Targeting a toll-like receptor could attack the root cause of lupus

Normally, one of two X chromosomes in women will "switch off" during embryonic development to prevent the overexpression of genes. But the gene that codes for TLR7 evades this process and could be the reason why lupus is prevalent in women. (Darwin Laganzon)

Like other autoimmune diseases, lupus disproportionately affects women. French scientists found that an X chromosome-linked abundance of a certain receptor protein could be the reason for this gender bias, and it could serve as a target for a new treatment for the autoimmune disease.

It was previously known that a person’s risk for developing lupus increases with the number of X chromosomes he or she has. So women (with two X chromosomes) and men with Klinefelter syndrome (XXY) are more susceptible.

Looking at blood cells from healthy women and men with Klinefelter syndrome, the scientists found that the gene that codes for toll-like receptor 7 (TLR7) dodges X-inactivation, a process that usually kicks in during embryonic development and randomly switches off one of two X chromosomes to keep gene expression in check.

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TLR7 was then expressed on both X chromosomes—a state called TLR biallelism—in many of the individuals’ immune cells, which made them more likely to “switch” the type of antibodies they produce. The researchers think it’s this switch that leads to a higher chance of the immune cells making antibodies that attack the body’s own tissues. A potential treatment would target TLR7 to tamp down on immune activity against normal tissues.

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Toll-like receptors have been harnessed in other areas. In a reversal, Mayo Clinic scientists combined TLR agonists with chemotherapy to trick the immune system into attacking tumor cells, which the body usually identifies as “self.” And a Boston University team found that blocking TLR4 prevents an inappropriate immune response from Ebola-infected white blood cells that worsens the disease.

The new findings, published in Science Immunology, could also have implications beyond lupus. TLR7 could be a target in another autoimmune disease, Sjögren’s syndrome, as well as in other viral infections, such as HIV.

“Currently, there is no drug that can target TLR7 in the market or used in the clinics. TLR7 is a known receptor for RNA nucleic acid which normally comes from viruses, so it is a sensor of RNA viruses, like HIV or flu virus," said Jean-Charles Guéry, research director at the French National Institute of Health and Medical Research (INSERM), in an audio interview with Science Immunology. “As such, there is some evidence that there’s a sex bias in the susceptibility to flu virus or HIV infection.”

Next up, the team plans to study TLR7 expression in women with lupus and compare their findings against the data from healthy women and men with Klinefelter syndrome.

“This may lead to new information regarding the level of biallelism of TLR7 in lupus patients, and whether this could be used as a predictive factor to predict the evolution of disease, which is currently very difficult to do,” Guéry said.

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