Tolerance and Autoimmunity Flashcards
How did we find out about tolerance?
During WW2 they took skin graphs from people and tried to replace the burned skin of pilots but this always failed
What experiments where done to find out tolerance?
They took a skin graft from one mouse (mouse A) and placed it on another (mouse B) - this was rejected.
They then took the mouse B and put another skin graft on it. This was also rejected but faster due to memory cells.
They then took a skin graft from mouse A and put it on a brand new mouse (mouse C) and transferred mouse B’s lymphocytes into mouse C - this was rejected.
What was the experiment done to show the theory self and non self are defined during embryogenesis?
Take a skin graft from strain A and put it on strain B = rejection
Take white blood cells from strain A into strain B embryos and then do the above graft you wont get rejection
Why do we need tolerance?
Because of the recombination of T and B cells this leads to some T and B cells being specific for self antigens which could lead to autoimmunity. These therefore need to be eliminated.
What is autoimmunity?
Reaction of the immune system against self components
What is central tolerance?
Occurs in generative lymphoid organs during development of the immune system in the thymus for T cells and bone marrow for B cells.
What causes central tolerance?
Negative selection - immature lymophocytes specific for sel-antigens undergo deletion (apoptosis) in both T and B cells, receptor editing (B cells) and differentiation into Treg cells (CD4 T cells).
What is peripheral tolerance?
Occurs in peripheral tissue
What happens to any mature self-reactive lymphocytes that escape central tolerance?
They are rendered nonresponsive, deleted or supressed by Tregs.
When does T cell tolerance occur?
During T cell development
What is negative selection in central tolerance?
Deletion or modification of autoreactive CD8 and CD4 T cells in the thymus.
Why do you need negative selection in central tolerance?
Recognition of self would lead to autoimmunity and therefore you need to get rid of autoreactive T cells
How does negative selection in central tolerance happen?
SP T cells interact with DC and mTECs (which present self antigens from tissues around the body). If there is high affinity binding apoptosis occurs
CD4 Tcells can bind with intermediate affinity for Treg differentiation.
What do naive Tregs do?
Go to the peripheral tissue and suppress other immune cells preventing autoimmunity
What is APECED?
A rare disorder that is autosomal recessive diagnosed by having 2 of the three symptoms (Candidiasis, hypoparathyroidism and addisons disease).
What is the cause of APECED?
Genetics defect causing mutations in the AIRE gene (AutoImmune Regulator Gene).
What happens when there is not AIRE?
No TRA’s in the thymus
How are mTECs able to present antigens that are only expressed in other tissues if they live in the thymus?
The protein AIRE drives expression of TRAs in mTECs around the body
Why do we need peripheral tolerance?
To prevent reactivity to self-antigens not expressed in the thymus/early life, harmless foreign antigens such as food etc. and fetal antigens
What is anergy?
State of unresponsiveness to stimulation
Anergy - what happens when an infection is seen?
T cells are activates and expanded due to the APC showing B7 to the T cells
Anergy - what happens when there is no infection?
The APC shows the T cell a self antigen without B7 and therefore no response. (this is why vaccines need adjuvents to work).
Can a person show both self-antigens and B7 at the same time?
Yes and this causes T cell activation, expansion and autoimmunity
How would you induce anergy in a patient with autoimmunity?
Block the B7/CD28 binding by abatacept used in rheumatoid arthritis
Apoptosis - what is AICD?
This is activation-induced cell death and is done by Fas/FasL interaction.
How does the fas/FasL interaction work?
Activated T cells express Fas on their surface. When fas binds FasL the apoptosis pathway is induced
Can T cells also express FasL and kill each other?
Yes
Whats is ALPS?
An autimmune lymphoproliferative syndrome which occurs in patients with mutations in the Fas, FasL, caspase 10 apoptotic pathway.
What are symptoms of ALPS?
Lymphadenopathy and/or splenomegaly
Autoimmune manifestations vary e.g. ITP, hemolytic anaemia, autoimmune hepatiti and uveitis
Where are Tregs generated?
In the thymus by negative selection and in the periphery which are generate in the presence of TGFb
What do all Tregs need for differentiation?
FOXP3
What do all Tregs express on their surface?
CD25 (IL-2 receptor)
CTLA-4 (inhibitory receptor)
What do Tregs do?
Supress other cells
How does contact dependant mechanisms (CTLA-4) Treg suppression work?
A) Blocks B7 on APC so it is not available for effector T cells to bind to CD28
B) Removes B7 from APC
C) Binding of CTLA-4 to B7 sends inhibitory signals to the APC -> less antigen presentation, less production of cytokines by APC
How do cytokine mediated mechanims cause Tregs to supress other cells?
A) Production of suppressive cytokines (IL-10 and TGFb)
B) Consumption of available IL-2 (through CD25), so T cell proliferation is reduced.
What is IPEX?
An X-linked diseases caused by mutations in FOXP3 gene meaning they lose functional Tregs.
What are symptoms of IPEX?
Enteropathy, type 1 diabetes and dermatitis
How do you diagnose IPEX?
Flow cytometry of peripheral blood cells
Out of APECED, IPEX and ALPS which disease can be cured by HSCT (haematopoietic stem cell transplant)?
IPEX and ALPS (cant do APECED as aire is seen in somatic cells not just haematopeitic cells).
