The girl’s lupus disease leads to a new understanding of the cause of the disease

THEThe young girl Gabriela Pikeras was not like the other boys in the class. He couldn’t play with his friends because any small wheel would instantly make a big mold bloom. He could not get much sun and spent a lot of time in the hospital as a teenager.

At the age of 7, while living in Madrid, Piqueras was diagnosed with lupus, which affects many organs, including the kidneys, spleen, heart, and brain.

Her rare pediatric lupus disease caught the attention of Carola Vinuesa, an autoimmune researcher at the Francis Creek Institute in London, who happened to be a friend of Pikeras’ doctor. Almost a decade later, a young girl’s lupus will help uncover some of the secrets of this amazing disease. Because in Pickeras’ study, doctors were able to determine the cause of his erythematous infection: the only variant in the gene that encodes a protein called Toll-like receptor 7 or TLR7. This defect caused the body’s exaggerated and incorrect immune response to its own RNA.


TLR7 receptors act as sensors and constantly scan the environment for unfamiliar RNA that may belong to the pathogen – a critical step in preventing infection from RNA viruses such as SARS-CoV-2. However, the problem arises in people like Pikeras, whose TLR7 receptors are unable to distinguish the genetic material from potentially dangerous viruses and the guanosine and nucleic acid found in the body’s RNA. Receptors call on a number of agents in the immune system to get rid of what they see as suspicious pathogens.

In most people, this process is usually well controlled and short-lived. And in people with lupus or similar autoimmune conditions, the immune response is aggressive and long-lasting. “It seems to be a constant activation,” said Nan Sheng, a professor of medicine and director of the Shanghai Rheumatology Institute.


The body sends B cells to fight unrecognized RNA and produces antibodies against it. If the target of the B cells is a person’s own cellular substance, it will form an army of antibodies against him, leading to a constant attack of immune attacks. In this regard, “lupus is the most classic model of autoimmune diseases,” a prototype of the emergence of such diseases – so it’s a great place to start as a researcher, said Shen, chief researcher at the Laboratory of Molecular Rheumatology. Shanghai Institute of Biological Sciences.

The findings of Pikeras’s lupus, published in the journal Nature in late April, are unusual because they are caused by harmful autoantibodies produced by some B cells, from TLR7 to full-blown lupus. In other patients, the disease was thought to be caused by multiple, repetitive genetic mutations. In general, the cause of lupus, including the sudden onset of the disease, is still unknown. Piqueras’ age has played a role in suggesting some clarity, as childhood lupus is thought to be more natural (genetic) than nurturing (environmental factors or age-related mutations).

The Centers for Disease Control and Prevention estimates that approximately 200,000 adults in the United States have a common systemic lupus erythematosus known as systemic lupus erythematosus. The vast majority of these cases are women. Black and Latina girls and women have a higher risk of developing the disease, but the causes are unknown.

Other studies have derived the concept of lupus from a single source. However, a paper developed by Vinuésa delves deeper into the long-running controversy over the origin of lupus in the body. Some believe – and have been taught to think – that the disease begins at the gender center of the lymph nodes, where immune cells interact with antigens to create a strong reaction against the pathogen (I think vaccines and infections). Although scientific studies have shown that lupus has many potential birthmarks in the body, “most fields continue to ignore this and continue to think about the dogma that everything should be through seed centers,” said Ignacio Sanz. Department of Rheumatology, School of Medicine, Emory University, Atlanta.

With the help of several Kikas, Vinuesa and his team were able to find a major alternative route that did not involve the lymph node seed center.

The original Kika is a stuffed elephant that a family friend gave to Piqueras during a long stay in a hospital in Madrid. The family dog ​​is also called Kika. But perhaps most importantly, Kikas are mice with a type of lupus attached to Pikeras’ genetic correction technology and cells.

After laboratory mice became several large cells, researchers at the Australian National University in Canberra modified TLR7 sensors to work like Piqueras receptors. The mice were very similar to the girl’s disease, with very low platelet counts, autoantibodies, kidney damage (high blood pressure due to lack of blood in Pikeras’ kidneys), and enlarged spleen and lymph nodes.

“Basically, most of the scenes we’re looking for are in mice,” Vinuesa said. “And it shows us that he is a worthy example.”

Gabriela Piqueras, now 17, with her trusted pharmacy at her home in Guatemala City. After graduating from high school, Piqueras hopes to study psychology in his hometown of Madrid. Pikeras with his family

Some people with lupus, such as Pikeras, also have problems with the central nervous system, brain and heart, but it is more difficult to study these problems in mice because butterfly-like rashes are more common on the cheeks of people with lupus, Vinuesa said. Pickeras’s case was rare because he was so young at the time of diagnosis, and Vinuesa and his colleagues linked it to receptors that are present in all people and could therefore be involved in other autoimmune diseases, including lupus, he said. He compares the dynamics of the TLR7-B cell with LDL receptors, which play a key role in controlling cholesterol in the body: if they do not work, they can lead to cardiovascular problems.

“Finding these very rare mutations, which can only occur in a few patients, is very important and informative because they show which pathways of the disease are important,” Vinuesa said. “Thus, although most patients do not have a mutation in Gabriela, or even no mutation in TLR7, they may still have an unregulated TLR7 pathway.”

Some drugs are being tested for their ability to suppress TLR7 signaling. If they work, they could be an alternative to aggressive immunosuppressive medications and steroids prescribed to many lupus patients to suppress the immune response and reduce inflammation.

The paper is “an excellent scientific work,” said Sanz, who reviewed the study, but said he wanted the findings to contain more information about how Pikeras’s lupus works immunologically. One way to do this is to conduct an “open” screening test to determine which autoantibodies are present in its system, more than 100 of which have been identified in patients with other lupus.

For Santz, the importance of the paper is that it documents a specific path leading to lupus, which in turn helps to divide the foggy, broad disease category into smaller groups. “Instead of ‘this is lupus, period,’ we can say, ‘This is lupus 1, lupus 2, lupus 3 subtypes,'” said Sanz, a well-known human immunologist with the Georgia Research Alliance. Candidates for medication can also be adapted to different types of disease.

Piqueras is now 17 years old and lives in Guatemala City, Guatemala. After graduating from high school, he returned to Madrid to study psychology. He still holds Kika by the side, reminding her how her illness is helping to advance science.

“It was a difficult course, but at the same time I have a lot of positives and I always knew that it would be something new and better and that there was a reason for it. That’s why it happened to me, ”he told STAT.

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