatic hypermutation) - normally good as it improves antibody quality
  • exposure to environmental antigens or self antigens in the context of infections can alter the outcome
  • e.g. anti-Streptococcus pyogenes antibodies can cross react with heart muscle
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14
Q

Mechanisms of peripheral tolerance - anergy

A
  • naive T cells need co-stimulatory signals in order to become activated
  • most cells lack co-stimulatory proteins and MHC class II
  • if a naive T cell sees its MHC/peptide ligand without appropriate costimulatory protein it becomes anergic
  • less likely to be stimulated in future even if costimulation is then present
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15
Q

Mechanisms of peripheral tolerance - ignorance

A
  • antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
  • immunologically privileged sites e.g. eye, brain
  • compartmentalisation of cells and antigen controls interactions
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16
Q

Mechanisms of peripheral tolerance - antigen induced cell death (AICD)

A
  • activation through the T-cell receptor can result in apoptosis
  • influenced by the nature of the initial T-cell activation events
  • in peripheral T cells is often caused by induction of expression of the death ligand, Fas ligand (FasL)
17
Q

T cell mediated regulation

A
  • a subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells and other cells
  • CD4 Treg - phenotype: CD4, high IL-2 receptor (CD25), FoxP3 transcription factor
  • mutation in FoxP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome
  • multiple mechanisms of action: secretion of immune-suppressive cytokines (TGFB, IL-10, IL-35); inactivation of dendritic cells or responding lymphocytes
  • regulation critical in pregnancy - Tregs only exist in mammals, exposure to new antigen, expressed in the context of foreign MHCI
18
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, IFNy
  • downregulates macrophage functions
  • viral mimics
19
Q

Regulatory T cell types

A

‘Natural’ regulatory T cells (nTreg)
- development (in thymus) requires recognition of self antigen during T cell maturation
- reside in peripheral tissues to prevent harmful reactions against self

Inducible regulatory T cells (iTreg)
- develop from mature CD4 T cells that are exposed to antigen in the periphery; no role for thymus
- may be generated in all immune responses, to limit collateral damage

  • Tregs reflect the Th subsets seen in T effectors
20
Q

CD4 T helper cells, cytokines and chemokines

A
  • T helper cells shape the immune response, tailoring for different pathogens
  • they do this through cytokines, which they produce and these have diverse actions on a wide range of cells and influence outcome of immune response

Cytokines:

  • program the immune response, focusing it for right purpose
  • can be inflammatory (increase response) or anti-inflammatory (decrease response)

Chemokines:

  • drive movement around the body
  • act like address labels sending stuff to the right place
  • chemokine receptor profiles change with activation state of the cells
21
Q

How do T cells shape the antibody response?

A
  • constant region is important in the function
  • different antibody classes have different constant regions
  • the differences in function reflect the different types of response required to clear pathogens
  • there are a number of gene cassettes that can be swapped in and out to increase variability
  • T cells cytokine drive Ig class switch - class switch under T cell influence (cytokines)
  • the cytokine depends on the type of T helper cell
  • the variable region does not change, so antigen specificity is not affected - instead the antibody can interact with different effector molecules while remaining affinity for the same antigens
22
Q

Summary of roles of cytokines produced by CD4 T cells

A
  • CD4 T lymphocytes regulate other cells of the immune system
  • CD4 T cells shape the immune response
  • CD4 T cells boost the B cell response
  • CD4 T cell cytokines drive Ig class switch