4: Immune Tolerance Flashcards
Need for immune tolerance
Increased immune function - hypersensitivity
Decreased immune function - immunosupression
Immunosuppression
reduced removal of unwanted cells or pathogens
immunocompromise (HIV, leukaemia, genetic disease)
Opportunistic infections
Cancer
Hypersensitivity
attacks own tissues
trigger: often unknown, sometimes infection
genetic, environmental factors, female predisposition
mechanism often unclear
Hypercytokinemia
Too much immune response
often in +ve feedback loop
Autoimmunity
Immune response against self-antigen
-Immune mediated inflammatory diseases
Happens from imbalance of immune activation and control
Allergy
Harmful immune responses to non-infectious antigens that can cause tissue damage and disease
Mediated by IgE/Mast cells/Tcells
T cell response is controlled by
“licensing” of immune response
T cell needs three signals to be activated:
Antigen (MCHI or MCHII)
Co-stimulation (receptors B7-CD28)
Cytokines (immune cells/infected cells)
Tolerance is
specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen
Tolerance occurs
before circulation - central tolerance
in circulation - peripheral tolerance
B cell Central tolerance
bone marrow
- IgM antibodies on cell membranes
-Tested for binding on stromal cells
-Autoreactive B cells undergo apoptosis
easier than T cell central tolerance, no TCR:MHC activation
B cell Peripheral Tolerance
picks up self-reactive B and T cells - important for B cells, which undergo somatic hypermutation
B cell stimulation - specific B cell divides=expansion
Gene transcription in B cell expansion, variable antibody region prone to errors - somatic hypermutation
Some cells antibodies with higher affinity , cells with more affinity survive, have stronger response to pathogen - affinity maturation
T cell central tolerance
Thymus
T cells must bind MHC complexes, without response in absence antigen
2 STAGES:
1. positive selection - does T cell bind MHC at all. if not = apoptosis
2. Negative selection - does T cell react to self-antigens and MHC too strongly, if they do= apoptosis
T cells need exposure to all antigens of body
What transcription factor do Thymic cells express
AIRE
- Autoimmune Regulator - antigens found in thymus
What do mutations in AIRE lead to
Autoimmune disease
What does negative selection determine the fate of
T cell - CD4 T-helper cell, CD8 cytotoxic T cell or T reg cell
T cell peripheral tolerance mechanisms
Anergy
Ignorance
Deletion/Antigen Induced Cell Deat (AICD)
Angery
T cell encounters specific antigen without co-stimulation :
most cells lack costimulatory receptors and MHCI
less likely response, even for antigen with co-stimulation later
Ignorance
T cells separated from antigens or too low concentration;
potentially self-reactive Naive T cell kept out “immunoprivileged sites”
- anatomical barriers preventing migration - compartmentalisation
-anti-inflammatory cytokines and apoptotic signals
Antigen induced cell dead / Deletion
Antigen presenting cell promotes apoptosis in presence of antigen:
- T cell binds to APC, encounters signal to undergo apoptosis often induced by- Fas ligand FasL/CD95 ligand
T reg cells are formed in
thymus
- originate from T cells that bind self-antigen but not kill them
Role of T reg cells
Start upregulating TF - FoxP3
helps develop into mature Treg cells
Babies with mutation in FoxP3 gene develop
IPEX syndrome
Function of Tregs in pregnancy
mother exposed to cells with different MCHI, immune response prevented
Two types of T reg cells
nTreg - natural regulatory cells ; develop in thymus, reside in periphery
iTreg - inducible regulatory cells; develop during T cell immune response
Tregs reflect the
Th subset seen in T effectors
What helps T cells differentiate into different subtypes
Cytokines
IL-10 Is the
master regulatory cytokine
IL-10
Pleiotropic - multiple functions
Inhibits production of pro-inflammatory cytokines
Inhibits macrophage function
- some viruses can mimic IL-10 to escape immune system
Costimulatory factors make T helper cells
develop into different subtypes
- produce cytokines= more subtype production
- downregulate formation of other subtypes
Different T helper cells secrete
different types of interleukins
What does the type of interleukin produced by T cells, determine
Type of antibodies produced
- different antibodies=different constant regions (important for Fc recognition)= different responses
Follicular T helper cells (Tfh-cells)
help shape antibody response
activate naive B cells to become plasma cells
Interaction between Tfh and B cell
1.B cell internalises antigen and presents on MHCII to Tfh
2.Co-stimulatory binding CD40L to CD40 activates B cell
3.T cell secretes cytokines that determine antibody class switch of B cell
Function of T follicular helper cells
-Activate B cells that present antigens on MHC complexes
-Provide link between cellular and hormonal immune response
-Produce IL-21 to stimulate B cell activation
Mutation in FoxP3 transcription factor results in
inability to allow T-reg cells to develop properly
in pregnancy; T-reg cells shut down immune response in womb because half antigens presented on foetus are non-self
