Lecture 22 - Type 2 hypersensitivity PDF

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Dr Bronwen Burton...

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Type 2 hypersensitivity! Type 2 hyperdensitivitiy reactions come about when an individual produces self reactive B cells that are able to escape central tolerance mechanisms, in the body these B cells become activated by self antigens on the surface of host cells and release antibodies, leading to an inappropriate IgG or IgM response. The antibody and antigen form a complex on the surface of a host cell, this activates the complement cascade and interacts with Fc receptors on various cells, leading to tissue damage. ! Mechanisms of tissue damage

- Activation of the classical complement cascade! - Phagocytosis! - Antibody-dependent cellular cytotoxicity! Complement activation 1. C1q binds the Fc region of an IgG/IgM on the cell’s surface - this activates C1q! 2. C1q goes on to activate other members of the complement cascade ! 3. C3a, C4a and C5a all act as chemotactic factors and recruit neutrophils ! 4. Neutrophils migrate to the site and MAC degranulate, releasing enzymes which damage the target cell ! 5. C5b, C6, C7, C8 and C9 come together Cell lysis to form the membrane attack complex (MAC)! 6. The MAC is inserted into the membrane of the target cell, creating an open channel that allows free flow of fluid ! 7. Fluid flows into the cell, leading to lysis !

Degranulation

Phagocytosis 1. C3b binds IgG/IgM on the cell’s surface - opsonisation ! 2. A phagocyte can then bind C3b or the Fc region of IgG/IgM via its Fc receptor ! 3. The target cell is phagocytosed ! Antibody-dependent cellular cytotoxicity 1. NK cells recognise the Fc tail of the IgG/IgM-antigen complex on the surface of the target cell ! 2. NK cells release toxic granules onto the cell containing perforin and granzymes ! 3. Perforin forms pores in the cell membrane, leading to lysis ! 4. Granzymes activate pro-apoptotic mechanisms in the target cell ! Type 2 hypersensitivity reactions against blood cells Red blood cells express a range of highly immunogenic glycoprotein antigens on their surface, most notably the ABO antigens form the basis for the main blood groups. Differences in the

structure of ABO antigens is determined by genes which encode enzymes that transfer terminal sugars onto their carbohydrate antigens.! Transfusion reactions If an individual is exposed to a blood transfusion containing incompatible ABO antigens an IgM response will be activated, leading to agglutination and complement activation. This leaves the patient with fever, low blood pressure and vomiting - 10% mortality rate (NB- IgM antibodies can’t cross the placenta so can’t farm a foetus with incompatible ABO antigens).! ! Haemolytic disease of the newborn If a Rh- mother is pregnant with a Rh+ foetus, during delivery some Rh+ antigens enter the mother’s circulation through breaks in the placenta and cause her to produce anti-Rh antibodies. Then in the second pregnancy with another Rh+ foetus, anti Rh-antibodies from the mother’s circulation cross the placenta and destroy foetal blood cells. This causes the foetus to have an enlarged liver and spleen as a result of red blood cell destruction, and can lead to spontaneous abortion or stillbirth. To prevent haemolytic disease of the newborn Rh- mothers pregnant with Rh+ foetuses are injected with anti-Rh antibodies at weeks 28-34, these antibodies eliminate any foetal red blood cells that reach the mother’s circulation and prevent her from producing any antibodies against them. ! Autoimmune haemolytic anaemia Autoimmune haemolytic anaemia occurs when an individual produces antibodies against their own red blood cell antigens. There are three types based on the causative agent and the antibodies produced:! - Warm antibody autoimmune haemolytic anemia: the most common form of autoimmune haemolytic anaemia, occurs when an individual produces antibodies which bind antigens at temperatures above 37℃, increasing the rate of red blood cell clearance. This can be idiopathic or come about as a result of other conditions such as systemic lupus erythematous chronic lymphocytic leukaemia! - Cold agglutinin disease: where an individual produces IgM antibodies that bind antigens at temperatures below 37℃, activating the complement cascade and leading to red blood cell lysis! - Antibodies against drugs such as penicillin ! Type 2 hypersensitivity reactions in tissues

- Goodpastures syndrome: where an individual produces antibodies against collagen IV, leading -

to necrosis of the basement membrane of the lungs and kidneys and permanent damage to these tissues which can result in death ! Pemphigus: where an individual produces antibodies against desmoglein 1/3, leading to breakdown of desmosomes and skin blistering ! Myasthenia gravis: where an individual produces IgG antibodies against the Ach receptor, preventing nerve impulses triggering muscle contractions and muscle weakness...