Considerable effort has been directed toward identifying physical, chemical, or functional characteristics that might be common for all allergens, but no common characteristics of all allergens have emerged. Thus, it appears that in a susceptible host, essentially any antigenic molecule can elicit an allergic response.
While any type of molecule appears to be able to elicit an allergic response, the search for common features of allergenic molecules has demonstrated that some clinically significant allergens are proteases. One ubiquitous protease allergen is the cysteine protease Der p 1, which is present in the feces of the house dust mite Dermatophagoides pteronyssinus. Der p 1 provokes allergic reactions in about 20% of the North American population. This enzyme has been found to cleave occludin, a protein component of intercellular tight junctions in the airway mucosa. This reveals one possible reason for the allergenicity of certain enzymes. By destroying the integrity of the tight junctions between epithelial cells, Der p 1 may gain abnormal access to subepithelial antigen-presenting cells (see Fig. 14.2). The tendency of proteases to induce IgE production is highlighted by individuals with Netherton’s syndrome (Fig. 14.5), which is characterized by high levels of IgE and multiple allergies. This disease is caused by a mutation in SPINK5 (serine protease inhibitor Kazaltype 5), which encodes the serine protease inhibitor LEKTI (lymphoepithelial Kazal type-related inhibitor). LEKTI is expressed in the most differentiated viable layer of the skin (the granular cell layer), just internal to the cornified cell layer of the epidermis. Absence of LEKTI in Netherton’s syndrome results in overly active epidermal kallikreins, proteases that can cleave desmosomes in the skin, leading to keratinocyte shedding and disturbed skin barrier function. Overly active kallikrein 5 leads to overexpression in the skin of TNF-α, ICAM-1, IL-8, and thymic stromal lymphopoietin (TSLP). TSLP is a major agonist of allergic manifestations in the skin, and is essential for the development of both the eczematous skin lesions and the allergic manifestations (including food allergy) seen in Netherton’s syndrome. Additionally, LEKTI is thought to inhibit the proteases released by bacteria such as Staphylococcus aureus. This may be of special significance in the eczematous process, since a very large fraction of individuals with chronic eczema show persistent colonization with S. aureus and resolution of the eczema is facilitated by elimination of the Staphylococcus, in addition to suppression of the inflammatory response.
The observation that loss-of-function mutations in a protease inhibitor in Netherton’s syndrome led to the development of multiple allergies provides additional support for the possibility that protease inhibitors might be novel therapeutic targets in some allergic disorders. Furthermore, the cysteine protease papain, derived from the papaya fruit, is used as a meat. Papain can