Uncoupling the two distinct roles of targeting BDCA2 in treating autoimmune diseases: direct inhibition of BDCA2-positive B cells and normalization of proinflammatory monocyte-derived macrophages via the global suppression of type I IFN

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease with two hallmarks: elevated levels of type I interferon (IFN) secreted by Plasmacytoid Dendritic Cells (pDCs) and autoantibodies produced by malfunctioning B cells. Indeed, the two marketed monoclonal antibodies for treating SLE are belimumab that targets B cells or anifrolumab that targets type I IFN. In this study, we developed a novel anti-BDCA2 monoclonal antibody, 230V5, with an enhanced interaction with Fc receptors. The antibody exhibited superior inhibitory effects on IFN production and IgM production. Further study using scRNA-seq revealed that CpG induced a group of proinflammatory macrophages whose expression could be suppressed by 230V5 in a BDCA2-targeting and FcR-dependent manner. More importantly, we showed for the first time that BDCA2 is also expressed in B cells. BDCA2 expression in B cells can be induced by CpG and BAFF. Treatment with 230V5 effectively inhibited IgM production by PBMCs in a CD32B-dependent manner and reduced the number of BDCA2-expressing B cells. Thus, targeting BDCA2 is a promising therapeutic method for treating lupus-related diseases by targeting both B cells and pDCs