58. Autoimmunity Flashcards
Organ-specific autoimmune diseases
- Graves disease – TSH receptors in thyroid
* Type 1 Diabetes – insulin producing cells of the pancreas
HLA B27-associated spondyloarthropathies
- Spondyloarthropathies include: Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis
- Spectrum of severity and HLA B27 association
- Associated with bowel inflammation
Systemic autoimmune pathologies – Systemic lupus erythematosus (SLE)
Multi-system disease
characterised by autoantibodies to nuclear antigens eg double stranded DNA
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.
Immune tolerance
- Immune system does not attack self proteins or cells – it is tolerant to them
- CENRAL 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
Expand on central tolerance
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered
T cell receptor and MHC binding
- Need to be able to select for T cell receptors which are capable of binding self MHC
BUT
- 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
=> We need to find that intermediate level of affinity.
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)
Peripheral tolerance
1) IGNORANCE
•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.
2) ANERGY
•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
3) REGULATION
•A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells ~ by releasing cytokines IL-10 and TGF-β
Endocrine factors
- 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 might trigger a breakdown of self tolerance?
- Loss of/problem with regulatory cells
- Release of sequestered antigen (where they are not seen by the immune system)
- Modification of self
- Molecular mimicry
Modification of self - Citrullination
- Citrullin is an amino acid, not coded for by DNA
- Arginine can be converted to citrulline as a post-translational modification by peptidylarginine deiminase (PAD) enzymes
- Citrullination may be increased by inflammation
- Autoantibodies to citrullinated proteins seen in rheumatoid arthritis. Now used for clinical diagnosis
Molecular mimicry – rheumatic fever
- Disease is triggered by infection with Streptococcus pyogenes
- Antibodies to strep cell wall antigens may crossreact with cardiac muscle, causing a rheumatic fever
Examples of antibodies in autoimmune pathology
1) GRAVES DISEASE
•Auto-antibodies bind Thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism
•Disease can be transferred with IgG antibodies
2) MYASTHENIA GRAVIS
•Autoantibodies bind to acetylcholine receptor and block the ability of acetyl choline to bind
•Also lead to receptor internalisation and degradation
•Results in muscle weakness
3) IMMUNE COMPLEXES IN SLE AND VASCULITIS
•Autoantibodies to soluble antigens form immune complexes.
•These complexes are deposited in tissues e.g. blood vessels, joints, renal glomerulus.
•This can lead to activation of complement and phagocytic cells.
•Immune complexes depositing in kidney can lead to renal failure.
