Autoimmunity Flashcards
How do autoimmune diseases differ?
Specificities vary greatly from organ specific (Grave’s) to systemic (SLE)
Name examples of autoimmune diseases in order of organ specific to systemic
- Grave’s Disease
- Hashimoto’s Thyroiditis
- Pernicious Anaemia
- Addison’s Disease
- Insulin dependent DM
- Goodpasture’s syndrome
- Myasthenia Gravis
- Multiple sclerosis
- Autoimmune haemolytic anaemia
- Idiopathic thrombocytopenic purpura
- Rheumatoid arthritis
- Scleroderma
- Systemic Lupus erythematosis (SLE)
What causes grave’s disease?
Type II HS reaction; cytotoxic reaction against TSH receptors in thyroid
Causes inflammation of eyes due to TSHr on fibre optics of eyes; mediated by T cells
What are HLA associated Spondyloarthropathies?
Group of autoimmune diseases: Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis
Spectrum of severity and HLA B27 association
Associated with bowel inflammation
What is SLE?
Systemic lupus erythematosus (SLE) is a multi-system disease
Characterised by autoantibodies to nuclear antigens
eg double stranded DNA
Relapse and remission occurs
What is autoimmunity?
Immune system regulatory controls prevent it from attacking self proteins and cells
Failure of controls results in immune attack of host components
Give examples how tolerance is developed against autoimmunity
Characteristics eg:
- Sex
- Genetics
- Environment
- Mechanisms of autoimmune disease e.g T cells, autoantibodies
What is meant by immune tolerance?
Immune system does not attack self proteins or cells – it is tolerant to them
What are the 2 types of immune tolerance?
- Central tolerance
- Peripheral tolerance
What is central tolerance?
Destruction of self-reactive T or B cells before they enter circulation
How is Peripheral tolerance achieved?
Destroy / control any self reactive T or B cells which enter circulation
How is central tolerance achieved?
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered
How do T cells recognise antigens?
T cells recognise antigens that are presented to them by MHC proteins
Which TCRs are selected for immunity?
Need to select for T cell receptors which are capable of binding self MHC
What is the consequence of weak self MHC binding to TCRs?
May not be enough to allow signalling when binding to MHC with foreign peptides bound in groove
What is the effect of too strong MHC binding of TCRs?
If binding to self MHC is too strong, may allow signalling irrespective of whether self or foreign peptide is bound in groove
Which TCRs are not selected for?
If cell doesn’t bind to any self-MHC at all
Death by neglect (apoptosis)
When can T cells be dangerous (autoimmune?)
Binds self MHC too strongly
Apoptosis triggered – negative selection
Outline characteristics of useful T cells that are selected for
Binds self MHC weakly
Signal to survive – positive selection
How do T cells become tissue specific?
T cells developing in thymus encounter MHC bearing peptides expressed in other parts of the body
Due to a specialised TF that allows thymic expression of genes expressed in peripheral tissues
How is autoimmunity regulated?
AIRE - Autoimmune Regulator
promotes self tolerance by allowing the thymic expression of genes from other tissues
What is the consequence of mutations in AIRE?
Mutations in AIRE result in multiorgan autoimmunity
Autoimmune Polyendocrinopathy Syndrome type 1
Autoreactive T cells that survive central tolerance control
What are the 3 types of peripheral tolerance?
- Ignorance
- Anergy
- Regulation
What is Ignorance in peripheral tolerance?
Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
Where is peripheral tolerance ignorance commonly seen?
Immunologically privileged sites e.g. eye, brain
What is anergy (peripheral tolerance)?
If 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
What do naive T cells require to be activated?
Naive T cells need costimulatory signals in order to become activated
Why does anergy arise?
Most cells lack costimulatory proteins and MHC class II
What causes Regulation Peripheral tolerance?
A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells
Defective Treg have been observed in multiple sclerosis
What markers are used to detect Treg?
Treg is detected using markers such as FOXP3, CD4 and CD25
Treg express transcription factor FOXP3
What does FOXP3 mutations lead to?
Mutation in FOXP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome
Which region of the genome is associated with disease the most?
MHC is associated with more disease than any other region of the genome
Outline the genetics of MHC molecules
Each copy of chromosome 6 carries 3 different MHC class I and 3 different MHC class II genes
High levels of genetic variation (polymorphism)
How does gender affect SLE epidemiology?
SLE is >10 times more common in females than males
Describe MS epidemiology in men and women
MS is approximately 10 times more common in females than males
Outline the prevalence of Ankylosing spondylitis between genders
Ankylosing spondylitis is approximately 3 times more common in males than females
What is the hygiene hypothesis of autoimmune diseases
Early childhood exposure to particular microorganisms (e.g. gut flora and helminth parasites) protects against allergic + autoimmune diseases by contributing to immune system development
What causes self tolerance breakdown?
- Loss of/problem with regulatory cells
- Release of sequestered antigen
- Modification of self
- Molecular mimicry
What is citrulline?
Citrulline is an amino acid, not coded for by DNA
How is citrulline generated?
Arginine can be converted to citrulline as a post-translational modification by peptidylarginine deiminase (PAD) enzymes
What increases citrulline levels?
Citrullination may be increased by inflammation
Describe presence of citrulline in rheumatoid arthritis
Autoantibodies to citrullinated proteins seen in rheumatoid arthritis. Now used for clinical diagnosis
Describe the molecular mimicry causing rheumatic fever
Disease triggered by Streptococcus pyogenes infection
Antibodies to strep cell wall antigens may cross react with cardiac muscle
How does Grave’s disease occur?
Auto-antibodies bind Thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism
Disease can be transferred with IgG antibodies
Describe the mechanism of myasthenia gravis
Autoantibodies bind to nAchR and block ability of Ach to bind
What is the consequence of nAchR blockage in myasthenia gravis?
- Leads to receptor internalisation and degradation
- muscle weakness
How are immune complexes formed in SLE and vasculitis?
Autoantibodies to soluble antigens form immune complexes
Where are immune complexes deposited in vasculitis and SLE?
Deposited in tissue e.g. blood vessels, joints, renal glomerulus
=> activation of complement and phagocytic cells
=> renal failure
How can AI disease in a mother affect the foetus?
Autoimmune diseases mediated by IgG can be transferred across the placenta
How do T cells contribute to autoimmunity?
Direct killing by CD8+ CTL
Self-destruction induced by cytokines such as TNFα
Recruitment and activation of macrophages leading to bystander tissue destruction
What is the role of CD4 cells in autoimmunity?
CD4 cells providing help for Ab and cytotoxicity
Give examples of autoimmune diseases caused by T cells
- Multiple sclerosis
- Insulin dependent diabetes mellitus
What are Th17 cells?
Th17 cells are helper T cells that produce the cytokine IL-17
implicated in AI diseases including spondyloarthropathy, MS and diabetes
What is the effect of Th17 activation?
Highly inflammatory
Produce cytokines which are involved in the recruitment, migration and activation of immune cells
What therapeutic strategies are used to overcome AI 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.
What is the role of central and peripheral tolerance?
Central and peripheral tolerance mechanisms eliminate and control autoreactive T cells
What is the defining genetic factor in AI disease?
The major histocompatibility complex is the most important genetic factor in autoimmune disease
