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As a young girl, Gabriela Piqueras wasn’t quite like the other children in her class. She couldn’t play with her friends, because any minor bump would cause a large bruise to bloom instantly. She couldn’t get much sun and, as a pre-teen, she spent long stretches of time in the hospital.

At age 7, while living in Madrid, Piqueras was diagnosed with lupus, a confounding and severe autoimmune disease that can be detrimental to many organs, including the kidneys, spleen, heart, and brain.

Her rare case of pediatric lupus caught the attention of Carola Vinuesa, an autoimmunity researcher at the Francis Crick Institute in London, who happened to be a friend of Piqueras’s doctor. Almost a decade later, the young girl’s lupus is helping unravel some of the secrets of this perplexing illness. That’s because in studying Piqueras, doctors were able to figure out the cause of her lupus: a single variant in the gene that encodes for the protein called Toll-like receptor 7, or TLR7. That defect set off an exaggerated and misguided immune response to the body’s own RNA.


TLR7 receptors work as sensors, constantly scanning their environment for unfamiliar RNA that might belong to a pathogen — a job that is vital for preventing infection from RNA viruses like SARS-CoV-2, among others. But a problem arises in people like Piqueras, whose TLR7 receptors can’t distinguish between genetic material in potentially dangerous viruses and guanosine, a nucleic acid found in the body’s own RNA. The receptors call in an array of immune system agents to get rid of what they see as a suspect pathogen.

In most people, that process is typically well controlled and short lived. But in individuals with lupus or similar autoimmune conditions, the immune response is aggressive and long-term. “It seems like nonstop activation,” said Nan Shen, a professor of medicine and director of Shanghai Institute of Rheumatology.


The body sends in B cells to fight the unrecognized RNA, and creates antibodies against it. But if the B cells’ target is a person’s own cell matter, that leads to the creation of an army of antibodies against oneself, a constant onslaught of immune attacks. In this regard, “lupus is the most classical model” of autoimmune diseases, a sort of prototype for how such illnesses occur — and therefore a great place to start as a researcher, said Shen, a principal investigator in the Lab of Molecular Rheumatology at the Shanghai Institutes for Biological Sciences.

The findings about Piqueras’s lupus, published in late April in Nature, are unusual because they point to a route from TLR7 to full-blown lupus driven by harmful autoantibodies made by certain B cells. In other patients, the disease has been thought to be driven by multiple, overlapping genetic mutations. In general, the cause of lupus — including what might suddenly trigger the illness — is still unknown. Piqueras’s young age played a part in offering some clarity, since childhood lupus is considered more likely to be caused by nature (genetics) than nurture (environmental factors or mutations that happen with age).

The Centers for Disease Control and Prevention estimates about 200,000 adults in the United States have common lupus, called systemic lupus erythematosus. Women account for a vast majority of these cases. Black and Latina girls and women are at the highest risk of developing the disease, though the reasons why are unknown.

Other studies have captured the concept of lupus from a single source. But the paper by Vinuesa also delves deeper into a longstanding debate about where, exactly, in the body lupus originates. Some believe — and were trained to think — the disease begins in the germinal center, a structure in the lymph nodes where immune cells interact with antigens in a way that creates a powerful pathogen-fighting response (think vaccines and infections). And despite scientific studies suggesting lupus has many potential birthplaces in the body, “a lot of the field continues to ignore that, and continues to just think about the dogma that everything has to happen through the germinal centers,” said Iñaki Sanz, chief of the division of rheumatology at Emory University School of Medicine in Atlanta.

Vinuesa and her team were able to figure out one key alternate pathway, one not involving the lymph node germinal center, with the help of a few Kikas.

The original Kika is a stuffed elephant that a family friend gave Piqueras during one of her long stays at a Madrid hospital. The family dog is also named Kika. But perhaps the most significant Kikas are the mice with Piqueras’s same kind of lupus, added into their cells with gene-editing technology.

When those lab mice were just a couple of cells big, researchers at Australian National University in Canberra tweaked their TLR7 sensors to act the same as the Piqueras receptors. The mice developed a disease that was strikingly similar to the girl’s illness, with very low platelet counts, ubiquitous autoantibodies, kidney damage (Piqueras had high blood pressure due to difficulty getting blood to her kidneys), and enlarged spleens and lymph nodes.

“Basically, most of the manifestations that we can look for are there in the mice,” Vinuesa said. “And that, well, tells us that it is a valid model.”

Gabriela Piqueras, now 17, with her trusty stuffed elephant at her home in Guatemala City, Guatemala. Piqueras hopes to study psychology in Madrid, her hometown, when she finishes high school. Courtesy Piqueras Family

Some lupus patients, like Piqueras, also have problems with their central nervous system, brain, and heart, but those complications are more difficult to study in mice, as is the signature butterfly-shaped skin rash that lupus patients often have on their cheeks, Vinuesa said. Although Piqueras’s case was rare because she was so young at the time of diagnosis, what Vinuesa and her colleagues found relates to a receptor that all humans have, and therefore could be implicated in other autoimmune diseases, as well as lupus, she said. She compares the TLR7-B cell dynamic to LDL receptors that function as key players in the body’s management of cholesterol: when they don’t do their job, it leads to cardiovascular problems.

“Finding these very rare mutations that might only be present in a few patients is enormously important and informative because they just point, illuminate which pathways are important for the disease,” Vinuesa said. “So even if most patients don’t have the mutation that Gabriela has, or might even not have any mutation in TLR7, they might still have a disregulated TLR7 pathway.”

Some drugs are already being trialed for their ability to dampen the overactive TLR7 signaling. If they work, they could be an alternative to the aggressive immunosuppressive drugs and steroids that many lupus patients are prescribed to stifle their immune response and reduce inflammation.

The paper is a “very good piece of scientific work,” said Sanz, who peer-reviewed the study, but he wished the findings included more details on how Piqueras’s lupus works, immunologically. One way to have done that is by performing an “open-ended” screening test to determine which autoantibodies she had in her system, given more than 100 of them have been identified in other patients with lupus.

To Sanz, the importance of the paper is that it documents a certain pathway that leads to lupus, and that, in turn, could help break a nebulous, broad illness category into smaller groups. “Rather than saying, ‘This is lupus, period,’ we can say, ‘This is lupus 1, lupus 2, lupus 3 subtype,’” said Sanz, a Georgia Research Alliance Eminent Scholar in Human Immunology. And if clinicians could sort lupus patients more precisely, drug candidates could be tailored to those with different types of the disease, too.

Piqueras is now 17, living in Guatemala City, Guatemala, and finishing out high school before returning to Madrid to study psychology. She still keeps Kika, her stuffed elephant, nearby, a reminder of how her illness is helping advance science.

“This has been a difficult course, but at the same time, I have had a lot of positivity and I’ve always known that there was going to be something new and good that comes out of all of this, and that there’s a reason why this happened to me,” she told STAT.

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