Autoimmunity Flashcards
What are 2 examples of organ-specific autoimmune disease?
Graves disease – antibodies against TSH receptors in thyroid
Type 1 Diabetes – destruction insulin producing cells of the pancreas
What are HLA B27-associated spondyloarthropathies?
Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis
Spectrum of severity and HLA B27 association
Associated with bowel inflammation
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 and how can it be broken down into two main areas?
Immune system does not attack self proteins or cells – it is tolerant to them
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
How does central tolerance apply to B and T cells?
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered
T cells recognise antigens that are presented to them by MHC proteins
T cells need to be able to recognise foreign peptides that are bound to self-MHC
What is T cell selection like 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
What does AIRE do?
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) the symptoms seen below
What are the three peripheral mechanisms?
Ignorance
Anergy
Regulation
How is Ignorance a peripheral tolerance mechanism?
Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
Immunologically privileged sites e.g. eye, brain where we don’t have a lot of T cell infiltration
How is Anergy a peripheral tolerance mechanism?
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. Less likely to be stimulated in future even if co-stimulation is then present
How is Regulation a peripheral tolerance mechanism?
A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells usually by producing cytokines such as IL-10 and TGF-b which inhibit other self-reactive T cells
Defective Treg have been observed in multiple sclerosis
What occurs with FoxP3 mutation?
Treg express transcription factor FOXP3
Mutation in FOXP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
How do endocrine factors affect autoimmunity?
SLE is >10 times more common in females than males
MS is approximately 10 times more common in females than males
Diabetes is equally common in females and males
Ankylosing spondylitis is approximately 3 times more common in males than females
What role do environmental factors play in autoimmunity?
Hygiene hypothesis: NOD mice and SPF conditions. Migration and T1D, MS and SLE
Smoking and rheumatoid arthritis -
13 pairs of identical twins where 1 of each pair smoked and 1 of each pair had RA
In 12/13 cases the twin with RA was the smoker
What might trigger a breakdown of self-tolerance?
Loss of/problem with regulatory cells
Release of sequestered antigen
Modification of self
Molecular mimicry
