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Peptidase allergens, occludin and claudins. Do their interactions facilitate the development of hypersensitivity reactions at mucosal surfaces?

Few issues of Clinical and Experimental Allergy arrive without some work connected with the identification and characterization of agents that cause the development of hypersensitivity conditions. In this issue, Shen and colleagues describe a 34-kDa allergen from Aspergillus fumigatus [1]. IgE reactivity to this allergen was detectable in a significant proportion of serum samples from patients with asthma, and amongst those samples that were known to be reactive to Aspergillus fumigatus extracts the frequency of reactivity to this allergen was high [1]. Microsequencing indicates that the IgE-reactive protein described by Shen and colleagues is a serine peptidase [1], adding to the list of allergens from diverse sources that are known or suspected to have proteolytic activity. Furthermore, the authors of this paper show that this serine peptidase from A. fumigatus is cross-reactive with allergens from P. notatum and P. oxalicum [1]. These findings prompt further speculation on the possible connection between proteolytic activity and the interaction of A. fumigatus with human hosts, and invite a general revisitation of the role of proteolytic activity as a potentially important component of developing hypersensitivity reactions to a wide range of antigens. A. fumigatus is a widely occurring airborne fungus which has small spores that facilitate its inhalation. Normally with little effect in healthy individuals, A. fumigatus has significant potential to be pathogenic, saprophytic or allergenic depending on the immunological status of the host and/or the presence of other clinical conditions. In the immunocompromized, invasive aspergillosis can result from exposure to vegetative A. fumigatus. In people who are immunologically competent, but who have lung tissue damage due to tuberculosis or sarcoidosis, A. fumigatus can behave as a saprophyte, resulting in aspergillomata. In asthma and cystic fibrosis, A. fumigatus is encountered as an allergen. Approximately 20% of asthma patients develop positive IgE-dependent skin test reactions to Aspergillus [2±4], whereas 31±59% of patients with cystic fibrosis show reactivity [5±7]. In the two serum libraries screened by Shen et al. 27% and 34%, respectively, of the sera showed reactivity to A. fumigatus extracts [1], generally consistent with the previously observed occurrence. In a subset of asthma or cystic fibrosis allergic bronchopulmonary aspergillosis (ABPA) can develop in those who are sensitized to A. fumigatus. ABPA is a hypersensitivity disease of the lung that results in chronic inflammation of the proximal bronchi. As defined by the classic work of Pepys and colleagues, ABPA involves a type III hypersensitivity reaction [8] presumably superimposed on a type 1 reaction because the presence of both reaginic and precipitating antibody is essential to elicit the lesions characteristic of the condition in a primate model [9]. The potential pathogenicity of A. fumigatus has prompted concerted interest in the molecular mechanisms involved in its virulence. Extracts of A. fumigatus contain many components, some being cytotoxic proteins with allergenic properties (e.g. restrictocin, Asp f1, an 18-kDa ribotoxin). Others are secreted peptidases, with representation from molecules with metallopeptidase (Asp f5), serine peptidase (Asp f13), aspartic peptidase (Asp f10) and dipeptidyl peptidase activity (Asp f11). Although early studies suggested that proteolytic activity released by Aspergillus fumigatus might be crucial to its invasive activity, current evidence does not support a major role for peptidases in this process, or at best suggests that considerable redundancy exists in the repertoire of Aspergillus secreted peptidases [10]. Targeted gene disruption has been used to create single mutants of Aspergillus that are negative for alkaline serine peptidase activity, metallopeptidase activity, aspartyl peptidase activity, or double mutants lacking both alkaline serine and metallo-peptidase activity. These single and double mutants are as lethal in mice as wild type Aspergillus, suggesting that these particular peptidases do not exert a critical influence in the development and progression of invasive aspergillosis [10]. This raises the question of whether the peptidases secreted by Aspergillus have any role to play in the development of human responses to this fungus. As noted above, enzymatic activity is a feature of several Aspergillus allergens, including the one now reported by Shen and colleagues (Asp f18) [1]. Of the enzymatic activities detected as allergens, proteolytic activity predominates, although allergens with oxidase activity are also known (e.g. Asp f6). Could it be that secreted peptidases are more relevant to the development of hypersensitivity than the rampant fungal colonization and destruction of blood vessels seen in invasive aspergillosis, or is it mere happenstance that these enzymes are allergens? At present, this question is unanswered, but Clinical and Experimental Allergy, 2001, Volume 31, pages 186±192