Autoimmunity Flashcards
Give some examples of organ-specific autoimmune disease.
Graves disease – overstimulation of TSH receptors in thyroid
Type 1 Diabetes –immune system attacks insulin-producing cells of the pancreas
Describe an example of MHC-specific autoimmunity.
HLA B27-associated spondyloarthropathies are an example of MHC-specific autoimmunity.
The spondyloarthropathies include:
- ankylosing spondylitis
- undifferentiated spondyloarthropathy
- reactive arthritis
- psoriatic arthritis
- urethritis
- iritis
There is a spectrum of severity and HLA B27 association.
It is associated with bowel inflammation.
Describe lupus as a systemic autoimmune pathology.
Lupus is also known as SLE (systemic lupus erythematosus). It is a multi-system disease.
It’s characterised by autoantibodies to nuclear antigens e.g. double stranded DNA.
You get devascularization of the fingers, membrane ulcerations, and alopecia are all manifestations of SLE.
It is a disease of relapse and remission.
What is autoimmunity?
The immune system has various regulatory controls to prevent it from attacking self proteins and cells.
Failure of these controls will result in immune attack of host components – known as autoimmunity.
What is immune tolerance?
Immune system does not attack self proteins or cells – it is tolerant to them.
To do this, we need to be able to identify what is self and what is not self.
Define the two mechanisms of tolerance.
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 cells which do enter the circulation.
Describe central tolerance.
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered.
If immature T-cells recognise the self-antigen presented by AIRE (AutoImmunty REgulator), it is destroyed.
How do we control TCR and MHC binding?
We need to be able to select for T cell receptors which are capable of binding self MHC.
If binding to self MHC is too weak, it may not be enough to allow signalling when binding to MHC with foreign peptides bound in groove.
If binding to self MHC is too strong, it may allow signalling irrespective of whether self or foreign peptide is bound in groove
We need to find that intermediate level of affinity.
What are the ‘filters’ the T cells go through to be selected in the thymus?
Is it useless?:
- this is if it doesn’t bind to any self-MHC at all
- results in death by neglect (apoptosis)
Is it dangerous?
- this is if it binds self MHC too strongly
- results in apoptosis triggered – negative selection
Is it useful?
- this is if it binds self MHC too weakly
- loses the signal to survive – positive selection
How can 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.
AutoImmune REgulator (AIRE) promotes self tolerance by allowing the thymic expression of genes from other tissues.
Mutations in AIRE result in multi-organ autoimmunity (Autoimmune Polyendocrinopathy Syndrome Type 1).
What happens to autoreactive T cells that survive central tolerance control?
We need to have a second way in dealing with these cells. This is where peripheral tolerance comes in.
What are the three parts of peripheral tolerance?
- ignorance
- anergy
- regulation
Describe ignorance in peripheral tolerance.
The antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering.
It could also be because the antigen is present in an immunologically privileged site e.g. eye, brain, where the immune system simply doesn’t go.
Describe anergy in peripheral tolerance.
Naive T cells need costimulatory signals in order to become activated.
Most cells lack costimulatory proteins and MHC class II.
If a naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic – i.e. it becomes less likely to be stimulated in the future even if co-stimulation is then present.
Describe regulation in peripheral tolerance.
IL-10 is a cytokine that can dampen down the immune response. It, amongst others, is released by cells called Treg, which go around calming down overactive immune responses. They do this either by the release of cytokine, or by direct contact inhibition.