Stephen J. Galli, Mindy Tsai, and Adrian M. Piliponsky
July 2008
Abstract
Allergic disorders, such as anaphylaxis, hay fever, eczema and asthma, now afflict roughly 25% of people in the developed world. In allergic subjects, persistent or repetitive exposure to allergens, which typically are intrinsically innocuous substances common in the environment, results in chronic allergic inflammation. This in turn produces long-term changes in the structure of the affected organs and substantial abnormalities in their function. It is therefore important to understand the characteristics and consequences of acute and chronic allergic inflammation, and in particular to explore how mast cells can contribute to several features of this maladaptive pattern of immunological reactivity.
The conception that antibodies, which should protect against disease, are also responsible for disease, sounds at first absurd.
Clemens von Pirquet (1906)
The term ‘allergy’ was coined by Clemens von Pirquet in 1906 to call attention to the unusual propensity of some individuals to develop signs and symptoms of reactivity, or ‘hypersensitivity reactions’, when exposed to certain substances1 (Box 1). Although the statement quoted above pertained to the cause of serum sickness2, allergic disorders (also known as atopic disorders, from the Greek atopos, meaning out of place) are also associated with the production of allergen-specific IgE and with the expansion of allergen-specific T-cell populations, both of which are reactive with what typically are otherwise harmless environmental substances. These disorders are increasingly prevalent in the developed world and include allergic rhinitis (also known as hay fever), atopic dermatitis (also known as eczema), allergic (or atopic) asthma and some food allergies. Some people develop a potentially fatal systemic allergic reaction, termed anaphylaxis, within seconds or minutes of exposure to allergens.
Management of allergies and allergic inflammation
The two key elements of allergy management are preventing the exposure of sensitized individuals to allergen and treating these individuals with therapeutic agents appropriate to the disorder. For example, antihistamines that target the H1 histamine receptor are a mainstay of treatment for allergic rhinitis but have been of limited value in asthma. Asthma is generally treated with inhaled corticosteroids (which suppress many of the pathways that contribute to inflammation) and agonists of β-adrenergic receptors (which induce bronchodilation). These treatments are effective in many (but not all) subjects. Some patients with asthma are helped by drugs that target cys-LTs. Omalizumab, which targets IgE, helps some subjects with moderate or severe asthma81 and is being evaluated in other settings.
The extent to which pharmacogenetic approaches can be used to understand the basis of variable clinical responses to the same agent, and to identify subjects who will benefit from particular treatments, is an area of active investigation. Allergen-specific immunotherapy should be considered in situations in which this approach has been shown to be beneficial.
Many new pharmacological or biological agents that target the various steps in the cell and mediator pathways implicated in allergic inflammation are being investigated. Some of these compounds are designed to exploit endogenous mechanisms to suppress effector-cell activation during allergic inflammation, such as co-engagement of FcεRI with the inhibitory receptor FcγRIIB, or to take advantage of other mechanisms that can negatively regulate FcεRI-dependent signalling.
Strategies to reduce sensitization and promote tolerance to common allergens are also being considered. One example is reducing exposure to allergens through routes that favour the generation of TH2-cell responses (for example, the skin and respiratory tract) while increasing exposure through routes that favour the production of tolerance (the gastrointestinal tract). Other approaches include attempting to devise vaccines that can be used (carefully) to induce tolerance to substances before natural sensitization can occur, using probiotics to promote the development of a ‘healthy’ immune system (that is, biased to TH1-cell responses or modified TH2-cell responses), and using data derived from epidemiological studies to promote aspects of lifestyle that may reduce the risk of developing allergic disorders. Examples of this last approach include reducing exposure to common aeroallergens, increasing exposure to certain pets (such as dogs), and increasing exercise and outdoor activities.
