Memory B cells during repeated antigen exposure

The immune system consists of two major arms, the innate and the adaptive immunity. The former one constitutes together with physical barriers the first defense against external threats such as microorganisms, whereas the latter one is a more specific system where the recognition is based on specific structures on pathogens called epitopes. The adaptive immune system is built on a cellular and a humoral part where the latter one relies on terminally differentiated B lymphocytes (B cells), also called plasma cells, secreting antibodies. The isotype class of the antibody determines the function e.g. IgE can activate mast cells or basophils whereas IgG is important for antibody-mediated phagocytosis. However, sometimes the control systems regulating the adaptive immune responses are not working properly permitting either the formation of autoantibodies or allergen-specific antibodies in autoimmune diseases and allergic diseases, respectively. Allergic diseases are widespread and e.g. birch-pollen allergy is mediated by the formation of IgE antibodies leading to activation of effector cells such as mast cells and basophils. The main causative treatment of birch-pollen allergy is allergen- specific immunotherapy and it consists basically of a chronic stimulation with the allergen of interest. The regulation of the B cell response to chronic stimulation is still rudimentarily understood. The type of stimuli plays a major role for B cell responses. To exclude strong effects of chronic tissue inflammation, we decided to longitudinally investigate the B cell response in a special model, namely during allergen-specific immunotherapy (AIT). This treatment comprises the regular administration of allergen to allergic individuals without inducing systemic inflammation. We will use single cell RNA seuqencing and Ig sequencing of allergen-specific B cells to decipher the longitudinal B cell response focusing on the mechanisms leading to more specific antibodies, also called affinity maturation. We hypothesise that allergen-specific B cells will undergo continuous somatic hypermutation towards the allergen leading to increased affinity over time. In addition, we will also investigate the transcriptional regulation of class switch recombination to IgE, the isotype dominant in allergies, in an attempt to increase our understanding behind the molecular factors driving the IgE response. We expect that the results from this project will significantly contribute to improve our understanding how B cells respond to chronic stimulation. The results could potentially also be used to improve the therapeutic success of AIT.