Lecture 12 - Autoimmunity Flashcards
What is the key discrimination in the immune response?
Self vs. non-self
What is the definition of tolerance?
Specific unresponsiveness to an antigen through prior exposure to that antigen
Who discovered tolerance, and how were they recognised?
Macfarlane Burnet and Peter Medawar.
Nobel Prize for Medicine, 1960
Describe the first demonstration of induced tolerance
Two mice of strain A
- One of the mice exposed to spleen cells from strain B during neonatal period
- Both mice given strain B graft as adults
- Graft only accepted in the strain that saw the spleen cells from strain B as a neonate
This tells us that tolerance is set up during the neonatal period
Why is tolerance important?
- Critical part of the adaptive immune response
- 10^11 different B and T cell specificities thanks to recombination, which potentially contain auto-reactive specificities
- auto-reactivity can cause major pathology in the host
Which factors determine whether a given lymphocyte becomes tolerant or responsive to an antigen?
• Avidity
also:
• timing
• duration
• costimuli
Compare location and cell type in central and peripheral tolerance
Central:
• Occurs in the thymus or bone marrow
• positive / negative selection of immature lymphocytes
Peripheral:
• occurs in 2° lymphoid organs
• ‘regulatory’ responses of mature lymphocytes
What are the mechanisms of T cell tolerance?
Central:
• Deletion (through apoptosis)
• Receptor editing, change of the specificity
• Development of Tregs
Peripheral:
• Anergy
• Apoptosis
• Suppression by Tregs
What is anergy?
Lack of co-stimulation
Lymphocyte won’t be activated
Which T cells are positively selected in the thymus?
Which are negatively selected?
Positive selection: those with an intermediate affinity for self-HLA
Negative selection: those with TCRs with a high affinity for self-HLA or any Ag in the thymus
Describe T cell peripheral tolerance
What are the mechanisms?
Mechanisms: • Ignorance • Deletion • Anergy • Negative regulation • Suppression
Describe the mechanism of suppression
Through Tregs
Which is more important, B or T cell tolerance?
T cell tolerance is more critical, because B cells must be first activated by T cells.
What happens when immunological tolerance breaks down?
What can cause this ‘breaking down’?
Activation of:
• Self-reactive T cells
• Auto-reactive antibodies
Caused by:
• Molecular mimicry
• Failure of regulatory networks
• Failure of tolerance (central or peripheral)
What are the key factors leading to autoimmunity
- Genetic predisposition
- Environmental exposure
- Loss of self-tolerance
Describe Molecular mimicry bringing about autoimmunity
Host and foreign antigen share a similar epitope (may be linear or conformational)
- S. pneumoniae infection and immune response against a specific antigen
- S. pneumoniae antigen resembles antigen on heart valves
- Immune response directed against heart valves
- Rheumatic heart fever
What are the important suppressive cytokines? Where do these come from?
Come from Treg
• IL-10
• TGF-β
Describe the role of Treg in autoimmunity
Suppresses APCs and T cells through:
• cell-cell contact
• release of suppressive cytokines (IL-10, TGF-β)
What are Milgrom and Witebsky’s criteria for autoimmunity?
• lymphocyte infiltrate in target organ
• circulating auto-antibody / auto reactive T cells against target organ
• identification of the auto antigen
etc.
What is the classic organ specific autoimmune disease?
Hashimoto thyroiditis
What is the classic non-organ specific autoimmune disease?
SLE: systemic lupus erythematosus
Which sort of antibodies are commonly seen in non-organ specific autoimmune diseases?
What about organ specific autoimmune diseases?
Non-organ specific:
• anti-DNA Ab (in SLE)
• anti-cytoskeleton Ab
Organ specific:
• anti-thyroglobulin antibodies (in Thyroiditis)
• anti-myeline basic protein (in MS)
etc.
Describe ‘ignorance’ in T cell peripheral tolerance
The lymphocyte is sequestered from antigen, and never encounters it
Describe suppression in T cell peripheral tolerance
The lymphocyte is downregulated by Treg and suppressive cytokines release by the Treg
Describe the mechanism of apoptosis in T cell peripheral tolerance
- T cell adheres to the APC
- Engagement of Fas by FasL on the APC
- Death receptor pathway to apoptosis
What are the mechanisms for B cell tolerance?
- Deletion
- Anergy
- Ignorance
Does the presence of auto reactive lymphocytes categorically mean that there is autoimmunity?
No, there are autoantibodies present in the body.
For example, B cells involved in mopping up cellular debris after apoptosis
What are some environmental factors that can lead to the production of auto antigen?
- Smoking
- Infection
- Drugs
What is the spectrum of autoimmune disease?
Where does Type I diabetes sit on this spectrum?
Organ specific to non-organ specific
Diabetes is organ specific
What is the auto-antigen in SLE?
- DNA histones
- DNA nucleotides
- Sm-RNP (Smith protein, Ribonucleoprotein)
Is Rheumatoid arthritis organ specific?
No, it’s non-organ specific
How are autoimmune disorders tested for in the lab?
Staining patterns
- Suspected autoimmune disorder
- Patient’s cells are taken and grown up in the lab
- Patient’s serum is taken and added to the cell culture
- If Ab in the serum reacts with their own cells, there will be specific staining pattern observed
What is ‘Diabetes’?
A group of disorders affect insulin production and / or function
What are some general features of Type I Diabetes?
Secondary disorders?
When is the onset?
- Break down in tolerance for β cells in the islets of Langerhans in the pancreas
- β cells destroyed
- No insulin production
2° damage: • Kidneys • Eyes • Nerves etc.
Onset:
• first year of life → adulthood
How does glucose get into cells?
Through the Glut 4 receptor
Outline the various types of diabetes
Type I:
• Autoimmune disorder
Type II:
• Lifestyle disorder; insulin resistance
Various other types:
• Type 1.5
• Gestational diabetes
• CFRDM
What is LADA?
Latent autoimmune diabetes in adults
‘Type 1.5 diabetes’
• Masquerades as ‘non-obese type II diabetes’
• Late onset of type I diabetes
Describe the pathogenesis of type II diabetes
Insulin is present and binds to IR (unlike in IDDM), but there is a defect in signalling through to Glut 4
→ Diminished glucose uptake through Glut 4
Describe in detail the pathogenesis of Type I diabetes
Insulitis → overt diabetes
Aetiology:
• Genetic (certain HLA alleles, CTLA4 polymorphism)
• Environmental (viral infections)
- Underlying genetic predisposition
- Environmental trigger → break down in tolerance (central & peripheral)
- CTL and Th1 infiltration into islets → Insulitis, appearance of auto-antibodies
- Decrease in β cell mass in islets
- Loss of insulin; glucose intolerance
- Loss of C peptide
Which auto antigens have a role in Type I diabetes?
Many different enzymes in the β cells that are responsible for insulin production and metabolism
e.g. • GADA (Glutamic acid decarboxylase) • ICA512 • Zinc transporter (ZnT8) • Insulin (IAA)
What is C peptide?
- part of proinsulin
* holds together the A- and B-chains in proinsulin
Describe histological features of Type I diabetes
- Progressive infiltration of inflammatory cells into the β cell islets in pancreas
- These cells are predominantly CTLs and Th1
• Infiltration of these cells leads to the destruction of the islet
Which specific things might be happening in break down of T cell tolerance in Type I diabetes?
- Defective deletion in central tolerance
* Defective regulation of T cells (peripheral)
At which point are clinical symptoms seen in Type I diabetes?
Can be years after the β cells have started to be destroyed.
Symptoms only seen when there are very few β cells left
What is ICA?
Islet cell antigen
Which autoantibodies are present in Type I diabetes?
Describe their presence and importance
Four main ones, called ICA
- Anti-GAD (Glutamic acid decarboxylase)
- Anti-ICA512
- Anti-Zinc transporter (ZnT8)
- Anti-Insulin (IAA)
Levels of these auto-Ab increase over time up to the onset at around age 15
Their role in pathogenesis is unclear
Which genetic factors are linked to Type I diabetes?
HLA DR3-DQ2
HLA DR4-DQ8
Certain CTLA alleles
How is the onset of SLE described?
• Remitting and relapsing
(goes away, then comes back)
• acute or insidious
Which organs are affected in SLE?
- Skin
- Kidneys (Glomerulonephritis)
These are the main ones, but most tissues in the body are affected
What are some of the criteria of SLE?
What is the diagnostic feature?
• Malar rash
(+ loads of other rashes)
• Antinuclear antibody (diagnostic feature!)
What components of the nucleus are targeted by antibodies in SLE?
- DNA
- Sm protein
- RNA
- histones
What are Sm-proteins?
- RNA binding proteins
* found in the nucleus
Describe the pathogenesis of SLE
- Cause:
• Breakdown in tolerance
• Environmental trigger (UV) → increased apoptosis → increased nuclear elements present - Anti-nuclear antibody forms complexes with the nuclear antigen
- Endocytosis of immune complexes
- Engagement of TLRs by the DNA
- B cells activated (through TLR activation)
- Production of high level anti-nuclear IgG
- More formation of immune complexes
- Type III sensitivity
What type of hypersensitivity is SLE?
Describe this
Type III (immune complex)
• Complex between Ab and nuclear antigen
• Complexes get deposited in places where blood is filtered (kidneys, joints)
• Complement activation (from IgG and IgM of immune complexes)
• Inflammation and infiltration of phagocytes
What is the main cause of death in SLE?
Renal failure
What is the treatment for SLE?
- Corticosteroids
* Immunosuppressants
