B-cell depletion therapy (BCDT) represents a rational approach to treat systemic lupus erythematosus (SLE). Surprisingly, clinical trials indicate that BCDT does not improve clinical outcome. The mechanisms underlying this failure are not known. We propose to test the highly novel hypothesis that BCDT results in near complete loss of marginal zone (MZ) B cells which leads to deterioration marginal zone macrophage (MZMs). The MZMs represent a follicular exclusion barrier for uptake of apoptotic blebs. Loss of MZMs converts the normally tolerogenic MZ microenvironment into an immunogenic microenvironment that drives the production of type I interferons (IFNs). In Aim 1, we will determine if BCDT promotes the loss of AC phagocytic MZMs and induction of type I IFNs in lupus mice. In Aim 2, we will determine if pharmacologic interventions that preserve the tolerogenic MZ barrier can establish tolerogenic repopulation of B cells in lupus mice. In Aim 3, we will determine if signatures that are associated with MZ tolerance defects are biomarkers for a poor BCDT response in SLE patients. The proposed work will set the stage for development of rational combination therapy for SLE that can be administered during “windows of opportunities” that will be defined in this proposal.