Autoimmunity Flashcards
List some examples of Organ-specific autoimmune diseases
- Graves disease - TSH receptors in the thyroid
- Type 1 diabetes - insulin-producing cells of the pancreas
What is HLA B27-associated spondyloarthropathes
- Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis
- Spectrum of severity and HLA B27 association
- Associated with bowel inflammation
Describe Systemic lupus erythematosus (SLE)
- Multi-system disease
- characterised by autoantibodies to nuclear antigens eg double stranded DNA
- 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 the idea of immune tolerance
The immune system does not attack self proteins or cell - It is just tolerant to them
What are the 2 types 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
How are T cells selected for MHC binding
- Need to select for T cell receptors which are capable of binding
self MHC - 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
- Undergoes negative selection in thymus gland
How does a T cell encounter MHC from all over the body
A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues (AIRE)
How does Autoimmune Regulator work
- Promotes self tolerance by allowing
the thymic expression of genes from
other tissues - Mutations in AIRE result in multi-organ
autoimmunity
What are the 3 areas of peripheral tolerance
- Ignorance
- Anergy
- Regulation
What is the Ignorance phase of peripheral tolerance
- 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
What is the Anergy phase of 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
What is the tolerance phase of peripheral tolerance
- A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells
- Defective Treg observed in multiple sclerosis
How can endocrine factors also be cause for autoimmune diseases
- 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
How can environmental factors be a cause for 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 can trigger a breakdown of self tolerance
- Loss of/problem with regulatory cells
- Release of sequestered antigen
- Modification of self
- Molecular mimicry
How is a modification of self carried out - 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
How is molecular mimicry take place in rheumatic fever
- Disease is triggered by infection with Streptococcus pyogenes
- Antibodies to strep cell wall antigens may crossreact with cardiac muscle
- This causes rheumatic fever
How does antibodies play a role in autoimmunity of grave’s disease
- Auto-antibodies bind Thyroid stimulating hormone (TSH)
receptor and stimulate it,
resulting in hyperthyroidism - Disease can be transferred with IgG antibodies
How does antibodies play a role in autoimmunity of Myasthenia gravis
- Autoantibodies bind to acetylcholine receptor and block the ability of acetylcholine to bind
- Also lead to receptor internalisation and degradation
- Results in muscle weakness
How does antibodies play a role in autoimmunity of Immune complexes in SLE and Vasculitis
- Autoantibodies to soluble antigens form immune
complexes - Deposited in tissue e.g. blood vessels, joints, renal
glomerulus - Can lead to activation of complement and
phagocytic cells - Immune complexes depositing in kidney can lead
to renal failure
How do T cell play a role in autoimmune pathology
- Direct killing by CD8+ CTL
- Self-destruction induced by cytokines such as TNF-a
- Recruitment and activation of macrophages leading to bystander
tissue destruction - CD4 cells providing help for Ab and cytotoxicity
- Multiple sclerosis
- Insulin dependent diabetes mellitus
How do Th17 cells play a role in autoimmune pathology
- Th17 cells are helper T cells that produce the cytokine IL-17
- implicated in autoimmune diseases including spondyloarthropathy,
MS and diabetes - Highly inflammatory * Produce cytokines which are involved in the recruitment, migration
and activation of immune cells
What therapeutic strategies can were employ against autoimmune diseases
- Anti-inflammatories: NSAID, corticosteroids * T & B cell depletion (RA: anti-CD4, anti CD20)
- Therapeutic antibodies (anti-TNF; anti-VLA-4 (blocks adhesion))
- Antigen specific therapies, in development. Glatiramer acetate, increases T-regs.
