Systemic Lupus Erythematosus due to Gain-of-Function Mutation in UNC93B1

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the loss of tolerance to nuclear antigens. Activation of type I interferon (IFN) induced by immune recognition of self-nucleic acids by endosomal Toll-like receptors (TLR) is central to SLE pathogenesis. In two siblings with early-onset SLE, we identified a homozygous mutation in UNC93B1, encoding a multi-transmembrane protein required for trafficking and maturation of endosomal nucleic acid-sensing TLRs. The mutation alters the interaction of UNC93B1 with TLR7 leading to TLR7 hyperactivation with constitutive type I IFN signaling. Moreover, we demonstrate that treatment with the Janus kinase inhibitor ruxolitinib is of therapeutic value.