Researchers may have uncovered a novel mechanism behind the development of lupus in pediatric patients, according to a novel study published by Mishra et al in Science Immunology. Previous mouse models have identified hyperactive TLR7 signaling as a contributing factor in autoimmune disease development; however, recent findings have indicated that TLR7 gain-of-function mutations may be monogenic drivers of lupus in humans. In the new study, researchers analyzed whether endosome dysfunction may lead to TLR7 signaling and the development of lupus in humans. They noted that the late endosomal BLOC-1–related protein (BORC) complex in combination with the small guanosine triphosphate (GTP)-binding protein ARL8B were capable of regulating intracellular TLR7 levels by controlling receptor turnover—thereby requiring direct interactions between the TLR7-associated trafficking factor UNC93B1 and ARL8B. Further, the researchers identified a patient with lupus who presented with an UNC93B1 mutation resulting in reduced BORC interaction and subsequent endosomal TLR7 accumulation. Consequently, immune cells began to recognize the body’s own genetic material as pathogenic, leading to systemic inflammation. The researchers underscored that an inability to regulate TLR7 turnover could disrupt immunological tolerance to nucleic acids, demonstrating the significance of an intact endomembrane system to prevent hyperactive TLR7 signaling. They concluded that testing for and targeting UNC93B1 mutations may become a routine component of lupus therapy.
February 01, 2024