Impaired B cell receptor (BCR) signalling in patients with primary B cell immunodeficiencies, such as common variable immunodeficiency (CVID), is not only linked to infection susceptibility, but also to autoantibody-mediated immunopathologies. However, there is an obvious dearth of animal models that recapitulate this association. It has long been postulated that a defective establishment of central tolerance should result in autoimmune scenarios and immunopathology. Indeed, defective signalling via the T cell antigen receptor results in impaired negative selection in the thymus (and/or impaired generation of regulatory T cells) driving systemic autoimmune disease in mice. The development of systemic autoimmunity in the setting of impaired BCR signalling is, in contrast to the T cell receptor-mediated scenario, lacking genetic mouse models. Indeed, B cell-intrinsic mutations that lead to autoimmunity in mice are in majority produced by enhanced BCR signalling. In the first funding period, we identified and characterized Caveolin-1 (Cav1) deficient mice as a new and unique model of autoimmunity in the setting of B cell immunodeficiency. We demonstrated that defects in plasma membrane organization resulted in sub-optimal BCR signalling, and consequently, defective elimination of autoreactive specificities from the repertoire and a break in central tolerance. Cav1-deficient mice allow us to interrogate whether abnormal central tolerance is necessary and/or sufficient to cause autoimmune diseases. In particular, additional defects in peripheral B cell tolerance, external triggers, resistance to apoptosis, crosstalk to pattern recognition receptors and/or T cells might be required and will be studied in this funding period.