148 - Hypersensitivity 3 Flashcards
Two broad outcomes of type II hypersensitivity
– Injury due to activation of effector mechanisms
• C’activation
• Recruitment of inflammatory cells
• Activation via Fc Receptor
– Abnormal physiological response (Graves & MG)
• Binding to receptors or proteins interfering with function
• Activation or inhibition.
Example of TIIH
ABO blood group mismatch.
Leads to RBC haemolysis, shock, nausea, vomiting and pain
Example of a rare TIIH against erythrocytes
1
2
3
1) Type II mediated drug allergies (rare)
eg penicillin, quinidine, methyldopa
2) Some produce antibodies against these drugs.
The drug becomes bound to red blood cells or platelets, which are then the target of anti-drug antibodies.
3) Splenic macrophages phagocytose the cells, resulting in haemolytic anaemia or thrombocytopenia
Haemolytic disease of the newborn
Due to preformed maternal IgG antibodies which react
against the child’s Rh antigens on their RBC’s in utero
→ removal of RBC via complement activation.
More of a problem for the second child, as mother will have a secondary adaptive response against Rh
How is haemolytic disease of a newborn treated?
Anti-Rh antibodies within 24 hrs of delivery remove foetal RBC’s in maternal circulation
Goodpasture’s syndrome
Antibodies are made against a variant of collagen type IV, a major component of basement membranes (EG: lining vasculature in kidney, blood vessels).
Antibodies can get stuck in glomeruli, which activates C’. This leads to glomerular disease.
What do people with Goodpasture’s syndrome present with/
Nephritis
Grave’s disease antibodies
Stimulatory antibodies against thyroid-stimulating hormone receptors in thyroid.
Thyroid gland role
Thyroid gland essential for regulating metabolism through the production of thyroid hormones.
Pituitary gland releases TSH, which leads to thyroid hormone release. Thyroid hormone negatively regulates release of TSH.
Effect of Grave’s disease
Hyperthyroidism
Myasthenia gravis
Ab against ACh receptors on motor endplates.
This leads to internalisation, degradation of ACh receptors
How can antibody binding to an allergen cause injury?
1)
2)
3)
1) C’ activation
2) Recruitment of inflammatory cells
3) Activation via Fc receptor
Haemolytic disease of a newborn 1) 2) 3) 4)
1) When a Rh+ baby is delivered from a Rh- mother
2) During delivery, baby’s RBCs enter mother’s bloodstream
3) Mother produces anti-Rh IgG - is now sensitised
4) If the mother has another child who is Rh+, maternal IgG cross the placenta, bind to foetus RBCs, cause C’ removal of them
How is haemolytic disease of a newborn treated?
1)
2)
1) During delivery of the first child, administer anti-Rh antibodies to mother within 24 hours of delivery
2) These clear Rh+ RBCs from mother, so mother doesn’t produce anti-Rh antibodies
What causes type III hypersensitivity?
Immune complexes formed from antibodies and antigens (self or foreign), that are either overproduced or improperly cleared
How are immune complexes normally removed?
Covered in C3b, which RBCs with C3bR bind to.
Removed by splenic macrophages
What determines the pathology of type III hypersensitivities?
Where the immune complexes deposit.
EG: Cationic complexes can deposit on blood vessel walls and the kidney glomeruli
Mechanism of type III hypersensitivity 1) 2) 3) 4) 5) 6) 7)
1) Immune complexes aren’t cleared (low Ab affinity, excess antigen, inefficient C’ activation)
2) Complexes deposited on blood vessel walls
3) Deposition eventually leads to C’ activation
4) Anaphylatoxins are generated (C3a, C4a, lead to neutrophil, mast cell degranulation)
5) Macrophage cytokine release stimulated
6) Immune complexes directly activate platelets, basophils, mast cells
7) Vasoactive amines lead to increased vascular permeability
Immune complex-mediate damage 1) 2) 3) 4)
1) Immune complexes deposit on vascular wall, lead to disrupted blood flow, turbulence
2) Vasculitis
3) Glomerulitis (form deposition in kidney basement membrane)
4) Arthritis (deposition in joint synovium, vessels)
What affects clearance from circulation of immune complexes?
Size.
Larger complexes activate C’ better, better at binding FcR.
–> are removed from the circulation more effectively
Examples of situations where immune complex clearance could be impaired
1
2
3
1) Complexes don’t form properly (too small to be effectively cleared)
2) Excessive antigens and antibodies, leads to overload mononuclear phagocyte system
3) Poor C’ activation
Possible sources of antigen leading to TIIIH
1
2
3
1) Persistent infection (can’t clear infection, EG with hepatitis B or C, HIV)
2) Autoimmune
3) Inhaled antigen (EG mould, plant or animal antigen)
Farmer’s lung
Exposure to hay dust or bacteria (Actinomyces) leads to alveolitis from type III hypersensitivity.
Stimulation of IgG, complex formation in alveoli leading to inflammation and fibrosis
Example of an autoimmune TIIIH
Systemic lupus erythematosus
Systemic lupus erythematosus
Anti-DNA autoantibodies produced.
Immune complexes deposited in the kidneys (basement membranes).
Multiple body systems are involved.
B-cell hyper-reactivity.
Two forms of immune tolerance generation
• Central Tolerance – Occurs during development in primary lymphoid organs – Removes self-reactive lymphocytes during development
• Peripheral Tolerance
– Occurs in the periphery
– Controls self-reactive lymphocytes
