Systems Biology of Immunoreceptor Signaling in Allergic Inflammation – iSa

Allergy is a disorder of the immune system that occurs in response to a variety of normally harmless substances known as allergens. Most allergens are environmental. They include pollens, animal hair, dust mites, moulds, and venoms from stinging insects. Other allergens are mostly food and medications. Allergies are initiated by the activation of mast cells by anti-allergen immunoglobulin E (IgE) antibodies, resulting in an acute inflammatory response. Such acute responses often evolve into chronic inflammation that result in progressive tissue lesions. Allergic manifestations affect primarily the respiratotory tract (rhinitis, atshma) and the skin (atopic dermatitis, eczema). Others are systemic (anaphylaxis). They can be benign or severe. Anaphylaxis is a hyperacute life-threatening reaction, and it takes only minutes for a mild allergic reaction to escalate to anaphylaxis.
Mast cell activation is a pivotal event in the initiation of inflammatory reactions associated with allergic disorders. It is triggered by the aggregation of high-affinity IgE receptors (FceRI), on the mast cell surface. FceRI aggregation is induced by the binding of a multivalent allergen to FceRI-bound IgE antibodies. Mast cell activation is a complex process relying on multiple layers of tightly controlled intracellular signaling molecules, which form an intricate and dynamic network. To understand and predict the behaviour of this signaling network it is crucial to study it as a complete system and not only its isolated parts. The iSa (iSa stands for immunoreceptor signaling in allergy) project, is such a comprehensive approach of immunoreceptor signaling in allergy through a multidisciplinary effort.
The iSa project specifically aims to understand at systems level, how information is generated and propagates through the FceRI signaling network with high temporal and spatial resolution. The iSa project will develop new analytical and mathematical tools to generate and integrate high-density quantitative data describing mast cell activation. Genetics, proteomics, high-resolution 3D imaging, and modeling will be applied to obtain a holistic model of the FceRI signaling network. By combining complementary state-of-the-art expertises, the iSa project will allow the identification of critical decision nodes within the FceRI signaling network that are likely to be highly vulnerable to pharmacological interventions and thereby can constitute new drug targets in the prevention and/or the treatment of allergic inflammation.