10. Immunological Tolerance and Autoimmune Disease Flashcards
What is the role of specific immunological tolerance?
Prevents undesirable immune response such as those to self-antigens
What are the two types of tolerance?
Central - involves T and B cells in bone marrow/thymus - occurs as lymphocytes are developing
Peripheral - everywhere else - backs up central
What is autoimmunity and autoantibodies? How is autoimmune disease different to these?
Autoimmunity - immune response of an organism against self tissues
Autoantibodies - T cells which can recognise self antigens
Autoimmune disease - negative symptoms arise, increase in differentiation and amount of autoantibody
What cells does specific immunological tolerance mainly involve?
Lymphocytes (NOT macrophages or eosinophils)
What is the most common way of maintaining tolerance?
Level of T cells - removing the self reactive helper T cells which cause the cascade
What is the process of thymic education?
Two stages: Positive and negative
1st Round Positive: Select T cell that interact with thymus epithelial cells - T cells can recognise MHCI and MHCII at this point (CD8 & CD4) so are checked to make sure their TCR can recognise OWN MHC, if they can then signal sent into cell which prevents apoptosis
2nd Round Negative - Select T cells which don’t recognise all MHC - T cells interact with dendritic and macrophages, default pathway switched to cell survival, apoptosis induced in T cells which have high affinity for MHC, if TCR interacts with MHCI then CD4 switched off, if interacts with MHCII CD8 switched off
So they become single positive T cells which don’t recognise own antigens
How does the expression of CD4/CD8 of T cells vary throughout the process of thymic education?
T cells start off double negative (CD4- CD8-), then go to double positive (CD4+ CD8+), then go to single positive
How does the default pathway change from positive to negative selection?
In positive selection the default pathway is apoptosis whereas in negative selection the default pathway is cell survival
Where does positive/negative selection of T cells occur? Describer the organ in question
In the thymus
Single organ in thoracic cavity overlapping the heart/lung, consists of lobules each with an outer cortex and inner medulla
What is the name of T cells which develop in the thymus?
THYMOCYTES
Where does positive/negative selection occur in the thymus?
Positive selection of cells occurs when binding to MHC cells in the cortex. Negative selection occurs when T cells migrate from cortex to medulla and interact with macrophages/dendritic cells (and die if they have affinity for own antigen)
Massive amounts of cell death goes on in the thymus.
What is the AIRE? What is it responsible for?
The Autoimmune Regulator - central tolerance
Binds to DNA in thymus and switches on expression of most self-genes (but not all - peripheral tolerance also helps) so T cells can mature with all the self antigens present. IF a defective thymus/AIRE is present then people will have lots of auto reactive cells
What are the two methods of central tolerance of B cells (badly worded but ygm)?
- Clonal Deletion
2. Receptor editing - if receptor is against own body proteins then receptor may be replaced
What is the role of peripheral tolerance? What are it’s processes?
Deals with self-reactive lymphocytes that escape central tolerance.
Uses clonal anergy and suppression
Describe the process of clonal anergy in peripheral tolerance
Removes lymphocytes by inactivating them (but not killing them) when there is not appropriate co-stimulation
Describe the process of suppression in peripheral tolerance
Suppress unwanted immune responses using two types of regulatory cells: Natural and induced. Natural regulatory cells always express FoxP3 and CD25 whereas induced express FoxP3 and CD25 when stimulated by self-antigen. These release IL-10/TGF-beta, cytotoxic granules or mop up IL-2 (so can’t be used by other cells)
Treg’s can also use CTLA-4 on their surface to grab CD80/CD86 and rip them off the APC (antigen presenting cell) preventing the APC from co-stimulating.
How do autoimmune diseases occur?
Breakdown in immunological tolerance - may break down at birth or later on in life. Strong genetic component.
How may autoimmune diseases will be split? Give examples of each type
- Organ specific - antigen only found in one organ (e.g. multiple sclerosis)
- Non-organ specific - antigen found throughout body (e.g. lupus, rheumatoid arthritis)
Even if non-organ specific some tissues may be affected more than others. For lupus immune complexes build and become trapped in small areas like skin and kidneys
What area of the body does Graves and rheumatoid arthritis affect? How?
Graves - thymus - TSH receptor overstimulated - overproduction of thyroid hormones
Rheumatoid arthritis - IgG antibodies recognise the Fc chain of other IgG antibodies
What percentage of individuals does autoimmune disease affect?
5%
What is Aetiology?
The study of causation/origin
What two things affect autoimmune disease?
Genes - MHC and CTLA-4 important - more common in females than males - if one twin has AID than 50% chance other will
Environment - infection (molecular mimicry - make antibody against pathogen which is similar to your own)
How does rheumatic fever cause autoimmune disease?
Streptococcal M protein from fever has a similar sequence to heart muscle cells, so antibodies developed against it, but then also attack own heart muscle cells.
Fuck that
