Selective regulation of IgE antibody responses by B cell receptor signalling

Allergic reactions to food and environmental substances affect more than 40% of the UK population, resulting in a major health burden and potentially fatal anaphylaxis. Many of the clinical symptoms are caused by overproduction of allergen-specific IgE antibodies. Interestingly, the IgE responses are normally low, transient and lack classical immunologic memory. Using new genome-wide approaches, we have discovered molecular mechanisms, which naturally inhibit the differentiation of IgE-switched B cells into antibody-secreting cells and limit their lifespan. These inhibitory mechanisms are triggered by spontaneous intracellular signalling by the IgE B cell receptor expressed on the surfaces of IgE-switched B cells and plasma cells and are different from the control of other antibody isotypes. We hypothesise that this suppressive signalling defines the self-limiting character of IgE responses and that its failure contributes to allergic disease. We will investigate this by elucidating the molecular mechanisms and dynamics of this signalling, and by determining its role in responses to allergens and in primary hyper-IgE syndromes. Our comprehensive characterisation of the molecular pathways underlying the behaviour of IgE-switched cells will illuminate the unique character of IgE responses and provide new therapeutic targets to selectively inhibit IgE production in allergic disease.