Novel therapies target the principal components of the immune system that contribute to LN pathogenesis. Novel therapies target the principal components of the immune system that contribute to LN pathogenesis. This schema illustrates current thoughts on the cells, cytokines, and growth factors and their interactions that amplify kidney injury and facilitate ongoing autoimmunity in LN. During LN circulating plasmacytoid dendritic cells enter the kidney and release IFN-α, and IFN-α then stimulates antigen presenting cells, promotes B cell differentiation into plasma cells, and facilitates production of TH1 and TH2 cells. B cells also present autoantigens to T cells which leads to T cell activation and release of proinflammatory cytokines such as IL-6. B cell and T cell proliferation is dependent upon costimulation which occurs independently from antigen presentation through interactions between CD28:B7 and CD40L:CD40 located on T and B cells respectively. Additionally, the B cell stimulators Blys and APRIL function to activate B cells and prolong survival. Autoreactive plasma cells produce autoantibodies that bind autoantigens and form immune complexes. These immune complexes deposit in the renal parenchyma, activate the alternative complement pathway, and recruit proinflammatory cells to the kidney leading to tissue damage and inflammation. The putative points of interaction of novel therapeutics and pathogenic mechanisms are indicated. Therapies with an asterisk have already been studied in clinical trials. Other therapies that are currently being studied or that we would like to see studied are also shown. Samir V. Parikh, and Brad H. Rovin JASN 2016;27:2929-2939 ©2016 by American Society of Nephrology