Autoimmunity Flashcards
name some autoimmune diseases?
myasthenia gravis
graves disease
Addison’s disease
hashimoto’s thyroiditis
example of an organ-specific autoimmune disease?
Type 1 Diabetes
– insulin producing pancreatic beta cells are destroyed, reducing insulin production and mediated by T cells
HLA B27-associated spondyloarthropathies
Arthritis in the knees and joints
Spectrum of severity
Associated with bowel inflammation
psoriatic arthritis, urethritis, iritis
Systemic autoimmune pathologies – Systemic lupus erythematosus (SLE)
Multi-system disease, autoantibodies to nuclear antigens eg double stranded DNA
Relapse and remission
Proteinuria, ends of fingers go white with lack of circulation, ulceration of mucous membranes
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.
Immune tolerance
Immune system does not attack self proteins or cells – it is tolerant to them
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
Central tolerance – B cells
if immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM (eg. a stromal cell), apoptosis is triggered
T cells need to be able to recognise what?
foreign peptides that are bound to self-MHC
T cell receptor and MHC binding - why is weak binding or too strong binding dangerous?
If binding to self MHC is too weak, 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, may allow signalling irrespective of whether self or foreign peptide is bound in groove
T cell selection in the thymus
Is it useless?
Doesn’t bind to any self-MHC at all
Death by neglect (apoptosis)
Is it dangerous?
Binds self MHC too strongly
Apoptosis triggered – negative selection
Is it useful?
Binds self MHC weakly
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
- AutoImmune REgulator (AIRE) - promotes self tolerance by allowing the thymic expression of genes expressed in peripheral tissues
- Mutations in AIRE result in multi-organ autoimmunity, eg. Autoimmune Polyendocrinopathy Syndrome type 1
What happens to autoreactive T cells that survive central tolerance control?
some autoimmune T and B cells get out of the thymus and bone marrow, so we need to have a second way of dealing with these cells
If they escape central tolerance, they become under the control of peripheral tolerance.
3 areas of Peripheral tolerance?
Ignorance - don’t see the antigen and you are not aware of it
-either the antigen is too low a concentration to reach the threshold for TCR triggering or they are in an immunologically privileged sites e.g. eye, brain, so the T cell will never come across them
Anergy - T cell will recognise the antigen but won’t respond to it as it doesn’t have the right signals, lack costimulatory proteins and MHC class II -Less likely to be stimulated in future even if co-stimulation is then present
Regulation - A subset of helper T cells known as Treg (T regulatory cells) that inhibit other T cells
- express FOXP3
- IL10, a cytokine that dampens the immune response
when are Treg numbers increased or decreased?
cancer - increase in Treg numbers
autoimmune disease - not enough Treg’
