Pathogenesis-driven biologic targets in systemic lupus erythematosus. The three stages in disease development include breach of tolerance in the adaptive immune system (loss of tolerance in B cells and T cells), amplification of autoimmunity through innate and adaptive immune system dysregulation, and end-organ damage. Examples of genetic predispositions (exclusively mouse; blue) at each stage are shown. Disturbances in innate and adaptive immunity in the middle panel contribute to both emergence and progression of disease. NETosis of neutrophils and production of autoantibodies by plasma cells (PC) leads to interferon (IFN) production by plasmacytoid dendritic cells (pDCs). Potential treatment targets are shown. Antibodies against B-cell surface antigens such as CD20 and CD19 can cause death of B cells. Antibodies against other B-cell surface molecules, such as the inhibitory receptor CD22, are alternative targets for both inhibition of B cells and induction of cell death. Inhibition of co-stimulation is another approach; for example, monoclonal antibodies against CD40 ligand or CTLA4-Ig block co-stimulatory signals, thus inhibiting B-cell activation, but also T-cell activation. B-cell survival can be inhibited via monoclonal antibodies against the cytokine B-cell activating factor (BAFF; belimumab) or other approaches to disrupting the BAFF receptor family. The possibility of interfering with other pathways such as Toll-like receptors (TLRs), IFN, and other cytokines with inhibitors and causing direct PC and pDC effects with proteasome inhibitors is also suggested. CD40L, CD40 ligand; mDC, myeloid dendritic cell; NET, neutrophil extracellular trap.