Allergy and hypersensitivity

What are type 1 hypersensitivity reactions? Give an example.

Allergies are type 1 hypersensitivity reactions, which is an excessive response to harmless antigens (allergens). It is usually specific and restricted, but multiple allergies are possible. Around 20-25% of the UK population have an allergy with 44% of adults estimated to have one or more. Common allergens include: peanuts, seeds, latex, shellfish, milk, pollen etc. The symptoms depend on exposure and can include watery eyes, nasal congestion, rash, inflammation, asthma and diarrhoea. Systemic responses can result in death via anaphylaxis. 

One example of a type 1 hypersensitivity is asthma. This occurs in the airway and is when there is lung epithelium inflammation, smooth muscle contraction and mucus production. This is mediated by IgE. There is also excess immune cell recruitment.

What are the phases of type 1 reactions?

Type 1 reactions have 2 phases; 

• Phase 1 is sensitisation and production of Ag specific IgE. Exposure to allergen leads to the stimulation of type 2 helper T cells (Th2), which make IL-4 and help B cells produce IgE Ab. This IgE circulates in the blood and associates with mast cells in mucosal and connective tissues via Fc-epsilon-receptors (binds to Fc portion of IgE). Mast cells act as sentinels.

• Phase 2 is reexposure and activation of the inflammatory response. The multivalent allergen binds to IgE on mast cells which cross links the IgE/FcERs which triggers the release of inflammatory granules (histamines, cytokines, prostaglandins and leukotrienes). This results in vascular permeability, inflammation, muscle contraction, mucus production, immune cell recruitment, swelling, redness, blistering and itching - although it depends on the region affected.

What role do eosinophils play in type 1 reactions?

Eosinophils also have FcERs and can play a critical role in allergies too. Often eosinophilia will be a dominant feature such as in asthma. They release effector products and cytokines, including IL4 (drives IgE production). IL5 is vital for eosinophil development.

What is anaphylaxis?

Systemic responses to an allergen can cause anaphylaxis. Large amounts of histamine trigger a systemic response. The dilation of blood vessels causes a drop in blood pressure and unconsciousness. As airways narrow, breathing becomes difficult. Oedema or swelling occurs in the surrounding tissues. It can happen instantly or over a few hours, and must be dealt with promptly or it can be fatal. 

What are food allergies and how can tolerance be formed?

Food allergies are much rarer than other type 1 hypersensitivities, with about 1/50 children having one (not to be confused with food intolerances). Nut allergy is thought to be the most common. Food allergies are the main cause for anaphylaxis.

Advice was to avoid foods that can trigger allergies until age 3 (also during pregnancy). Peanut allergy has become so common that some schools ban the ingredient. Evidence since this advice suggests this is wrong, and in fact, eating peanuts while the immune system is still developing can reduce allergies. It was estimated that there is a 77% reduction in allergy when peanuts were introduced to the diet at 4 months.

How do hypersensitivities hinder medicine?

Hypersensitivities can hinder medical interventions, since people can have allergies to commonly used drugs like penicillin. Allergic responses to eggs can also limit vaccines such as the seasonal flu ones since they contain egg proteins, This can contribute to reduction in vaccination rate and increase in fear of drugs. 

What are type 2 hypersensitivity reactions?

Type 2 is characterised by the production of IgG or IgM and reacts with Ags on cells or tissue. There are 3 major syndromes clinically are blood transfusion reactions, haemolytic disease of the newborn/anaemia, and drug induced hypersensitivity. 

• Blood transfusion reactions due to the wrong type of blood. It is usually IgM mediated and binds to transfused RBCs. IgM is good at triggering the complement system. It causes fever, chills, nausea and vomiting.

• Haemolytic disease of the newborn is when a Rh- mother has a Rh+ partner. During the first pregnancy, there can be mixing of the blood between the fetus and mother which sensitises her to Rh+. Upon second pregnancy, the new child can have their RBCs attacked by the mothers Abs. It is preventable by giving the mother anti-Rh Ag antibodies before birth which bind to any free foetal RBCs and destroy them before they sensitise the mother.

What are type 3 hypersensitivity reactions?

Type 3 hypersensitivity is also IgG mediated and against soluble Ags in immune complexes. It can be caused by system disease (pathogens, serum sickness etc) or local disease (repeated inhalation of Ag). For example, Pigeon Fancier’s disease is a local disease caused by dried faecal Ags. 

• Serum sickness is when animal serum stimulates Ab response. The first does sensitises and the second dose triggers the response. The Abs bind to serum proteins, form immune complexes which get deposited in blood vessels. This causes fever, rash, arthritis and kidney disorder.

What are type 4 hypersensitivity reactions?

Type 4 hypersensitivity does not involve Ab, but rather Th, Tc and macrophages. It is not always against harmless Ags. It can contribute to anti-pathogen response. It is delayed type (DTH; taking 24-72 hrs). It is contact hypersensitivity which causes swelling, redness, blistering etc. Contact hypersensitivity reactions occur against poison ivy, nickel etc.

What tests are used for allergies?

Allergies, particularly type 1, can be tested using a skin prick test, which introduces an allergen to the epidermis by a lancet. They are really sensitive and fast, exhibiting a reaction within minutes (lasts for 1 hr). It is replaced by a late phase reaction 4-6 hrs later. 

Other allergy tests can be looking for the presence of IgE in the blood, such as using ELISA. The presence of IgE in serum is termed atopy (out of place) and does not necessarily mean that you have an allergy, just that you are predisposed to one (ie: could be first exposure). There are also patch tests which are skin tests where allergens are applied topically and left 24-72 hrs to assess type 4 hypersensitivity. 

What genetic and environmental factors affect allergy?

The reason only some people get allergies is due to genetics and environment. The likelihood of allergy increases with 2 atopic parents. In identical twins, concordance rate of atopy is only 60% therefore the environment must play a role. The genes implicated include MHC genes, and non MHC-genes for immune responses (IL4, FcER…), epithelial barrier function and tissue integrity.

Prevalence of allergy has increased dramatically over the last 50 years, demonstrating environmental influence. This could be due to Th2 polarising substances, pollutants urbanisation, hygiene etc. The combination of all these life events/environmental factors is the exposome. 

What is the hygiene hypothesis and the old friend’s hypothesis?

The hygiene hypothesis is the original idea of allergic origin. Strachen noticed that children from large families in rural areas developed less allergies than small family urban children. The exposure to lots of germs from an early age trains the immune system against hypersensitivity. It puts into question if clean living conditions skewing the immune response against allergens to Th2 and allergy. This evolved into the old friend’s hypothesis which takes into account more about the exposome. There is reduced microbial diversity in our microbiome due to western diets and urbanisation, and a reduction in worm infections. 

• Babies given significant antibiotics early on are more likely to develop allergies due to their altered microbiome. There is a very low prevalence of asthma in populations highly exposed to microbial environments. There seems to be a link between eosinophils in asthma due to altered exposure of short chain fatty acids derived from the microbiome. 

What evidence supports these hypotheses?

Th2 and IgE immunity is important for the resistance to extracellular/parasitic worm infection under normal conditions. Humans evolved with parasites. This provides evidence for the hypotheses;

• Correlation of higher incidences of allergies where there is lower incidence of parasites and other infections.

• Following a massive deworming campaign in Kenya, many children now have allergies.

• There is a European divide. More allergic disease is found in industrialised European countries compared to the old countries.

• Rural vs urban epidemiological studies. 

What evidence is against these hypotheses?

There is also evidence against these hypotheses:

• South/Latin America has more asthma than Spain/Portugal, despite similar culture and poor living conditions (but higher pollution).

• Worm infections are still quite common in parts of the USA (not all infections impact allergy).

• Asthma is increasing in African Americans living in poverty.

• Are industrialised nations really clean?

• Industrial pollution, diesel, toxins and water etc contaminate our environment. 

• Climate change and pollution can change allergy seasons, they are starting earlier and lasting longer. This increases pollen and worsens allergy symptoms.

What therapies are used in allergy?

The first line therapies for asthma include avoidance. Treating symptoms can be done with antihistamines, steroid-anti inflammatory drugs (reduce inflammation), and adrenaline (Epi-pen; vasoconstriction). Over therapies include low dose allergen therapies (desensitisation) which include intramuscular injection of low dose allergen monthly for 2-5 years to raise IgG rather than IgE (done in the past for severe allergies) to not stimulate mast cells. Ab therapy such as dupilumab can be used to block cytokines like IL-4 that promote Th2 activation of B cells. Oral tolerance is oral/mucosal exposure to Ags that normally leads to T cell tolerance - low doses of ingested Ag is used to retrain the immune system. 

• Future therapies like Palforzia is a peanut derived protein used to redirect the immune response. Benraliuzumab targets IL-5R which is important for eosinophil/basophil survival - it treats asthma and COPD. There are many targets that can be used for eosinophilic asthma.

How are parasites used to treat allergy?

Many parasitic worms can regulate the immune response. This has been done in many experimental models, including a human trial using hookworm to treat asthma with promising results. It is also being investigated in coeliac disease (autoimmune response). Mouse models have also investigated purified parasite products, rather than actual infection. This is not used clinically. 

How does owning a pet affect allergy?

The microbiome can be diversified to prevent allergies by owning a pet. Research has shown that owning an animal slightly diversifies the microbiome, meaning the owner is less likely to develop allergies.