One girl’s genetic mutation sheds light on the causes of lupus

Neurons in the brain transmit thoughts, white blood cells fight infection and platelets help with blood clotting. They all know what to do thanks to DNA, a kind of instruction book made up of over 3 billion chemical letters. A team of scientists has now discovered that Gabriela Piqueras, a 16-year-old girl from Madrid, has a mutation in a single letter of her DNA, which causes her to suffer from systemic lupus erythematosus, a disease that causes the human body to attack itself. The researchers, whose study has been published in Nature, believe that this finding opens the door to new treatments for this disease, which affects millions of people around the world.

Gabriela speaks about her illness with ease. When she was five years old, even minor bumps caused her to bruise, and she was admitted to the Niño Jesús Hospital in Madrid. Since then, she has lived under near-constant medical treatment. Her genetic mutation activates a receptor called TLR7 in her cells’ membranes. The receptor is normally used to recognize threatening viruses, but in Gabriela, it reacts to her own DNA and unleashes an attack on her own organs. The bruises she had as a child were caused by her defenses destroying her blood platelets, causing her to bleed profusely.

Gabriela’s memories resemble those of many children who have received treatment for serious illnesses at the Niño Jesús pediatric hospital located near Madrid’s Parque del Buen Retiro. “Between appointment and appointment, because I had a thousand appointments a day, I went with my father or mother to see the peacocks in El Retiro. It is a nice way to clear your mind,” she recalls by videoconference from Guatemala, where she now lives with her family. During one of her hospital stays, when she was seven years old, a friend of her father gave her a stuffed elephant, which she named Kika. She shows it to the camera: Kika plays a role in this story.

The immunologist Carola García de Vinuesa led the scientific study of the girl’s DNA. After discovering the suspected mutation, the researcher’s team altered that same letter in a family of mice in a lab at the Australian National University in Canberra. The rodents also developed the disease. “It was already known that this receptor appeared to be activated in lupus patients, but no one knew if it was a cause, a consequence or a side effect of inflammation. Now we can show that it is the cause,” says García de Vinuesa, who has recently joined the Francis Crick Institute in London.

The 52-year-old scientist from Madrid believes that “most” people with lupus have TLR7 activated, as some previous studies had already suggested. Following the discovery in Gabriela, the team found similar mutations in a Chinese and an American family. In the study published in Nature, the strain of mice is named Kika, in homage to Gabriela’s cuddly toy. “It was my idea,” Gabriela recalls. “This elephant is very important to me, because it was given to me when I was hospitalized for a long time,” she explains with a smile.

Nine out of 10 people with lupus are women. García de Vinuesa argues that the TLR7 receptor could cause the disease. Cells’ DNA is distributed among 46 packages, called chromosomes, which in turn are divided into sections, called genes. The gene with the instructions for making TLR7 is located on the X sex chromosome, of which women have two copies, while men have only one. “This could explain why lupus and other autoimmune diseases are much more common in women,” says the immunologist.

During the pandemic, the scientific community discovered that some men suffered from more severe Covid due to genetic mutations that deactivated their TLR7 receptor, responsible for detecting viruses. “It’s like the Goldilocks effect,” says García de Vinuesa, citing the scientific principle that suggests that conditions must be “just right” for a phenomenon to exist. “You can’t have too much or too little. It has to be the exact amount. With little TLR7 activity, men can have very serious Covid. With too much activity, women can get lupus,” the researcher explains.

Systemic lupus erythematosus affects 210 out of every 100,000 people in Spain. The rheumatologist María Galindo, of the Madrid 12 de Octubre hospital, says that the disease is still “an enigma,” but she stresses that it is clear that there is “a base of genetic susceptibility that, in the presence of external stimuli, triggers an exaggerated autoimmune reaction.” Galindo, part of the scientific committee of the Spanish Lupus Federation, applauds the new study, but she is cautious about overstating its implications. “Everything indicates that the TLR7 pathway is very important, but it is not the only one,” she says.

Galindo says that her center is participating in a clinical trial of Enpatoran, a TLR7 inhibitor drug produced by the German pharmaceutical company Merck, meant to treat lupus in adults. “We lack treatments for serious presentations of the disease,” she laments. “Lupus is a very heterogeneous disease. The more therapeutic targets there are, including TLR7, the more possibilities patients have. It is a bit exasperating to see that a large part of the targets that have been tried have fallen by the wayside,” she says.

Lupus can affect multiple parts of the body, including the joints, kidneys, heart, and brain. Gabriela Piqueras, about to turn 17, lists her visits to hematology, cardiology, rheumatology, ophthalmology and nephrology specialists. “I think the only specialist I haven’t visited is traumatology. I hope it stays that way,” she jokes.

The disease, chronic and incurable, is characterized by periods of dormancy and aggressive outbreaks, controllable with drugs that treat inflammation or reduce the immune response. Gabriela says that her health now is “great.” Much of the credit goes to the pediatrician Carmen de Lucas, who has treated her since she was young at the Niño Jesús Hospital. “It is good for people who are ill with lupus to know that there is a future, that people are researching, that there will be new things, and that in a few years, the prognosis will probably have changed,” says De Lucas. “This finding is a very important step, and I think it will have many consequences in the medium term.”