Autoimmunity Flashcards
What is the action of Graves’ disease?
It is an antibody response against the TSH receptor in the thyroid. It leads to inflammation in the eyes due to low levels of TSH receptors expressed by the fibroblast in the eye. Therefore, thought to be mediated by B cells due to the antibodies.
What is the action in Type 1 disease?
T cells attack the beta cells in the pancreas leading to no production of insulin. Therefore, thought of to be mediated by T cells due to the direct killing of the cell.
What are spondyloarthropathies?
A family of long-term (chronic) diseases of joints. It is MHC specific autoimmunity.
What is the major gene associated with spondyloarthropathies?
HLA-B27
HLA B27-associated spondylarthropathies
Give examples of HLA B27-associated spondylarthropathies diseases
Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis.
All of these are associated with bowel inflammation as well.
What is spondyloarthropathy in the knee?
Arthritis in the knee joints and spine
What is psoriasis?
Disease of the skin cut can get arthritis inflammation of the joint associated with B27.
What is systemic lupus erythematosus (SLE)?
A multi-system disease characteristed by autoantibodies to nuclear antigens such as dsDNA. It is a disease of relapse and remission.
What is autoimmunity?
When the immune system has various regulatory controls to prevent it from attacking self-proteins and cells. The failure of these controls will result in immune attack of host components which is autoimmunity.
What are the 2 pathways that allow the immune system to know what to attack?
Central tolerance: destroy self-reactive T or B cells before they enter the circulation.
Peripheral tolerance: destroy or control any self-reactive T or B cell which now enter the circulation.
Describe the central tolerane of B cells
B cells mature in the bone marrow and go through a series of maturation and differentiation pathways. They gain specific surface bound immunoglobulins which will be complementary to antigen.
When they mature in the bone marrow, if they recognise a self-antigen (for example from a stromal cell) and they bind to it via their IgM, an apoptotic signal will be triggered, and they will get destroyed.
Describe the action of T cells
- T cells recognise antigens that are presented to them by MHC proteins.
- Therefore, the T cells need to be able to recognise foreign peptides that are bound to self-MHC on either APCs.
- This happens so a certain threshold is reached for the T cell to get activated.
What is important about the binding between TCR and MHC binding?
TCR need to bind to self MHC not too weakly or else there will not be enough signalling when binding to the foreign antigen peptide and not too strongly binding otherwise lead to signalling and activation of the T cell irrespective of whether there is a foreign antigen on the groove or not.
How is the central tolerance in T cells checked?
- Is it useless: if it doesn’t bind to any self-MHC than it is killed by apoptosis.
- Is it dangerous: if it binds to MHC too strongly, it is killed by apoptosis via negative selection.
- Is it useful: If it binds to MHC weakly (but too weakly), it will survive via positive selection.
How does a T cell developing in the thymus encounter MHC bearing peptides expressed in other parts of the body?
A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues. This gene is called AIRE.
What is AIRE (autoimmune regulator)?
This is a gene which promotes self-tolerance by allowing in the thymic expression of genes from other tissues.
What happens if there is mutations in the AIRE gene?
Mutations in this gene leads to multi-organ autoimmunity. It causes other diseases such as hypoparathyroidism, candidasis etc.
What is the function of peripheral tolerance for auto-active B cells and T cells?
They are able to escape central tolerance, and enter the circulation, therefore there needs to be a second way of controlling them. This is peripheral tolerance which is broken down into 3 main areas.
What are the 3 main areas of peripheral tolerance?
- Ignorance
- Anergy
- Regulation
What is the ignorance of peripheral tolerance?
- This is when the T or B cells is not aware of the antigen presence, due to it being present in low concentrations.
- Therefore, the threshold to activate the cell is not reached.
- This may be in immunological privileged sites such as the eye or the brain.
What is anergy of T cells (peripheral tolerance)?
- This is when co-stimulatory signals needed to activate the cell such as naive T cells are not present. Most cells lack costimulatory proteins and MHC II.
- This means that even if a naive T cell sees a self MHC antigen peptide molecule, without the appropriate costimulatory signals it becomes anergic.
- This means it is less likely to be stimulated in the future even if the presence of co-stimulation.
- Also, for a T cell to work, they need to see the MHC antigen complex on a professional APC (dendritic cell) and therefore, if it presented by a different type of cell for example it won’t get activated.
- Therefore, anergy is a state where the immune cell will not response even though it recognises the MHC molecule because the correct signals are not present.
What is the regulation of T cells in peripheral tolerance?
A subset of T cells are known as Treg cells (T regulator). These are inhibitor other T cells and prevent the overactivation of the immune system. When Treg cells bind to antigens on the surface of APCs, they can send negative signals to other cells via IL20 and TGFbeta. Treg cells express transcription factor FOXP3 which allows them to do their function.
What happens to Treg when there are mutations?
- Defective Treg cells are associated with multiple sclerosis.
- Certain cytokines such as IL10 dampen down the immune response.
- In cancer, there are increased levels of Treg.
- In autoimmune diseases, there are decreased levels of Treg.
- Mutation in FOXP£ leads to severe and fatal autoimmune disorder called IPEX.
What is IPEX?
A severe and fatal autoimmune disorder which stands for immune dysregulation, polyendocrinopathy, enteropathy X linked syndrome.
