Abstract
Serodominant group 1 allergens of house dust mites (HDMs) are cysteine protease digestive enzymes. By increasing the detection of any allergen by dendritic antigen presenting cells, upregulating inflammatory signalling molecules, and activating cells crucial to the transition from innate to acquired immune responses, the proteolytic activity of these HDM allergens also underlies their behaviour as inhalant allergens. The significance of this property is underlined by the attenuation of allergic responses to HDMs by novel inhibitors in experimental models. The group 1 HDM allergens act as prothrombinases, enabling them to operate the canonical stimulation of protease activated receptors 1 and 4. This leads to the ligation of Toll-like receptor 4, which is an indispensable component in HDM allergy development, and reactive oxidant-regulated gene expression. Intermediate steps involve epidermal growth factor receptor ligation, activation of a disintegrin and metalloproteases, and the opening of pannexons. Elements of this transduction pathway are shared with downstream signalling from biosensors which bind viral RNA, suggesting a mechanistic linkage between allergens and respiratory viruses in disease exacerbations. This review describes recent progress in the characterisation of an arterial route which links innate responses to inhaled allergens to events underpinning the progression of allergy to unrelated allergens.
Highlights
Understanding the nature of allergens is an obvious facet of the discipline of allergy, yet detailed work on the enigma of allergenicity was relatively neglected until the last thirty years
The problem is not confined to allergens of house dust mites (HDMs) origin; we have reported on intransigent serine peptidase contamination of the serodominant cat allergen, Fel d 1 [20]
Allergen uptake into epithelial cells could form an alternative route to antigen presentation, but secondary antigen presentation pathways such as this result either in the development of tolerance, or are less significant compared to antigens that can present via Dendritic cells (DCs) [27,28,29,30]
Summary
Understanding the nature of allergens is an obvious facet of the discipline of allergy, yet detailed work on the enigma of allergenicity was relatively neglected until the last thirty years. It becomes even more significant in the surrounding context of a phenomenon which operates within this clustering of allergen families which we have referred to as “molecular hegemony” This phenomenon has been tacitly recognised for many years at a descriptive level in terms of the serodominance of a limited range of allergens from key triggers of disease, and as a functional principle it is supported by the concept of initiator allergens and the sequential events which occur in allergen polysensitisation [1,2]. Because group 1 HDM allergens are recognised as “initiator allergens” which can facilitate polysensitisation and its effects, their inhibition is likely to exert a previously unanticipated broad spectrum of benefits It is clear from work conducted on other clinically significant allergen sources where proteases form a part of the allergen repertoire (e.g., fungi) that similar protease-dependent events operate as central underlying processes of disease. It became the creation of a novel opportunity for an unprecedented approach to the treatment of allergic disease and a new class of small-molecule drugs which have been named allergen delivery inhibitors (ADIs) [7,9,10,11]
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