Low affinity Fc receptors, immune regulation and disease. (360G-Wellcome-083650_Z_07_Z)

We will continue our long-standing efforts to understand the biology of low affinity Fc receptors, in particular FcgammaRIIb and FcgammaRIIIb, and their effect on disease. In particular we will follow up our recent observation that FcgammaRIIb is critical for plasma cell survival, to define its role in maintaining B cell tolerance, and thus how it contributes to autoimmune disease. We will use recently generated as well as new mouse models to define the involvement of FcgammaRIIb in autoimmune disease as well as in infection, with these mouse studies being carried on in parallel to functional and genetic studies in humans. We will also investigate FcgammaRIIIb, an activatory low affinity Fc receptor, defining the functional impact of copy number variation, and correlating this with susceptibility to autoimmunity (in particular vasculitis) and both pneumococcal and malarial infection. Finally we will take novel approaches to targeting each of these two receptors in the hope of using the knowledge we have gained about them to open new therapeutic pathways in autoimmunity and infection.