Studies on the biology of IgE and specifically on the regulation of IgE response

In the last years, many working groups, including ourselves, have described several B cell specific control mechanisms that indicate a tight control of the IgE response, impressively reflected in a 1000 - 10,000 fold difference in the steady state serum levels of IgE compared to IgG1 in mice. Nevertheless, the precise understanding of the IgE regulation and its biological function is, at best, limited. With the current project proposal we want to gain deeper insights into both, by focusing on two independent but related topics: 1) Chemokine expression of Th1 and Th2 dependent Ig-isotypes; 2) Construction of an IgE/IgA only mouse. 1. In general, chemokines and their receptors play an important role in the regulation of the development and maintenance of immune responses. In the first part of the present project proposal, we want to analyze and compare the distinct signal transduction of Th1 and Th2 dependent Ig-isotypes. Genomic and proteomic approaches will be performed to evaluate isotype-specific chemokine expression patterns. 2. In a different but synergistic approach, the humoral immune response of IgE will be further analyzed by constructing a mouse strain exclusively expressing IgE/IgA. This mouse strain will be a perfect tool to study the biological relevance of the IgE response during humoral immunity and to describe the development and maintenance of IgE memory. In our opinion, these two promising strategies together are an ideal and unique way to study the in vivo function of the IgE immunoglobulin itself, the IgE antigen receptor and therewith connected isotype-specific signal transduction. We are convinced our findings will provide new insights into the biology of IgE development and the maintenance of the IgE response in vivo.

Antibodies are effective weapons of our immune system to neutralize pathogens, such as bacteria and viruses. B cells, having their developmental compartment within the bone marrow, are the major source of antibody production. B cells have to adapt the produced antibodies to the invading foreign antigen, and therefore are effective key players in the later so called Adaptive Immune Response. Generally, B cell are able to produce different types of antibodies (isotypes), which are secreted into the blood. One antibody class, the IgE molecule, is normally produced in very low amounts but remains enhanced in allergic individuals and causes the severe symptoms of allergic rhinitis or even live threatening asthma. The actual function of the IgE antibody class has not yet been clarified in detail; therefore, we aimed to investigate the development of IgE producing B cells and the composition of the developmental compartments. Additionally, molecules playing a role in the transmission of signals to induce different maturation stages of the B cells are in our focus, e.g. molecules specific for IgE producing B cells versus molecules which are generally important for the B-cell signaling. Mouse strains with specific genetic alterations are effective tools to study the raised questions and are therefore an important part of our experimental design.