Improper activation of innate immune sensors, including Toll-like receptors (TLRs), is linked to several autoimmune diseases, including systemic lupus erythematosus (SLE). The TLR chaperone protein unc-93 homolog B1 (UNC93B1) is critical for endosomal trafficking of various TLRs and is therefore important for immune homeostasis. Two new studies have identified variations of UNC93B1 that promote the development of SLE via increased responsiveness of TLR7 and TLR8.

Using an NF-κB luciferase reporter assay and TLR agonists, the researchers found increased signalling via TLR7 and, to a lesser degree, TLR8 in cells transfected to express the UNC93B1 variants I317M and G325C, both associated with SLE but not with chilblain lupus. Conversely, the expression of variants associated with a chilblain lupus phenotype (L330R, R466S and R525P) led to increased TLR8 signalling but not increased TLR7 signalling.