Epidermolysis bullosa acquisita (EBA) is an autoantibody driven blistering dermatosis. Like many autoantibody-mediated disorders, the disease is difficult to treat. IL-10 producing plasma cells formed in the natural course of murine EBA can limit EBA skin inflammation. Strikingly, our previous work shows that in vivo stimulation of the B cell receptor (BCR) IgD induces IL-10+ plasma cells which induce Tregs, suppress inflammatory T cells and inhibit neutrophil functions and the effector phase of murine EBA. Despite this success, it is still unclear how BCR signals integrate with co-stimulatory signals to initiate changes in cellular organization and cell metabolism that result in the formation of IL-10+plasma cells.
In order to address these questions we developed a construction kit that allows to stimulate B cells with various BCR signals strengths, via variable BCR-subclasses, including IgD, IgM and co-stimulators, either alone or in combination. This project aims to use this method to identify the signals required to induce IL-10 in plasma cells and to elucidate the underlying mechanism. In addition, the project is designed to optimize BCR-mediated induction of IL-10 in plasma cells for a therapeutic setting. Because plasma cells co-localize with potential target cells of IL-10 and provide local, rather than systemic, IL-10 mediated immune suppression, we expect that induction of IL-10+ plasma cells has less side effects and will be more long-lasting than treatment with IL-10 itself.