Allergy and other hypersensitivities

• What are type I hypersensitivities?

  This is defined as an excessive immune response to harmless antigens, known as allergens. This response is usually specific and restricted by can have multiple allergies. Nearly half of adults in the UK are estimated to have one or more allergies, with the most common being nuts, pollen, antibiotics, milk, etc. Symptoms include watering eyes, nasal congestion, rash and inflammation with systemic responses resulting in death, anaphylaxis.
• Describe asthma

  This is an airway hypersensitivity where lung epithelium becomes inflamed, smooth muscle contracts and mucus is produced in response to allergens such as pollen and animals. The response is mediated by IgE and is a common example of a type I hypersensitivity.
• Describe phase 1 of type-1 hypersensitivity reactions

  1. Exposure to allergen leads to stimulation of type 2 helper T cells, which secrete IL-4 in order to help B cells to produced IgE
  2. B cells produce IgE, which recognises the allergen
  3. IgE circulates in the blood and associates with mast cells in the mucosal (airways and GI tract) and connective (skin) tissue via IgE receptor, FcεR.
• Describe phase 2 of a type-1 hypersensitivity reaction

  Re-exposure and activation of inflammatory response

  1. Allergen binds to IgE on mast cells and these specialise to release mediators of inflammation
  2. Mast cells release chemicals including histamines, cytokines, prostaglandins and leukotrienes
  3. This results in vascular permeability, inflammation, mucus production, immune cell recruitment, swelling, redness, blistering and itching.
• Describe the response to mast cell degranulation in different areas of the body

  GI tract- increased fluid secretion and peristalsis leading to diarrhoea and vomitting

  Airways- decreased diameter and increased mucus secretion leads to congestion and blockage of the airways and swelling and mucus production in the nasal passage

  Blood vessels- increased blood flow and permeability, leading to increased fluid in tissue and therefore greater flow of lymph to lymph nodes
• What is anaphylaxis?

  This is a systemic response to an allergen triggered by large amounts of histamine. This results in dilation of blood vessels, which causes drop in blood pressure and unconsciousness. Airways narrow, which makes breathing difficult. Oedema results in swelling of surrounding tissue. This response can happen instantly or over a few hours and can be fatal if not dealt with properly.
• Describe type 2 hypersensitivity

  This is mediated by IgG and IgM, which reacts with antigens on cells or tissue. There are three major syndromes clinically:

  • Blood transfusion reactions- usually IgM mediated due to difference in blood groups
  • Haemolytic disease of the newborn- occurs in Rh -ve mother with Rh+ foetus
  • Haemolytic anaemia
• Describe haemolytic disease of the newborn

  Occurs when a rhesus negative mother carries a rhesus positive foetus, which, upon birth, rhesus positive RBCs cross the placenta and sensitise the mother. This results in the production of antibodies which, upon second pregnancy, can cross the placenta and attach the foetal RBCs and causes erythroblastosis fetalis. This is usually preventable by giving the mother anti-Rh Ag antibodies before birth which will mop up any free foetal RBCs before they can sensitise the mother.
• Describe Type III hypersensitivity

  This is IgG mediated leading to the formation of immune complexes between allergen and antibody. It can be characterised into:

  • systemic disease- infection, e.g., malaria or serum sickness
  • local disease- repeated exposure to antigen, e.g., Farmer’s lung
• What is serum sickness?

  This is an antibody response triggered by animal serum, then on the second dose immune complexes form between the antibody and serum proteins, which are deposited within blood vessels, such as in the skin, kidney and joints. Leads to fever, rash, arthritis and kidney disorder.
• Describe type IV hypersensitivity

  This is a delayed type hypersensitivity (DTH) that does not involve antibody, instead it is cell-mediated by Th, Tc and macrophages. Takes 24-72 hours to develop and can contribute to anti-pathogen responses. Contact hypersensitivity reactions, poison ivy.
• Describe allergy testing

  One of the major allergy tests is the skin prick test, which is where an allergen is introduced to the epidermis by a lancet. Sensitivity is indicated by a wheal and flare reaction within minutes, which is replaced with a late phase reaction (4-6h later). Patch tests are skin tests where allergens are applied topically and left for 24-72 hours to assess type IV hypersensitivity.
• Describe the relationship between allergy and genetics

  Likelihood of allergy increases with two atopic parents and in identical twins that is a concordance of atopy is 60%. Therefore genetics is important but environment must also playa role. Many genes could be involved, such as MHC genes and genes linked to tissue integrity.
• Describe the relationship between allergy and the environment

  The prevalence of allergies has increased dramatically in the last 50 years, which can be largely attributed to changes in the environment; namely, increased pollution, urbanisation and reduced exposome. Exposome refers to our cumulative exposure to things in our environment.
• Describe the hygiene hypothesis

  This was developed to explain observations that small families in urban dwellings experienced more allergies than larger families in rural areas. This theory was developed by D. Strachen and he suggested that exposure to microbes in the environment may help to prevent hypersensitivities. This hypothesis has now evolved to consider the microbial diversity in our microbiome due to western diets and urbanisation. Babies treated with antibiotics early in life were more likely to develop allergies later on that those that weren’t treated.
• Describe the evidence for the hygiene hypothesis

  • Correlation of higher incidences of allergy where there is lower incidence of parasite and other infections
  • Following de-worming campaigns, many children now have allergies
  • European divide: more allergic disease in industrialised European countries
• Describe some of the current and future therapies for allergies

  • Avoidance of allergens
  • Treat symptoms:
  • Anti-histamines: prevent to actions of histamine
  • Steroid anti-inflammatory drugs: reduce the inflammation
  • Adrenaline (Epi-pen): cause vasoconstriction
  • Low dose allergen therapies- intramuscular injection of low dose allergen, monthly for 2-5 years, leads to raise in IgG rather than IgE.
  • Antibody therapy- duplimab to block cytokine (IL-4) that promotes Th2 cell activation of B cells)
• What is Palforzia?

  This is peanut-derived protein used to redirect immune response. It is now being offer by NHS England to children with peanut allergy.