MASSACHUSETTS GENERAL HOSPITAL, THE
This research proposal is based on the clinical observation that a small number of potential allergens that humans encounter account for the large majority of allergic responses. The immune system's sentinel cells, dendritic cells (DC), play a crucial role instructing and boosting the specific and long-lasting immune response to antigen. Many pathogen-associated molecules are known to promote effective immunity to bacteria and viruses (Th1 immunity). However, few signals that promote allergic-type (Th2 immunity) immune responses have been characterized in molecular detail. An exception to this is certain related sugar structures identified from parasitic worms, which have been shown to be both necessary and sufficient as Th2 immune boosters. Sugar structures of this type are common in plants, arthropods (e.g., crustaceans, insects), and parasitic worms - but not mammals. This suggests that recognition of these sugar structures may have evolved to protect humans against parasitic infections. Recognition of such structures associated with potential allergens, may contribute to the establishment of an allergic response in some individuals. Our preliminary data suggest that sugar structures from peanut are necessary for uptake and activation of DC through specific receptors to induce strong Th2 immunity. We will further test this hypothesis and identify active molecules from peanut by testing fractions of soluble peanut extract for the capacity to activate DC (Aim I). We will identify the receptor(s) and mechanisms involved in DC activation by peanut sugars (Aim II). We will also test the importance of these sugars for the induction of peanut anaphylaxis using a mouse model of peanut allergy established by my mentor (Aim III). Relevance: Allergy to peanut (Arachis hypogaea) tends to be persistent and severe. More than 3 million Americans have peanut and/or tree nut allergy. This project attempts to contribute to our understanding of why peanut allergy is particularly common and persistent. Better understanding of the mechanisms that contribute to the establishment of allergic responses may eventually be used in novel preventative or therapeutic strategies.