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Lupus Linked to TLR7 Mutations, Related Signaling Changes

NEW YORK – An international research team has shown that gain-of-function alterations in a single gene — TLR7, which encodes Toll-like receptor 7 — can cause systemic lupus erythematosus (SLE), an autoimmune condition that is usually polygenic.

For their study, published in Nature on Wednesday, researchers from the UK, Australia, China, Spain, and the US sequenced the genome of a Spanish child with severe SLE, uncovering a de novo Y264H missense mutation in TLR7, a component of a signaling pathway that has been previously suspected of having excess activity in systemic autoimmune conditions.

The team went on to track down still other TLR7 variants for several more SLE patients, using exome sequencing data, before more fully characterizing the Y264H-variant version of TLR7 with genetically modified mutant mouse experiments. Indeed, the missense mutation caused lupus in these mice, altering the survival of downstream B cells, among other immune changes.

"Our work proves that gain-of-TLR7-function causes lupus, thus targeting this pathway is a reasonable therapeutic strategy," senior author Carola Vinuesa, a researcher at the Francis Crick Institute who is also affiliated with the Australian National University and the University of South Australia, said in an email. The available evidence suggests "TLR7 is likely to be a central hub" in other monogenic forms of lupus, she added.

In addition to experiments showing similar lupus-related phenotypes in peripheral blood mononuclear cell samples from the child with the Y264H variant and in the mutant mouse model, the researchers found that they could dampen down B cell alterations and autoimmune symptoms in mice by targeting the TLR7 pathway with inhibitors.

In animals with TLR7 gain-of-function changes, they reported that they could dial back these disease features by removing an adaptor protein called MyD88 that is found downstream of TLR7, hinting at the possibility of developing targeted inhibitor treatments for SLE.

"Unlike other molecules implicated in lupus, TLR7 can be expressed on the surface of pathogenic B cells (not only present in endosomes), [which are] thus easily targetable by inhibitors," Vinuesa wrote.

Such findings may help to explain why SLE is far more common in females than in males, she noted, since the TLR7 gene is found on an X chromosome region with incomplete silencing, leading to somewhat higher TLR7 expression in females. While too little TLR7 activity can dampen the body's ability to ward off viral interlopers, the latest results suggest that excess TLR7 activity caused by genetic factors or environmental triggers can spur SLE.

"Although highly damaging TLR7 [gain-of-function] mutations are rare, our data, together with evidence of increased TLR7 signaling in a large fraction of patients with SLE, suggest that TLR7 is a key upstream driver of human SLE," the authors concluded. "Therapies blocking TLR7 itself or MyD88 may be more effective than therapies blocking [germinal centers] in patients with SLE due to increased TLR7 signaling."