Abstract
Abstract Self-reactive B cells in the periphery are maintained in a tolerized state through low levels of sCD40L and BAFF (B-cell Activating Factor) signaling. Loss of tolerance due to hyperproduction of CD40L or BAFF, or uncontrolled downstream signaling following activation is associated with multiple autoimmune diseases. In this study we identify Deleted in Breast Cancer 1 (DBC1) as a novel suppressor of B cell activation and autoantibody production. Mice with targeted deletion of Dbc1 gene have hyper-responsive B cells, which produce immunoglobulin, in particular IgG and IgA isotypes, against self-antigens when immunized with antigen without adjuvant. At the molecular level, DBC1 suppresses B cell function by regulating alternative NFΚB members RelB and p52 during the early phase of CD40 and BAFFR stimulation. In addition, IKKα regulates DBC1 interaction with RelB:p52 during B cell activation by phosphorylating a serine cluster at the C-terminus of DBC1. Finally, loss of DBC1 results in spontaneous autoantibody in aged mice. This study reveals that DBC1 functions as a critical regulator in the B cell immune tolerance checkpoint by suppressing the alternative NFκB pathway.
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