Immune dysregulation caused by novel gain-of-function UNC93B1 variant with enhanced antigen presentation

UNC93B1 is a crucial chaperone protein for the trafficking of Toll-like receptors (TLRs) and regulates antigen presentation in dendritic cells (DCs), which activates downstream immune responses. Here, we identified a novel homozygous gain-of-function (GOF) UNC93B1 variant in an early-onset lupus patient. The patient presented with an elevated level of inflammation and auto-antibodies, and organ damage. The Unc93b1 R95L/R95L transgenic mice also exhibited autoimmune and autoinflammatory phenotypes. The transcriptional analysis revealed increased inflammation and elevated activation of DCs in the patient's peripheral blood mononuclear cells and bone marrow-derived DCs from Unc93b1 R95L/R95L mice. In addition to the selected TLR7/8 activation in previously reported UNC93B1 GOF variants, the single-cell transcriptome and flow cytometry of splenocytes from Unc93b1 R95L/R95L mice demonstrated increased phagocytosis activity and T helper cell differentiation with altered ICAM and MHC signaling in DCs and T cells, respectively. These results suggest that the UNC93B1 GOF variant enhances antigen presentation from DCs to T cells in the pathogenesis of immune dysregulation. Our study expands the pathogenic variant spectrum of UNC93B1 and offers insight into the underlying mechanism of antigen presentation in immune dysregulation caused by UNC93B1 beyond TLR trafficking dysfunction.