Autoimmunity Flashcards
What is graves disease?
Grave’s disease- TSH receptor activating.
What is Grave’s ophthalmopathy?
Grave’s ophthalmopathy, fibroblasts in the eye may express TSH leading to inflammation.
Type 1 diabetes-
Type 1 diabetes- insulin producing cells of pancreas (inactivating beta cells).
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 a systematic autoimmune disease characterised by?
- Multi-system disease
- characterised by autoantibodies to nuclear antigens eg double stranded DNA
- Relapse and remission
What is autoimmunity?
- When you respond against your own proteins
- 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
- We need to identify what is self and what is not
What is central tolerance and peripheral 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 B and T cell tolerance
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered
- 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
- Selection- remove useless and dangerous cells.
- Specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues.
How can a T cell be 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
What is the autoimmune regulator?
- Promotes self tolerance by allowing the thymic expression of genes from other tissues
- Mutations in AIRE result in multi-organ autoimmunity fatal
- (Autoimmune Polyendocrinopathy Syndrome type 1)
- It promotes the expression of all the genome. It allows the thymus to express all peptides
What happens to autoreactive T cells that survive central tolerance control?
• B cells and autoimmune IgM, no T cell help and so no class switch..
What are the 3 types of peripheral tolerance?
- Ignorance
- Anergy
- Regulation
Ignorance
Ignorance- antigen present in too low a concentration to reach TCR threshold. Immunologically privileged sites like eye and brain.
- 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
- You don’t see the antigen. You are not aware of the antigen. The T cells will never come across the antigen
Anergy
Anergy- naïve T cells need costimulatory signals to be activated. Most cells lack these proteins and MHC class II. If naïve T cell sees MHC/peptide ligand without appropriate costimulatory protein, it becomes anergic and less likely to be stimulates in future, even with costimulatory signal present.
- 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 its 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
Regulation
Regulation- Treg cells inhibit self-reactive T cells by producing IL-10 and TGF-B. Defective Treg observed in MS.
- A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells
- IL-10 can dampen down the immune response. When Tregs bind an antigen, they can send a negative signal.
- Treg express transcription factor FOXP3, expressed in CD4 Treg cells
- Mutation in FOXP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
- It is expressed in CD4 Treg cells
- If you knockout FOXP3, you get a smaller mouse
How do endocrine factors influence AU disease?
- SLE (Systemic lupus erythematosus) is >10x more common in females than males.
- MS ~10x more common in females than males.
- Diabetes in men = women.
- Ankylosing spondylitis is ~3x more common in males than females.
Can environmental factors cause AU disease and give some examples
- 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
- If you don’t get exposed to bacteria when you are developing, the immune system is compromised.
- The mice who were kept in the pathogen free environment did not get diabetes.
- When you move to a rural environment from an urban environment, T1D, MS and SLE tend to become more prevalent.
What might trigger a breakdown of self tolerance?
- Loss of/dysfunction of regulatory cells.
- Release of sequestered antigen.
- Modification of self- Citrulline is an AA not coded for by DNA. Arginine converted to citrulline as post-translational modification by peptidylarginine deiminase (PAD) enzymes. Citrullination may be increased by inflammation. Autoantibodies to citrullinated proteins seen in rheumatoid arthritis- now used in clinical diagnosis.
- Molecular mimicry- rheumatic fever triggered by streptococcus pyogenes infection. Antibodies to strep cell wall antigens may cross-react with cardiac muscle.
- Grave’s disease can be transferred by IgG antibodies across the placenta. Plasmapheresis can remove maternal anti-TSHR antibodies to cure baby.
Describe Molecular mimicry – rheumatic fever
- Disease is triggered by infection with Streptococcus pyogenes
- Antibodies to strep cell wall antigens may cross-react with cardiac muscle
• These antibodies can react with the heart muscle
- Response to infection, cross reacts with some heart tissue
- Image shows plasma cell producing antibodies for bacteria, antibody binds to bacteria and clears the disease
- But same antibodies also cross react with some of the proteins in the heart, causing inflammation within the heart – this is molecular mimicry
Describe graves disease
Can it be transferred from mother to fetous?
- Auto-antibodies bind Thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism
- Disease can be transferred with IgG antibodies
- Disease can transfer from mother to foetus as IgG is small and can get through placenta
• In Hashimoto’s, the antibody binds to the same receptor but just causes inflammation
Describe Antibodies in autoimmune pathology (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
- Myasthenia Gravis is response against acetylcholine receptors
- Normally, at a neuromuscular junction get a neural impulse producing NTs which bind to ACh receptors, causes Na influx, and causes muscle contraction
- In myasthenia you get an antibody response against these receptors, essentially blocking these receptors
- In myasthenia gravis, same production of ACh but not activating the nerve cell receptors as they are blocked resulting in muscle weakness
Describe Antibodies in autoimmune pathology (3) – Immune complexes in SLE and vasculitis
- SLE disease characterised by anti-DNA antibodies, anti-dDNA
- Autoantibodies to soluble antigens form immune complexes
- Immune complexes can be deposited in tissue e.g. blood vessels, joints, renal glomerulus and cause many problems
- Can lead to activation of complement and phagocytic cells
- Immune complexes depositing in kidney can lead to renal failure
Describe T Cells in autoimmune pathology
- Direct killing by CD8+ CTL
- Self-destruction induced by cytokines such as TNFa
- Recruitment and activation of macrophages leading to bystander tissue destruction
- CD4 cells providing help for Ab and cytotoxicity
- CD4 cells direct the immune response.
- Multiple sclerosis CD4 cells are important
- Insulin dependent diabetes mellitus CD4 cells are important
- CD4 cells direct the immune response
Describe Th17 cells in AU disease
- Th17 cells are helper T cells that produce the cytokine IL-17 a very powerful inflammatory cytokine
- 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 be used to treat AU diseases?
- Anti-inflammatories: NSAID good way to get the immune system to dampen down, corticosteroids
- T & B cell depletion (Rhematoid Arthritis: anti-CD4 (used to deplete T cell population), anti-CD20 (used to deplete B cell population)) not used often though as it can remove the whole immune system.
- Therapeutic antibodies (anti-TNF; anti-VLA-4 (blocks adhesion))
- Antigen specific therapies, in development. Glatiramer acetate increases T-regs so you will dampen down the immune system.
