Review Article
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Mechanisms of peripheral tolerance to allergens
Article first published online: 18 DEC 2012
DOI: 10.1111/all.12085
© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd
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- Edited by: Thomas Bieber
Abstract
The immune system is regulated to protect the host from exaggerated stimulatory signals establishing a state of tolerance in healthy individuals. The disequilibrium in immune regulatory vs effector mechanisms results in allergic or autoimmune disorders in genetically predisposed subjects under certain environmental conditions. As demonstrated in allergen-specific immunotherapy and in the healthy immune response to high-dose allergen exposure models in humans, T regulatory cells are essential in the suppression of Th2-mediated inflammation, maintenance of immune tolerance, induction of the two suppressive cytokines interleukin-10 and transforming growth factor-β, inhibition of allergen-specific IgE, and enhancement of IgG4 and IgA. Also, suppression of dendritic cells, mast cells, and eosinophils contributes to the construction of peripheral tolerance to allergens. This review focuses on mechanisms of peripheral tolerance to allergens with special emphasis on recent developments in the area of immune regulation.
Immune responses are strictly regulated to protect the host from exaggerated signals that may cause tissue injury by establishing a state of immune tolerance. Certain environmental and genetic factors disturb this fine balance of immune regulation, leading to diseases such as allergic or autoimmune disorders. Although allergens are ubiquitously distributed in the environment, the normal response to allergens in healthy individuals is either absent or results in antigen-specific immune tolerance [1].
The immune system must recognize pathogenic stimuli and respond appropriately. Under nonallergic conditions, soluble proteins do not induce a vigorous immune response. Sensitization to a specific antigen is a prerequisite for the onset of atopic diseases in predisposed individuals, which is dependent on the potential of the allergen to prime the Th2 cell response in which interleukin-4 (IL) and IL-13 drive immunoglobulin E (IgE) class-switch in B cells [1-3]. An allergen should induce both early- and late-phase clinical reactions.
There are unique functional and structural features of allergens. There are several crossreactivities among allergen families due to IgE and T-cell epitope sharing. Particularly, food allergens possess structural cavities and tunnels that bind ligands for resistance to heat and proteolysis. Also, repetitive structures, aggregates, and glycation increase immunogenicity. A high number of disulfide bonds and occasionally disordered structures designed for protein stability and mobility have been observed [4]. The amount of allergen in the extract, increased transepithelial allergen delivery, activation of airway epithelial cells, and suppression of local defense mechanisms by the allergen or other substances released from the allergen carrier might contribute to the allergenicity of the protein.
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