Immunological Tolerance and Autoimmune Disease Flashcards
Who has autoantibodies?
Everyone
How many people get autoimmune disease at some point in their life?
5%
Why do small number of autoantibodies suddenly turn into autoimmune diseases?
Increase in number, class switch, T cell proliferation
How do we prevent undesirable autoimmune responses?
Specific immunological tolerance
What types of immunological tolerance are there? Where?
Central and Peripheral
Central is in bone marrow and thymus as lymphocytes develop
Peripheral is everywhere else
Where is most effort put into when tolerising? why?
T cells, needed to make high affinity B cells, and produce IFNy to activate macrophages
What is tolerising T cells called?
Thymic education
Two stages of thymic education are: where?
Positive selection (mostly cortex of thymus) Negative Selection - mostly medulla
Describe positive selection from when T cells enter thymus:
They enter the thymus as double -ve T cells, then become double +ve.
They are destined to die.
If they recognise Self MHC on Thymic epithelial cells (both MHC I and MHCII on them) - they are saved (signal sent in to save them)
If they don’t they die from apoptosis by neglect
Describe negative selection:
There are macrophages and dendritic cells there too. If the T cells have a high affinity for self MHC and self proteins then they are killed - induced apoptosis
How do double +ve T cells become single +ve?
If they recognise MHCII, CD8 is switched off
If recognise MHCI, CD4 is switched off
Why do a lot of T cells die in the thymus?
Genetic recombination isn’t specific
How do the T cells become tolerant to tissue specific antigens?2
The AIRE transcription factor switches alot of them on in the thymus.
We also have peripheral tolerance
What happens if you are AIRE deficient?
Lots of autoreactivity
2 types of central tolerance for B cells:
Clonal deletion and receptor editing
Where does peripheral tolerance occur and what does it deal with?
Outside thymus or bone marrow
deals with self reactive lymphocytes that escape central tolerance
2 main mechanisms of peripheral tolerance are:
Clonal anergy and suppression
Describe anergy in peripheral tolerance
Inactivate the lymphocyte if only Ag recognised in the absence of co stimulators like VCAM1, ICAM, B7 (so only CD4 and TCR active).
This is because pathogens upregulate the costimulators but self antigens don’t.
Lymphocyte can be reactivated though
What are natural and induced Tregs and how do they do peripheral tolerance?
So natural T regs are FOXP3 and CD25+ when leave thymus
Induce Tregs begin expressing these after meeting antigen
They all produce anti inflammatory cytokines like TGFB and IL10
4 things that Tregs do:
Produce mainly immunosuppressive cytokines like TGFB and IL10
Have lots of IL2 receptors and mop up IL2 from vicinity
CTLA4 grabs and internalises B7 from APCs
Release cytotoxic granules
Why does Autoimmune occur? two types:
Break down of immune tolerance
Primary (born with it)
or breaks down later in life
5 Organ specific autoimmune diseases:
Brain - MS Thyroid - Hashimotos thyroditis Stomach - pernicious anemia Adrenal - addisons Pancreas - type I diabetes
4 non organ spec autoimmune:
Muscle - dermatomyosis
Kidney SLE
Skin - SLE and scleroderma
Joints -RA
Why does SLE affect kidney?
Large immune complexes get trapped in glomeruli
What are rheumatoid factors?
IgG recognises Fc bit of another IgG
What are 3 genetic factors associated with autoimmunity?
MHC issues, CTLA4 issues, female
How does infection cause autoimmunity?
B cells respond to microbial agent that cross reacts with self - eg rheumatic fever from group a strep
Ag is similar to cardiac myosine
Hashimotos is:
Ab against thyroglobulin and thyroid peroxide
