Immune tolerance and autoimmune disorders Flashcards
(45 cards)
How is the diversity of antigen recognition increased
T and B cells adapt the genetics of the antigen receptor gene
What happens to cells that bind to self-antigens
These are destroyed before peripheral release
What ensures T cells are restricted to self MHC
Positive selection in the thymus
What must self-restricted T cells also tolerate
Self-antigens
What will negative selection do
Negative selection will kill any T cell that exhibits strong binding to self-antigen
B cells go through the process of negative selection in the bone marrow (B cells do not go through positive selection)
What does negative selection ensure
that our adaptive immune cells do not react to self-antigen once in the periphery
Known as central tolerance
What are issues with central tolerance
Autoimmune diseases can occur
This means that positive and negative selection has failed to a degree
However, many people without autoimmune disease have circulating autoantibodies which don’t cause pathogenesis
They could be useful in clearing apoptotic debris
What is fetal microchimerism
Mother is exposed to paternal antigens via
the foetus
Foetal T-cells pass into the mother and
circulate for decades
Maternal T-cells pass into foetus and
circulate for decades
Requires tolerance to antigens which can’t
be centrally derived
Why must tolerance and sensitivity be balanced
Too much self tolernce is linked with cancer development and progression
less self tolerance causes autoimmune disorders
How does autoimmunity happen
Autoimmunity occurs when cell of our adaptive immune system
activate towards ‘self’ antigen
What are immune privileged sites
Sites of the body protected from the immune response (evolutionary
conserved)
Include the liver, adrenal cortex etc
What is peripheral tolerance
As self reactive B and T cells can slip through the central tolerance net we are protected by peripheral tolerance
Mechanisms of how it works
Ignorance – T cells rely on co-stimulation for activation
Anergy – immunosuppressive molecules on perpheral tissues suppress T cell activation
Apoptosis – T and B cell death receptor
Immune suppression – conversion to regulatory T cell
How does ignorance work as a peripheral tolerance mechanism
Ignorance —> anergy
T cell activation requires antigen presentation by MHC (coded for by HLA) and co-stimulation through the CD28 receptor interacting with B7 molecules
How does anergy work as a peripheral tolerance mechanism
Anergy —> CTLA-4 and CD200
T cells express negative co-receptors (like CTLA-4) - this switches T cell activation off
Also interacts with B7 molecules on cells
CD200 expression is high in peripheral sites of low immune activation (immune privileged sites)
See slide 14 for image
Loss of CD200 expression is observed in MS and rheumatoid arthritis
Also important for protecting the placentafrom immune attach
during pregnancy (loss
of CD200 linked to pre-
eclampsia)
What CD molecule is upregulated in cancer
CD200
How does apoptosis work as a peripheral tolerance mechanism
poptosis —> programmed cell death
T and B cells express a receptors called PD-1 (programmed death 1)- this interacts with a surface molecule called PD-L1
This interaction suppresses T and B cell activation and in high concentrations can trigger apoptosis
Cancer cells upregulate PD-L1
How does immune suppression work as a peripheral tolerance mechanism
Immune supression —> cytokines and cells
T cells need co-stimulation (receptor and CD28) - cytokines also play a role in T cell differentiation
Broadly have 2 cell classes
T cytotoxic (express CD8)
T helper (expresses CD4)
Both require co-stimulation and cytokine exposure for full differentiation
Cytokines exert a diverse effect on T cells
What is an important cytokine in peripheral sites
TGFβ is an important cytokine in many peripheral sites e.g.
endothelium –> drive the induction of regulatory T cells (Tregs)
What do Tregs do
Tregs are a subclass of T helper cell
and carry the immunophenotype
CD4+ CD25++ FoxP3+
CD4 – MHC-II restricted
CD25 – IL-2 receptor
Foxp3 – transcription factor
Tregs
Sequester IL-2, produce IL-10, TGFβ
compete for MHC binding
Low Tregs seen in ulcerative colitis
High Tregs seen in cancers…
Difference between central and peripheral tolerance
Naïve T and B lymphocytes generate a unique antigen receptor via somatic
recombination (central selection insures
self-tolerance)
Peripheral molecular & cellular mechanisms further protect tissues from immune destruction (CTLA-4, CD200,
PD-1, TGFβ, Tregs)
What mechanisms mediate the loss of peripheral tolerance
Release of sequestered self-antigens
Cryptic/modified self – genetic changes that induce a slightly different protein
Molecular mimicry
Inappropriate MHC expression
Cytokine imbalance
What is the induction theory
The theory states that pathogens share epitopes (i.e., amino sequences or structures) with the host; therefore, when the immune system of the host reacts against those epitopes of the pathogens, it will also accidentally cross-react with the same epitopes of the host.
How does cryptic/modified self trigger autoimmunity
self antigen changes what it looks like – could be advantageous in cancer immunology – chromosomal translocation that result in chimeric protein
Could be self antigen denatures and exposes immune reactive site
Drug induced – autoimmune hepatitis
Post-translational modifications
How does molecular mimicry cause autoimmunity
previous exposure to a pathogen that has close homology to self
Measles has an antigen called virus P3 antigen which has a region of homology to myelin basic protein
Measles infection expands effector T cells that have self cross reactivity
