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 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

Sensitisation

• 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.

Re-exposure

• 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.

Allergens

• 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).

Allergens include:

• 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).

Anaphylaxis

• Profound systemic response to allergens.
• Vasodilatation due to histamine etc. –
  • Hypotension (low BP).
  • Oedema.

• Bronchoconstriction (histamine, bradykinins).
• Treatment is symptomatic –
  • Adrenaline.
  • β-agonists.
  • Intravenous fluids.
  • Corticosteroids.

 

• 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 –
  • Phagocytosis.
  • Antibody-dependent cellular cytotoxicity (ADCC).
  • Complement-mediated lysis.

• Outcomes –
  • Cellular dysfunction.
  • Inflammation.

Example diseases

• 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.

 

 

• 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 –
  • Kidneys.
  • Joints.
  • Skin.
  • Blood vessels.
• Immune complexes lead to inflammation and tissue damage; acute inflammation with inflammatory cell recruitment, vasodilatation etc.

Serum sickness

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.

• Delayed-type hypersensitivity.
• T cell-mediated.
• Response 1-3 days after contact with antigen.
• Associated conditions –
  • Contact hypersensitivity.
  • Granuloma formation in Tuberculosis (tuberculin test).

 

Tuberculin reaction

• Exposure to tubercle bacilli.
• CD4+ T cell & macrophage accumulation with associated cytokine expression (IFNγ, TNF etc).
• Epithelioid macrophages surrounded by lymphocytes.