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
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
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
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
5
Q
Phases of cell mediated immunity
A
- 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 - 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 - Memory
- effector pool contracts to memory
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
7
Q
Licensing a response - the three signal model
A
- antigen recognition
- co-stimulation (cell to cell contact, through protein production)
- cytokine release
- this licenses the cell to respond
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
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
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)
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)
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
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
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
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
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
