Immune Tolerance Flashcards
Immune regulation
Control of immune response to prevent inappropriate reactions
Why do we have immune regulation
Avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
Prevents inappropriate reactions against self antigens
3 failures of immune regulation
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
Hypercytokinemia and sepsis
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
3 phases of cell mediated immunity
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
How is immune response self limiting
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
What are three signals needed to license and immune response
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
How do responses against pathogens decline as infection clears
- Apoptosis of lymphocytes that lose their survival signals (antigen etc)
- Memory cells are the survivors
How are responses to persistent antigens limited
- 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
3 outcomes of infection
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
Immunological tolerance
Specific unresponsiveness to an antigen that’s induced by exposure of lymphocytes to that antigen
Autoimmunity occurs when there’s a lack of it
Why is immunological tolerance significant
- 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
Central tolerance
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
T cell central tolerance
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
AIRE
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
Peripheral tolerance
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
How can affinity maturation cause autoimmunity
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
What 4 mechanisms occur through peripheral tolerance
Regulation
Anergy
Ignorance
Antigen induced cell death
Anergy
- 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.
Ignorance
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
Antigen induced cell death
- 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
Treg cells
A subset of T helper cells called T regulatory cells inhibit other T cells and other cells through production of cytokines
Phenotypic markers of treg cells
CD4
High IL-2 receptors
Foxp3 transcription factor
Mechanism of action for treg cell so
- Secretion of immune-suppressive cytokines (TGFbeta, IL-10, IL-35)
- Inactivation of dendritic cells or responding lymphocytes
Foxp3
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
IL-10
- 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
Why do treg only exist in mammals
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)
Different types of tregs
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
Cytokines
- 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)
Chemokines
- 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
Cross regulation in T cells
Where cytokine response from 1 type of Th cell will shutdown response of other Th cell types
How do T cells boost B cell response
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
Communication signals
Antigen
Costimulation
Cytokine
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
Cytokine types and function
Tfh- pro antibody
Th1:boosts immune response
Th2:anti multicellular organism
Th17-controls bacterial and fungal infection
Treg(Th0)-Anti inflammatory
Cross regulation
Where cytokine response from 1 type of Th cell will shut down response of other Th cell types
What three pathways can be cell undergo after activation by T cell
Antibody production
Memory cell
Affinity maturation where antibody changes shape to better bind via somatic hypermutation
