Author(s): Tim Kendall and David Dorward
By the end of this CAL you will be able to:
- Describe the cellular basis of the four types of hypersensitivity reaction.
- Describe clinical examples of each.
Introduction Part 1 of 7
Hypersensitivity occurs when the immune system stops being helpful and starts to do damage, and includes allergies.
Hypersensitivity and allergies are increasing:
- Each year the number of allergy sufferers increases by 5%.
- 615% increase in hospital admissions for anaphylaxis in 20 years, 1992-2012.
- Over 20,000 admitted to hospital each year with allergy.
- £68million per annum is the cost of hospital admissions due to allergy.
There are four types of hypersensitivity.
Type I hypersensitivity Part 2 of 7
- Type I hypersensitivity includes hayfever, allergic rhinitis, anaphylaxis.
- It is the classical “allergy”.
- It is a rapid immune response to an allergen.
- It is driven by pre-existing IgE to the allergen.
Host response to allergen
- Exposure of a genetically predisposed individual to an allergen leads to processing by antigen presenting cells such as dendritic cells.
- Antigen presentation by APCs primes naive T cell bearing specific receptors.
- After antigen priming, differentiation of naive T cells is skewed towards Th2 cells.
- Allergen-primed Th2 cells release cytokines including IL-4 and IL-13; these act on B cells to promote IgE antibody production.
- IgE is bound by receptors on mast cells for the Fcε part of the antibody.
- Upon re-exposure, allergen crosslinks FcεR bound IgE on the surface of mast cells.
- Degranulation releases pre-formed mediators including histamine, serotonin and proteases, leading to immediate symptoms and signs.
- Synthesis and release of additional mediators including leukotrienes, prostaglandins and cytokines lead to inflammatory cell recruitment (especially eosinophils) producing the late phase response.
- Proteins, often proteases.
- A low dose may favour IL-4-producing Th2 responses.
- Low molecular weight and highly soluble – diffuse into mucus.
- Very stable – can survive in a desiccated particle.
- Contain peptides that can bind MHC class II (T cell priming).
- Pollens – birch tree, ragweed, oilseed rape.
- Foods – nuts, eggs, seafood.
- Drugs – penicillin, aspirin.
- Insect products – bee venom, house dust mite faecal pellets.
- Animal products – cat hair, dander (skin and saliva).
- Profound systemic response to allergens.
- Vasodilatation due to histamine etc. –
- Hypotension (low BP).
- Bronchoconstriction (histamine, bradykinins).
- Treatment is symptomatic –
- Intravenous fluids.
Type II hypersensitivity Part 3 of 7
- Antibodies formed against an altered component on host cells – IgG or IgM.
- The host IgG or IgM binds to host cells.
- Bound antibody accelerates cell clearance by –
- Antibody-dependent cellular cytotoxicity (ADCC).
- Complement-mediated lysis.
- Outcomes –
- Cellular dysfunction.
- Haemolytic anaemia.
- Rhesus disease of the newborn.
The Rhesus reaction
This causes haemolytic disease of the newborn – HDNB.
- A RhD- mother, pregnant with a RhD+ foetus, can lead to sensitisation of the mother at birth.
- Red blood cells from the RhD+ foetus can pass into the maternal circulation. The first baby is unaffected.
- In the postpartum period, the RhD- mother produces anti-RhD IgG antibodies.
- In subsequent pregnancies with a RhD+ foetus, the anti-RhD IgG crosses the placenta into the foetal circulation.
- This leads to haemolysis in the second, and subsequent, pregnancies.
- Identification of RhD- mothers during their first pregnancy allows intramuscular injection of anti-RhD antibodies at the time birth to destroy any foetal RhD+ red cells before they can elicit an immune response to sensitise the mother.
Type III hypersensitivity Part 4 of 7
- Immune complex (antigen-antibody) mediated disease.
- Complexes arise from persistent infection or inhalation and long-term exposure to proteins.
- Persistent exogenous or endogenous protein leads to the formation of immune complexes if an appropriate antibody is present.
- Complexes deposit in tissues with high blood filtration pressure –
- Blood vessels.
- Immune complexes lead to inflammation and tissue damage; acute inflammation with inflammatory cell recruitment, vasodilatation etc.
Serum sickness is a transient immune-complex-mediated syndrome caused by the injection of foreign serum proteins.
These lead to the formation of a large number of circulating immune complexes that produce systemic symptoms and signs (fever, vasculitis, arthritis, nephritis).
Host antibody rapidly clears the foreign serum proteins.
Type IV hypersensitivity Part 5 of 7
- Delayed-type hypersensitivity.
- T cell-mediated.
- Response 1-3 days after contact with antigen.
- Associated conditions –
- Contact hypersensitivity.
- Granuloma formation in Tuberculosis (tuberculin test).
- Exposure to tubercle bacilli.
- CD4+ T cell & macrophage accumulation with associated cytokine expression (IFNγ, TNF etc).
- Epithelioid macrophages surrounded by lymphocytes.
Summary Part 6 of 7