Mechanism of local and systemic allergies against protease allergens

About This Grant

Project Summary Food and environmental allergies are a significant health burden in developed countries. However, it remains still unclear why some allergy patients develop systemic, potentially fatal anaphylactic responses even after a local allergen exposure (e.g., acute hypothermia upon bee sting), while others experience localized reactions in the areas not directly exposed to the allergen (e.g., skin manifestations of food allergy). Numerous studies indicate the critical involvement of allergen-specific IgE antibodies in acute allergy and anaphylaxis, but high levels of IgE against a particular allergen do not always induce anaphylaxis or an ectopic reaction in a remote site upon exposure to that allergen. Thus, in addition to the dose of IgE and the allergen, there appears to be unknown factors affecting the severity and organ specificity of allergic responses. However, the host’s mechanism responsible for the systemic and ectopic dissemination of allergic reaction remains unclear. One of the current limitations to address this question is the lack of animal models, as most animal models of severe allergy requires systemic or repeated challenge with a high dose of allergen, making it often challenging to definitively address how the allergic response is originated. Proteases are a common type of allergens. Papain, a cysteine protease in papaya and a known occupational allergen, is widely used as an experimental adjuvant to induce type 2 inflammation in mice, but papain-specific allergic response has not been well-characterized. We recently found that a second exposure to papain in previously exposed animals induces prolonged edema and hypothermia, a hallmark of local and systemic anaphylaxis, respectively. In contrast to most animal models of systemic anaphylaxis in which the allergen is systemically administered, the systemic response is induced by local sensitization and a single challenge in our model, making it an ideal model to study how the local challenge leads to disseminated responses. We here propose to use this new model in combination with cutting-age mouse genetic and transcriptomic approaches to dissect how a local challenge induces systemic anaphylactic response and ectopic inflammation in a remote site. We hypothesize that local MCs and neurons coordinately trigger systemic and ectopic responses in allergic reactions. In this application, we aim to understand (1) how local challenge develops into a systemic allergic response, and (2) how the allergen-specific immunity modulates local immune responses to protease allergens. If successful, future studies will follow to investigate the molecular mechanism and therapeutic intervention, to examine its relevance in responses to other allergens, and to extend the knowledge to other clinically relevant organ systems such as food and airborne allergies.