Genome of girl with severe lupus pins down genetic target for treatments | Science

There is no cure for lupus, a disease that causes the body’s immune system to attack itself. But researchers are now closer to a genetic explanation for the puzzling condition, thanks to the genome of a child with a rare inherited form of the disease.

A new study fingers a gene called TLR7 that helps fight off viruses; when overactive, it unleashes the immune system on the body’s organs and tissues. Although TLR7 is not the only gene implicated in lupus, targeting its activity or protein could help many patients. “TLR7 is likely to be a central hub, if not the central signaling pathway in lupus, ”says Carola Vinuesa, an immunogeneticist at the Francis Crick Institute who led the work, published today in Nature.

“It’s a great paper,” says Betty Tsao of the Medical University of South Carolina, who studies lupus genetics but was not involved with the research.

At least 200,000 people in the United States have systemic lupus erythematosus (SLE), the most common form of autoimmune disease. Patients can develop skin rashes, joint pain, fatigue, blood clots, kidney failure, heart disease, and psychiatric problems. Lupus is thought to involve both genetics — it runs in families — along with environmental triggers. Patients usually receive immune-suppressing drugs, but these can make them vulnerable to infections.

In 2016, Vinuesa, then at Australian National University, and collaborators came across a 7-year-old Spanish girl named Gabriela who had symptoms of SLE, which is unusual in children. Sequencing Gabriela’s genome revealed a single-base change in the gene for TLR7, which encodes a pathogen-detecting protein called toll-like receptor 7 on the surface of multiple types of immune cells, including antibodymaking B cells. A TLR7 mutation had never been implicated in lupus before, but the researchers subsequently found several other lupus patients with similar mutations. Mice that were gene edited to carry Gabriela’s TLR7 mutation developed lupus symptoms such as low platelets and kidney damage.

The TLR7 protein’s job is to spot RNA viruses. When the receptor is triggered, cells carrying it produce biochemicals called interferons that block the virus from replicating in other, infected cells; TLR7 also tells B cells to produce antibodies to the virus. (People who lack a functioning TLR7 are prone to severe COVID-19 from SARS-CoV-2, an RNA virus.)

But Gabriela’s TLR7 mutation makes the receptor it encodes much more sensitive, Vinuesa’s team found. Studies of the gene-edited mice showed their TLR7 protein is activated simply by encountering the molecule guanosine, which is present in the DNA and RNA of healthy human cells, her team reports today. “Basically, any nucleic acid component triggers a signal,” Vinuesa says.

The resulting overproduction of interferon leads to an immune attack on normal cells. But an even more important effect was that the mutant TLR7 protein promotes the survival of B cells that recognize normal cell proteins, leading to the production of self-reactive antibodies to those proteins that harm human tissues. Normally those traitorous B cells are weeded out by the immune system.

Researchers already knew mice with extra copies of TLR7 develop a mild lupuslike disorder, and that lupus patients often carry mutations near the gene that slightly alter its activity. But “this is definitive proof” of TLR7‘s role, Vinuesa says. Because the TLR7 pathway is often overactivated in people with lupus, even if they do not have mutations in the gene, her team thinks blocking this pathway with drugs — either targeting the receptor or downstream signals, “is a reasonable therapeutic strategy.”

A role for TLR7 also helps explain why most people with lupus are women: The gene is on the X chromosome in a section where, unlike with most genes, both copies of a gene are often expressed. Men, with their X and Y chromosome pair, have just one copy so they make less of the immune receptor overall, even if they carry the TLR7 mutation.

Tsao says the team makes “a very convincing” case that TLR7 is “a pivotal pathway” in lupus. Rheumatologist Amr Sawalha of the University of Pittsburgh notes that an interferon-blocking drug approved last year called anifrolumab has already been used to treat lupus. The new study, he says, “reinforces targeting TLR7 as a potential treatment. ”

Gabriela, now a teenager, takes a cocktail of immunosuppressants to control her disease; the drugs have had the side effect of stunting her growth. She said in a press release that she hopes the new research will lead to better treatments for “so many lupus warriors who suffer from this disease.”

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