A team of researchers in France may have found an explanation for women’s predisposition for lupus. A new study published in the journal Science Immunology on Friday examined the role of TLR7, a gene that is encoded from the X chromosome.
As a way of controlling gene expression, genes on one of the X chromosomes in women’s cells become inactivated. In the study, scientists found that TLR7 can escape attempts to restrict its expression and avoid X chromosome inactivation. The overexpression of TLR7 – called biallelism since both alleles are expressed – resulted in changes in cells and cell proteins that could cause autoimmune problems.
Although the hypothesis had been found in many reviews, “it had never been demonstrated,” Jean-Charles Guéry, one of the authors of the study, told Andrew Joseph at STAT News. Guéry is a scientist at the French National Institute of Health and Medical Research (Inserm).
Nine out of every 10 individuals who develop lupus are women. Although the cause of lupus remains unclear, the autoimmune disease occurs when the body’s immune system attacks its own tissues, causing swelling, inflammation, pain, and tissue damage. Symptoms range from mild to severe, with patients commonly experiencing joint pain, fever, fatigue, and a rash. There is no cure for lupus, but the condition is managed with anti-inflammatory and immunosuppressant medications, along with lifestyle changes and stress reduction.
In the study, researchers measured the expression of TLR7 in immune cells of healthy women and men who have an additional X chromosome. Men with this condition, known as Klinefelter syndrome, develop lupus at significantly higher rates than men with one X chromosome. In some cells, scientists found that both copies of the gene were producing TLR7 protein. This was observed in both the men and women studied, indicating that TLR7 was able to escape X chromosome inactivation.
The TLR7 protein normally helps the immune system identify viral infections; in past studies, however, researchers have found that animals can develop a version of lupus when immune cells produce excess TLR7.
The new study’s findings reinforce the belief that higher amounts of the TLR7 protein increase a person’s chance of developing lupus, autoimmune disease expert Dr. Hal Scofield told STAT News.
Dr. Scofield, who works at the Oklahoma Medical Research Foundation and was not involved in the study, added that lupus is associated with dozens of genes. “Given all the genes that escape X inactivation, there might be others,” he said. “You might find others that interact with TLR7. You might find a whole cascade.”
As a follow-up to the study, Guéry and his team are planning to compare TLR7 levels in healthy women with those in lupus patients.
Although the research did not reveal the mechanisms through which TLR7 avoids X chromosome inactivation, Guéry said it raised the possibility of a new way to treat lupus: limiting TLR7 protein levels would likely be easier than successfully inactivating the duplicate TLR7 gene. He said, “It’s true that if we can reestablish inactivation of the X chromosome, that might be good for patients… But what might be better is to target TLR7 directly.”