W12L18 - Hypersensitivity Flashcards
Hypersensitivity Diseases
Disorder caused by an immune response
Types of Hypersensitivity
Type 1 (immediate)
- mediated by IgE
- occurs within 30 mins of exposure
- allergies
Type 2 (cytolytic or cytotoxic)
- mediated by IgG or IgM antibodies binding to antigens on cell surfaces
- activating complement cascade causing cell destruction
Type 3
- mediated when immune complexes activate complement
- granulocytes are attracted to site of infection and damage caused by lytic enzymes
- reaction within hours
Type 4
- involves both cytotoxic and Th1 cells - no antibody involvement
- mediated by Th1 cells which upon activation release cytokines
- accumulation and activation of macrophages and cytotoxic T cells causing local damage
- reaction occurs days to weeks
What is Atopy?
IgE mediated hypersensitivity
Patients who suffer from allergies are atopic
Involved with Type 1 hypersensitivity
Steps in an Allergic Reaction
- Sensitisation - IgE antibody produced in response to allergic stimulus and binds receptors to mast cells
- Activation - re-exposure or challenge to antigen triggers mast cells to respond and release contents of their granules
- Effector step - complex response results from the effects of inflammatory mediators released by mast cells
Type 1 Hypersensitivity - Sensitisation
First step production of IgE
When someone has produced IgE in response to an antigen re-encounters the same allergen = allergic reaction
Binding of antigen to IgE - cross links FcεRI causing release of chemical mediators by mast cell leading to allergic reaction
Certain antigens and antigen routes favour IgE production
- presenting antigen at low doses across a mucosal surface favours activation of Th2 cells over Th1 cells
- Th2 cytokines required for IgE generation (cause B cells to differentiate into plasma cells producing IgE)
Type 1 Hypersensitivity - Activation Step
Triggering of mast cells by the cross linking of its FcεR1 receptors causes a rapid set of events resulting in
- mast cell degranulation
- release of potent inflammatory mediators
Examples of Preformed and Synthesised Mediators
Preformed
- histamine
- cytokines and chemokines
- IL-3-5, IL-8-9, TNF-α and GM-CSF
Synthesised
- leukotrienes and prostaglandins (contraction of bronchial and tracheal smooth muscle, vascular permeability and mucous secretion)
- platelet activating factor (PAF) (causes platelets to aggregate and release their mediators
Allergy - Clinical Consequences
Rhinitis
- mast cell mediators cause increased vascular permeability
- sneezing and runny nose etc
Food allergies
- mast cell mediators lead to localised smooth muscle contraction and vasodilation
- vomiting and diarrhoea
Atopic dermatitis or eczema
- mast cell mediators stimulate chemotaxis of large numbers of inflammatory cells, especially eosinophils
- inflammatory skin lesions
Asthma
- eosinophil infiltration leads to inflammation of bronchial mucosa and causes significant tissue damage
Airway hyperreactivity
- bronchial contraction stimulated by non-specific stimuli like histamine
- occlusion of bronchial lumen
Type 2 Hypersensitivity - Mechanism
IgM or IgG antibody binding to cell surfaces distinguishes type 2 from type 3 hypersensitivity
Targeted cell damaged or destroyed by either complement mediated reactions of antibody dependent cell mediated cytotoxicity
Type 2 Hypersensitivity - Complement Mediated Reactions
IgM antibody reacts with a cell surface component
Fixes complement, activates cascade to:
- opsonisation and phagocytosis by macrophages or neutrophils expressing receptors for C3b, or
- lysis by membrane attack complex
Type 2 Hypersensitivity - Antibody Dependent Cell Mediated Cytotoxicity
Uses Fc receptors on many cell types e.g. NK cells macrophages, eosinophils
Lysis requires contact and involves release of lytic granules containing perforin and granzymes
No phagocytosis of complement fixation
Triggered by IgG binding to IgG-specific Fc receptors
Type 2 Hypersensitivity - Transfusion Reactions
E.g. transfusion of ABO-incompatible blood leads to complement mediated cytotoxic reactions
People with type O blood have IgM anti-A and B antibodies
If transfused with type A transfused RBCs bind IgM antibody in serum activating complement and transfused cells destroyed
Can lead to kidney damage from blockage due to large amounts of RBC
Type 3 Hypersensitivity - Mechanism
Triggered by immune complexes deposited in tissues where filtration of plasma occurs (e.g. blood vessel walls, synovial membrane, kidney)
C3a and C5a increase vascular permeability and neutrophil accumulation at site of immune complex deposition
- causes release of lytic enzymes
C3a and C5a induce mast cells to release their mediators
- additional inflammatory cells into area = release of more toxic mediators
Large complexes removed more easily - small complexes more pathogenic
IgG
Examples of Type 3 Hypersensitivity Diseases
Local - Arthus
- repeated injection of antigen
- antigen reacts with already formed Ag-specific IgG antibody
Causes
- insoluble immune complexes
- vessel wall damage
- necrosis
Systemic - Serum Sickness
- triggered by horse anti-snake venom given as anti-cancer treatment
- antibodies synthesised to foreign Ig -> immune complexes
- complexes deposited in small vessels and activate complement and phagocytosis
- induce fever, vasculitis and arthritis
Type 4 Hypersensitivity - Mechanisms
Involves activation, proliferation and mobilisation of antigen specific effector T cells
Caused by release of large amounts of cytokines and chemokines
- attract and activate monocytes
