Lec 11- Hypersensitivity II Flashcards
Type II hypersensitivity
-Caused by Abs specific for altered components of cells
-IgG mediated
-Caused by small molecules (molecule binds to surface protein causing conformational change, this change could trigger immune response)
+Bond covalently to human cell surfaces–> Modified structures (Neo-Ag)
-Hypersensitivity to drugs
+Penicillin, cephalosporins
+Quinidine (Anti-arrhythmias)
+Methyldopa (Anti-HTN)
-Chemically reactive drugs bind to cell surface to create Neo-epitopes
-B cell response
-IgG produced leading to destruction of cells
+Haemolytic anaemia
+Thrombocytopaenia
Type II hypersensitivity: penicillins
- Penicillin binds to bacterial transpeptidase and inactivates it
- Penicillins modifies proteins on human erythrocytes to create foreign epitopes (Neo-epitopes)
- RBC most commonly effected
- Neo-Ag (something that wasn’t an Ag previously but now is), protein based
- Stimulated Ab production
Type II hypersensitivity
- Penicillin binds cell associated Ag
- Complement deposits on the RBC
- Complement-coated penicillin modified RBC are phagocytosed by macrophages using there complement receptors
- Macrophages present peptides from there penicillin protein, this activates specific CD4 Th2 cell
- B cells are activated by Ag and by help from activated Th2 cells
- Plasma cells secrete penicillin-specific IgG which binds to modified RBC
- Repeat exposure the more severe the reaction
Ab production leads to RBC destruction
- Penicillin specific IgG binds to penicillin modified proteins on erythrocytes
- Activation of complement components c1-9 and formation of membrane attack complex to punch holes in membrane and causes lysis
- Also activation of complement components C1-3 leads to bonding of C3b on RBC surface and so phagocytosis of Ab and complement coated erythrocyte
Type II hypersensitivity- blood transfusions
Look At ABO slide on BB
- A risk for blood transfusion
- You may introduce cells that can be targeted
- Matching required
- Getting this wrong leads to major clots (AMI< stroke ….)
To test for presence for anti-TBC Abs
Indirect Coombs test/ indirect antiglobulin test
- Recipients serum is obtained containing Ab (Ig’s)
- Donor’s blood sample is added to the tube with serum
- Recipients Ig’s that target the donors RBC form Ab-Ag complexes
- Anti-human Ig (Coombs) are added to the solution
- Agglutination of RBC occur, because human Ig’s are attached to RBC (if there is aggregation its positive)
Haemolytic disease of the newborn
- First pregnancy of Rh- mother carrying a Rh+ fetes
- Sensitisation of the Rh Ag on the foetus erythrocytes
- Primary immune response, IgM plus low amounts of low-affinity IgG
- Minor destruction of fatal erythrocytes by Anti-Rh IgG
- Healthy baby
Haemolytic disease of the newborn: 2nd baby
- 2nd and subsequent pregnancies of Rh- mother carrying a Rh+ baby
- Memory B cell reacts
- 2nd immune response, abundant, high affinity IgG transcytosed to foetal circulation
- Massive destruction of foetal erythrocytes triggered by anti-Rh IgG
- Anaemic new born babies
Type III hypersensitivity
- IgG mediated
- Caused by small molecules= soluble Ag
- B cell response produces IgG
- Immune complexes (IC) formed –> deposited –> pathology
- Immune complexes are formed in all Ab responses
- Why the problem in only some cases
Type III hypersensitivity
1) Early in the response there is little Ab and an excess of Ag
- Small immune complexes are formed that don’t fix complement and are not cleared from the circulation
2) At intermediate stages in the response, there are comparable amounts of Ag and Ab
- Large immune complexes are formed that fix complement and are cleared from the circulation (if they don’t fix complement they don’t get cleared and eradicated)
3) Late in the response there are large amounts of Ab and little Ag
- Medium sized immune complexes are formed that fix complement and are cleared from the circulation
Ag exposure leads to localised IC
- Locally injected Ag in immune individual with IgG Ab
- Local immune-complex formation activates complement. C5a binds to a C5a receptor on the mast cell
- Binding of immune complex to Fc’gamma’RIII on mast cell induces degranulation
- Local inflammation increased fluid and protein release, phagocytosis and blood vessel occlusion
Type III hypersensitivity
Small immune complexes
-Don’t fix complement
-Aren’t cleared efficiently this causes
Deposits in the tissues
-Build up permits complement fixation
+Stimulates mast cells to release histamine
-Complex can be bound by Fc’gamma’RIII (CD16) on leukocytes (NK,phagocyte, macrophages)- this causes TISSUE damage
-Platelet accumulation
+Clot formation, blood vessels burst- hemorrhagic rash
Pathology
-Determined by site of IC deposition and site of Ag encounter
IV DOSE (High dose)
-can lead to vasculitis= blood vessel walls (these are the sites of immune complex deposition)
-Nephritis= renal glomeruli
-Arthritis= joint spaces
Subcutaneous
-Arthus reaction= perivascular area
Inhaled
-Farmers lung- alveolar/ capillary interface
Serum sickness
-From administration of IV Ag \+Passive immunisation \+mAb therapy and IVIG \+Lots of Ag, little Ab- small IC (immuno-complexes) -Systemic disease -7-10 days -Requires generation of IgG -Symptoms depend upon tissues affected -Can get arthritis, vasculitis and nephritis -Haemorrhage -Urticarial rash
Type IV hypersensitivity
Caused by effector T cells
- Delayed-type hypersensitivity DTH
- Occurs 1-3 days after Ag exposure- Ag processing inefficiency
Contrast
- Ab- mediated hypersensitivity- minutes
- 100-1000 times more Ag needed for DTH than for Ab-mediated hypersensitivity
