Disrupted degradative sorting of TLR7 is associated with human lupus 2024 Mishra et al

Abstract

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and is associated with human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system in preventing pathological TLR7 signaling and autoimmune disease.

Paywall, https://www.science.org/doi/10.1126/sciimmunol.adi9575

 

Lupus Tracked to Changes in a Single Gene That Tames The Immune System

Led by the Max Planck Institute for Infection Biology in Germany, the team discovered that a group of proteins called the BORC complex is needed to properly break down a protein called toll-like receptor 7 (TLR7).

TLR7 identifies nonspecific genetic material belonging to viruses and bacteria, serving as part an innate defense system that holds the front line until our adaptive immune system takes over. A balance of these receptors is important for a quick immune response.

"We wanted to understand what happens when this balance is disturbed," explains infection biologist Olivia Majer from the Max Planck Institute.

"From earlier experiments in mice carried out a few years ago at the University of Berkeley in California, we already knew that too many of these receptors are a problem."

Majer and colleagues found that when the BORC complex isn't working properly, TLR7 can accumulate in immune cells, making them less sensitive to activation by intruder genetic material and more likely to attack our body's tissues.

https://www.sciencealert.com/lupus-tracked-to-changes-in-a-single-gene-that-tames-the-immune-system

 

The impact of TLR-7 malfunction is a very neat story. It may be worth noting, however, that it would make sense for this to be very specific to lupus, because of the link to nucleic acid scavenging (RNA/DNA).