Lecture 7 Flashcards
Why do we need immuological tolerance?
Many self reactive specificities would be produced, and autoimmune diseases would results from the immune system attacking urself
What happens if we don’t have tolerance?
Would lead to serious pathology
What are the two types of bad tolerance for TCR?
- T cells fail to recognise self MHC
- T cells recognise self MHC + peptide (autoreactive)
What is a useful type of T cell tolerance?
Recognise self MHC + any other peptide not present in thymus
What is negative selection of TCR tolerance?
When the T cells recognise their own self-MHC
What is T cell survival and tolerance based on?
TCR affinity
What is the best mechanism for T cell survival?
A population with TCRs that have a medium affinity - capable of binding peptides derived from antigens NOT present in the thymus
Not all self antigen are expressed in thymus, what else can be?
Insulin
What does AIRE stand for?
Autoimmune regulator protein
What is AIRE?
A transcription factor
What is the job of AIRE?
Allows lots of tissues specific genes to be expressed in the thymus at low levels
What is the reasons for insulin being expressed in the thymus?
Deletes autoreactive T cells
What does a global transcription factor allow?
Allows us to become tolerant as it controls expression
What is AIRE deficiency?
When People have major autoimmune syndromes
What leads to b cell tolerance?
Random Ig gene arrangements leads to self reactive BCRs
Where are autoreactive B cells negatively selected?
In the bone marrow
What is different about b cells than T cells in tolerance?
B cells get another change to re-arrange the self-reactive BCR
What is it called when self-reactive BCR can rearrange?
Receptor editing
What is receptor editing?
A new chain may remove self-reactivity changing the specific of the BCR
What does binding of self antigen by immature B cells lead to?
Death or anergy
What happens in anergy?
Sneak out the bone marrow by lowering the B cell receptor so they don’t get killed
What are the levels of BCR like in a anergic B cell?
Low levels of BCR become unresponsive
What happens when receptors encounter an AG that is not multivalent?
They done regulate BCR and leave the bone marrow unresponsive
Can T cells be made anergic?
Yes - if a T cell encounters an Ag in the absence of co-stimulation becomes anergic
What happens if a T cell only gets signal 1?
The T cell will override and not work
What are some other mechanisms of tolerance?
Immunological ignorance and privileged sites
What is immunological ignorance?
When the T cells don’t get enough expression to drive signal 1 or 2
What are privileged sites?
Stops immune cells going into the central nervous system with barriers
Where are the barriers in privileged sites?
Eyes, testis, CNS
What do B cells hope in tolerance?
They are dependent on T cell tolerance, they hope they will never get help from an autoreactive T cell
What are regulatory T cells?
Subsets of cells which are there to portrol other cells
What happens if you dont have regulatory T cells?
You will have autoimmunity
Where do Treg cells arise?
In the thymus from T cells with high affinity receptors or self antigens
What are induced Tregs (iTregs)?
Cells that have come out of the thymus that have avoided negative selection
What does IL-10 do?
Turns off antigen presentation function
What happens if a cell produces IL-10?
It is turning off potentially self reactive cells
What are Breg/10?
They are crucial for preventing autoimmunity
What is regulation of immune responses?
To make that the response that is targeted towards the pathogen is pathogen specific and is controlled and regulated once it has done its job
What are cytokines in TH2 (helper cells)
IL-4,5 and 13
What are cytokines in TH1 (helper cells)?
Infrerferongamma
What does interferongamma do?
Activates macrophages
Why is interferongamma good for TH1?
If you have a bacteria infection then response will go to TH1 - macrophage will do its job better at engulfing the bacteria
What are cytokines 4,5 and 13 good for TH2 if you have a parasitic worm?
The recruitment of innate cells release things to kill large cellular parasites
What do naive CD4+ T cell differentiate into?
Effector T cells
What do CD4+TH1 do?
Activate macrophages, NK cells and cytotoxic T cells
What do CDR4+Th2 do?
Promote responses mediated by enosiophils and mast cells, antibody IgE
What do CD4+Th17 do?
Promote responses against fungi
What do CD4+ Treg/Breg do?
Suppress unwanted responses
What do CD4+TFH do?
Specialised Th found in GC to help B cells (GC - germinal centre)
What can CD4+TH1 cells express?
CD40L which binds to CD40 on macrophages
What can CD4+TH1 kill?
Chronically infected macrophages, bacteria
What cells are involved in CD4+Treg? (Biomarkers)
CD4+CD25+ and some CD8+ CELLS
What is the function of Treg cells?
To make anti inflammatory cytokines to suppress other T cell responses
What cels do CD4+Treg cells suppress?
TFG-beta and IL-10
What does IL-10 inhibit?
Antigen presenting cells
What is the Th response influenced by (helper cells)?
By signal 3 - influenced by cytokines that are present when T cells are activated
Can cells go down TH1 and TH2?
No only one route at a time
What do cytokines do to T cells?
They polarise them
What is another cytokine in TH1?
IL-12
What is a key process in TH helper cells?
Autocrine positive feed back loop
What do PAMPS drive on dendritic cells?
Il-12
WHAT IS PAMPS recognised by?
PRR
What does pRR lead to?
CD80/86
WHAT IS SIGNAL 2 in th1 responses?
CD86
What is signal 3 in th1?
IL-12 moves to TH1 to its effector cell
What is signal 2 in TH2?
Upregulates co-stimulator
How does each route (TH1 and tH2) turn off the other route?
They inhibit the opposite pathway
What do TH1 cytokines inhibit?
TH2 and TH17
What do TH2 cytokines inhibit?
TH1 an dTH17
What do TH17 inhibit?
Treg
What do Treg inhibit?
TH1,TH2,TH17
What does Treg allow?
A successful pregnancy
How does Treg work in pregnancy?
Prevents the mother from rejecting her unborn foetus
What causes allergy?
Excessive TH2
What is a way viruses use to stop a mechanisms form happening?
To not infect APC but use cross presentation
