39 Immunopathology Flashcards
Name 6 ways in which the immune system can go wrong and cause disease.
- Autoimmunity
- Transplant / transfusion rejection
- Leukaemia and lymphoma
- Immunodeficiency
- Septic shock / sepsis / failure of ‘tissue tolerance’
- Immune-type hypersensitivity
What are the 5 types of hypersensitivity?
- Type 1 = Anaphylactic
- Type 2 = Cytotoxic
- Type 3 = Immune Complexes
- Type 4 = Delayed Type Hypersensitivity
- Type 5 = Stimulatory Hypersensitivity
Describe the morphology of mast cells
- Oval/irregularly shaped
- Dense granular cytoplasm - often obscures nucleus
- histamine and heparin-rich granulocytes.
- Mononuclear, with central nucleus
Where are mast cells located?
Connective tissue or mucosa surrounding blood vessels and nerves in deeper systems or underlying the mucosal barrier to the outside world.
What can trigger the anaphylactic hypersensitivity response?
Allergic responses such as hay fever, asthma, and food allergies.
What is the role of IgE in type 1 hypersensitivity?
Plays a central role in triggering mast cell degranulation.
What is the receptor IgE binds to on mast cells?
FcRε
Describe the mechanism of Type 1 hypersensitivity.
- An allergen is presented by APCs to helper T cells, which activate B cells to produce IgE immunoglobulins against it
- IgE binds to high-affinity IgE receptors on the surfaces of mast cells, which means that these cells are now primed to react the next time the cells come into contact with the allergen
- Cross-linking of IgE on the cell surface causes rapid degranulation of histamine, proteases, heparin and chemotactic factors
- There is also synthesis and release of platelet activating factor (PAF), leukotrienes and prostaglandins
- The histamine leads to smooth muscle contraction
- Widespread activation of mast cells leads to systemic effects -> Circulatory shock, hypotension, chest tightness and, in the most severe cases, respiratory arrest and death. This is called anaphylactic shock.
What does widespread activation of mast cells lead to?
Anaphylactic shock:
- Circulatory shock
- Hypotension
- Chest tightness
- Severe cases: respiratory arrest, death
What are the three main mediators released by mast cells on degranulation? Are they each newly synthesised or released from stores?
- Histamine: released from stores
- Leukotrienes: newly synthesised
- Prostaglandins: newly synthesised
Which enzyme do mast cells express to convert arachidonic acid to leukotrienes?
Lipoxygenase
Which enzymes do mast cells express to convert arachidonic acid to prostaglandins?
COX1, COX2
What are the actions of prostaglandins?
- Increase vascular permeability
- Attract neutrophils
Where are the H1 (histamine) receptors found?
Smooth muscle cells and endothelial cells
What are the effects of mast cell degranulation in the:
- GI tract
- Airways
- Blood vessels
Over what time frame do type 1 hypersensitivity reactions occur?
Rapidly (within approximately 20 min of an insult) so they are also called ‘immediate hypersensitivity reactions’.
What are the immediate treatments for anaphylaxis?
- Anti-histamines (stop histamine effects on H1) e.g. chlorphenamine or mepyramine.
- Adrenaline (increase BP, improve perfusion by vasoconstriction/ bronchodilation)
What is the action of anti-histamines?
prevent action of the mediators on H1 receptors for the Gq-associated bronchoconstriction and release of NO from endothelial cells for vasodilation via the cGMP pathway
What are the long-term treatments for people at risk of anaphylaxis?
- Cromoglycate (stabilise mast cells and oppose degranulation)
- Leukotriene receptor antagonists (prevent effect of mediators released in degranulation)
- Glucocorticoids (down-reg immune system, however slow onset + immunosuppression)
- Anti-histamines
What is the mechanism of type 2 hypersensitivity?
Antibodies directed against cell surface antigens
–> cell destruction via complement activation or antibody-dependent cell-mediated cytotoxicity (ADCC)
What are the cytotoxic effects mediated by in type 2 hypersensitivity?
By Ab binding to surfaces with or without the complement system leading to cell lysis or opsonisation.
How do transfusion reactions occur causing type 2 hypersensitivity?
- There is a mismatch of the transfused product and recipient
- Significant for ABO and Rhesus blood groups
- E.g. Person with type B blood receives type A blood - anti-A antibodies bind to and agglutinate the type A RBCs
- Strong inflammatory response
How does haemolytic disease of new-borns occur causing T2 hypersensitivity?
If maternal IgG crosses placental barrier –> attacks infant RBCs in a similar process to transfusion reactions
Various types: anti-ABO, anti-RhD etc
What is the only immunotherapy given for prevention of haemolytic disease of the newborn?
- Rho(D) immunoglobulin given to mother when Rh- mother is carrying a Rh+ infant
- Binds any foetal RBCs with D antigen before mother is able to form an anti-D IgG response
How does hyperacute allograft rejection occur?
- In the space of a few hours - recipient Igs mount an immune response against received organ due to markers such as ABO
- Organ is destroyed
- T2 hypersensitivity
How is hyperacute allograft rejection prevented?
- Check for ABO compatibility
- Exclude presence of antidonor HLA antibodies by cross-matching between donor and recipient
What event in development may result in type 2 hypersensitivity?
B cells that produce Ig against native cells are not deleted
How does type 3 hypersensitivity occur?
- Normal state: Ag:Ab complexes are maintained as soluble immune complexes by C2 and C4
- Type 3 hypersensitivity: Production of immune complexes is greater than their clearance rate in the spleen. Initiates acute inflammation.
–> Precipitation:
- Complement activation
- Recruitment of immune cells
- Tissue damage
What are the different complexes in T3 hypersensitivity?
*Local - at specific sites (e.g. inhaled antigen - farmer’s lung)
*Diffuse - circulating complexes with deposition in microvasculature of joints, kidneys (e.g. systemic lupus erythematosus [SLE]) With involvement of autoantibodies.
How does farmer’s lung occur?
- Person inhales antigen (such as from mould spores/dust)
- Stimulates immune complexes in alveolar vessels –> local inflammatory response
What is Systemic lupus erythematosus (SLE) caused by?
Due to fewer complement receptors on RBCs, which means that immune complexes are cleared at a slower rate. The deposition is often renal.
Why is type 4 hypersensitivity ‘delayed’?
It takes time for the activation of T-cells/ for cells to accumulate.
What are examples of persistent antigens causing the chronic type 4 response?
Mycobacteria (TB)
Self-antigens in autoimmunitIV
How does the Mantoux test work to detect Mycobacterium Tb?
- Tuberculin analogue injected subcutaneously
- Develops a reddened and inflamed area (shows contact sensitivity)
- Due to reactivation of primed Th1 cells
Describe the mechanism of type IV hypersensitivity reactions.
- An antigen is taken up by local innate immune cells such as macrophages and Langerhans cells.
- These APCs activate previously sensitized? CD4+ T cells.
- These T cells tend to take on a Th1 profile and migrate to the area of high antigenic load where they release inflammatory cytokines, including IFN-γ, IL-1, IL-2 and IL-6.
- This leads to local inflammation and further immune cell migration and activation
- No B cells or antibodies are involved
- The process takes over 12 hours, so it is known as delayed type hypersensitivity (DTH)
In type IV hypersensitivity, what happens if the antigen exposure is prolonged? When might this happen?
- If an antigenic challenge is prolonged, the chronic inflammatory response can result in granuloma formation characterised by multinucleate giant cells produced by the fusion of macrophages. Granulomatous reactions can take weeks to resolve.
- This can occur in pathogenic infections, such as tuberculosis, or in autoimmune conditions
Describe the mechanism of type V hypersensitivity. Give an example of a condition where it is seen.
- It is caused by an autoantibody acting as an agonist on cell surface receptors
- Example: Grave’s Disease (hyperthyroidism).
How does Graves’ disease occur?
Autoantibodies activate TSH receptors –> constant production of T4
–> Hyperthyroidism
