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Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, metronidazole side effects dogs constipation PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London, England.

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution — one letter in the 3 billion letters of the genome,” Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”

One Pathway Among Many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York City, and director of the Montefiore-Einstein Institute for Lupus Care and Research, told Medscape Medical News that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin,” she said.

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the Lupus Genomics and Global Health Disparities Unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS), described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”

A Step Toward Personalized Medicine

Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the Childhood Arthritis and Rheumatology Research Alliance (CARRA) 2022 Annual Meeting. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Lewandowski, who has recently begun a research collaboration with Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Lewandowski said about the intersection between her research and Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjogren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Vinuesa, Schwartz, and Lewandowski report no disclosures.

Nature. Published April 27, 2022. Full text.

CARRA 2022 Annual Meeting. Update on the Child/adolescent Lupus: Understanding Etiology (CLUE) Study. Presented May 2.

Tara Haelle is a Dallas-based science journalist. Follow her @tarahaelle.

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