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The pathophysiology of allergic responses

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Allergic disease is estimated to affect around 15-20% of the population of the western world, with a two- to three-fold increase being seen in the past 20-30 years (Royal College of Physicians, 2003). It is a condition that has a huge impact on the lives of those who experience it (Bousquet et al, 2001).

A range of immune cells and mediators are responsible for the symptoms of allergy, which can occur both early and late in the overall response. An understanding of the pathophysiology of allergic disease can assist in the management, treatment and therefore in the prevention of allergy.

Despite its increasing prevalence there is a shortage of allergists in the UK with just one consultant allergist per two million of the population compared with one per 100,000 of the population for other specialties (RCP, 2003).

Allergic rhinitis

Allergic rhinitis is characterised by the presence of two or more of the following symptoms:

- Nasal itch;

- Sneezing;

- Blockage;

- Rhinorrhoea (a persistent watery discharge).

While there are many causes of rhinitis, it is thought that allergy is the most common, implicated in 50% of all cases (Skoner, 2001). The symptoms of allergic rhinitis are often accompanied by conjunctivitis and asthma (Strachan, 1995).

Guidelines published in 2001 state that up to 80% of patients with asthma have co-existing rhinitis and that 60-70% of patients with rhinitis also have asthma (Bousquet et al, 2001).

Studies have also shown that allergic rhinitis is a risk factor for developing asthma (Aronsson et al, 2005). See pages 49-52 for further information on allergic rhinitis.

Seasonal allergy

The symptoms of allergic disease can occur both seasonally and perennially and are caused by a variety of allergens. Offending allergens can often be identified by matching the timing of symptoms experienced by the patient and the prevalence of allergens at particular times of year.

In the UK, tree pollen is the predominant allergen between February and April and can cause severe symptoms affecting both the upper and lower airways - particularly the pollen of the silver birch (Fig 1). Interestingly, silver birch pollen shares cross-reactivity with some fruits and vegetables such as apples, potatoes and celery (Anhoej et al, 2001), consumption of which can lead to symptoms such as itching and swelling of the lips, oral mucosa and soft palate. This ‘oral allergy syndrome’ affects up to 70% of people with birch pollen allergy (Asero, 1996).

Summertime hayfever is most commonly caused by grass pollen allergy and symptoms are experienced from May to July in the UK. As some patients experience their most severe symptoms early in the morning and in the evening, it may be helpful to avoid the outdoors at these times and keep windows closed in the evening. The most frequently experienced symptoms occur in the upper airways but the allergen can fragment, reducing in size and reaching the lower airways and resulting in seasonal asthma symptoms.

Other seasonal allergens include weed pollens, prevalent during late summer, and moulds and fungi, which provoke symptoms usually between the months of July and October.

Perennial allergy

Many allergens provoke symptoms all year round. For example, pet allergy, in particular cat allergen, causes perennial symptoms in sensitised individuals, and severe symptoms can be experienced in both the upper and lower airways. Cat allergen exists in high concentrations in the homes of cat owners, but it has also been shown that a level high enough to provoke symptoms can be carried into public places. Studies have shown that cat allergen can be found in many unusual places, including bus and train seats, cinemas and schools (Munir et al, 2003; Ritz et al, 2002).

Probably the most prevalent perennial allergen is that of the house-dust mite. These spider-like creatures are invisible to the naked eye and inhabit bedding and other soft furnishings. Allergic symptoms are caused by the digestive juices in mites’ faeces. Many patients may associate symptoms with exposure, experiencing, for example, sneezing and a blocked nose after making the bed.

Pathophysiology of allergy

Atopy is the predisposition for producing the antibody IgE, which is defined by the presence of one or more positive skin prick tests (SPT) to common aeroallergens (Durham and Church, 2001). Allergy is the clinical expression of atopy - the physical symptoms of allergy related to exposure.

The immune response is dependent on the body’s two subsets of T-lymphocytes, known as T helper cells TH1 and TH2. In the normal immune response, TH1 cells release a range of mediators to help the body to defend against invasion from parasites, bacteria and viruses.

In atopic individuals, TH2 cells and their mediators encourage the immune system to recognise allergens as an invader, and mount a response against them. Strachan (2000) suggests that because of reduced natural exposure to bacteria and viruses as children, as a result of living in an increasingly sterile environment, allergy is increasing and immune responses are more likely to develop along the TH2 pathway. This principle is widely accepted and is known as the hygiene hypothesis.

For allergy to exist, allergen sensitisation must first occur. Antigen-presenting cells, such as macrophages and dendritic cells that are present in the mucosal surfaces of the body, detect the allergen. This can occur in many ways, including inhalation into the nose and lungs, through the skin and through the gastrointestinal tract.

The antigen-presenting cells come into contact with the allergen which, in people predisposed to atopy, is perceived to be an invader. The allergen is then absorbed, processed and displayed on the surface of the antigen-presenting cell. This cell then migrates to the T-lymphocyte (T-cell) and presents the allergen, which then stimulates the B-cell to produce antibodies specific to the allergen. These specific antibodies, IgE, are then released, and attach themselves to high-affinity receptors on the surfaces of mast cells in the mucosal surfaces and on basophils in the blood.

After the period of sensitisation described above there is a period of latency, and on subsequent re-exposure to the allergen the allergic response is triggered: allergen cross-links with the IgE on the surfaces of the mast cell or basophil, causing the cell to ‘degranulate’ or release inflammatory mediators. These include largely histamine and other mediators, including cysteinyl leukotrienes, prostaglandins and kinins. They have different actions in terms of symptoms in different organs.

Allergy in the lung

It is increasingly clear that the pathological event underlying most cases of asthma is chronic inflammation and that the most commonly identified cause of this is inhalation of allergens (Platts-Mills et al, 2001). Asthma symptoms can occur immediately (early-phase response) or some hours after allergen exposure (late-phase response). Many immune cells and mediators are involved in the asthmatic response and all play a role in the evolution of both the early and late responses.

The early asthmatic response After allergen exposure, inflammatory mediators, including large quantities of histamine, are released from mast cells on the mucosal surfaces. Histamine causes immediate bronchoconstriction and bronchospasm, resulting in narrowing of the small airways (bronchioles). Cysteinyl leukotrienes, also released from mast cells, are also potent bronchoconstrictors of airway smooth muscle, amplifying the action of histamine. Cysteinyl leukotrienes also increase microvascular permeability, resulting in oedema and narrowing of the airways and stimulation of the secretion of mucus in the lower respiratory tract (O’Byrne et al, 2001). Prostaglandins, released by mast cells, are also involved in the early-phase response.

In the management of allergy it is important to match the drug with the symptom. In research, inhaled allergen challenge is used to provoke symptoms in allergic volunteers to mimic natural environmental exposure and measure bronchial hyperreactivity.

Pre-treatment with a combination of a leukotriene receptor antagonist and an antihistamine can almost completely prevent the early-phase asthmatic response after controlled allergen challenge (O’Byrne et al, 2001), although once the early asthmatic response has occurred introduction of an inhaled bronchodilator is recommended (British Thoracic Society, 2003).

The late asthmatic response A characteristic of the late-phase asthmatic response is the infiltration of the airways with inflammatory cells and mediators, in particular eosinophils, which results in airway narrowing and associated bronchial hyper-responsiveness (Lordan and Hellewell, 2001).

Atopic individuals have increased levels of the cytokine inflammatory mediator interleukin 5 (IL-5), which is produced by immune cells such as mast cells and T-lymphocytes. This mediator stimulates the production of eosinophils and also attracts them to the site of inflammation. Eosinophils play an important role in the pathophysiology of asthma, and their migration into the lungs is associated with inflammation and bronchoconstriction. They produce a host of enzymes, proteins and mediators that are directly associated with epithelial tissue damage in asthma. This damage contributes to the chronic changes seen, such as airway remodelling and associated airway hyperresponsiveness.

The allergic nose

As with the lung, the allergic response in the nose can be separated into early and late phases.

The early-phase reaction After sensitisation to an allergen has occurred, and on subsequent re-exposure, cross-linking of allergen on IgE displayed on the surfaces of mast cells in the nasal mucosa causes degranulation. The proinflammatory mediators within are released and act upon cells, nerve endings and the vasculature in the nose (Bousquet et al, 1996). Histamine plays the biggest role in this process, acting upon nerve endings to produce the symptoms of itch and sneeze, and on the small veins and capillaries, causing vascular permeability, which results in nasal blockage, which is one of the primary symptoms of allergic rhinitis.

The late-phase reaction After the early response in the nose following allergen exposure, inflammatory cells continue to be recruited. These cells and their mediators sensitise the nose to both allergen exposure and non-specific stimuli. This nasal hyper-responsiveness is a characteristic of the late-phase response; sufferers describe allergy-like symptoms on exposure to a range of stimuli, including strong smells such as bleach, hairspray and tobacco smoke. During this phase ‘priming’ occurs, where nasal cells are ready to respond to stimuli, so that often a smaller amount of allergen is needed to provoke allergic symptoms.

As with the asthmatic late response, eosinophils play an important role in the late-phase response in the nose, with the enzymes and proteins released causing tissue damage and further inflammation (Miller et al, 2001).

Again, matching drug to symptom is crucial in the management of allergic rhinitis, with the early phase of the allergic response, which is largely due to histamine, being treated with a long-acting antihistamine. The later, more chronic symptoms, should be treated with a topical nasal corticosteroid. This combination is the preferred and first-line treatment for allergic rhinitis (Bousquet et al, 2001).


An understanding of the pathophysiology of allergic disease is crucial in assisting in the management of allergic disease and symptoms. This can assist in research and in the development of new treatments.


- Education for Health: a leading educational institution for health professionals. For information regarding Open University-accredited diploma and degree-level modules in allergy and management of respiratory disease call 01926 493313 or visit

- British Society of Allergy and Clinical Immunology (BSACI) annual meeting: 10-12 July, Nottingham. Details: 020 7404 0278 or

This article has been double-blind peer-reviewed.

For related articles on this subject and links to relevant websites see

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