Gene on X Chromosome Could be Reason Why Lupus Disproportionately Affects Women
9 of 10 individuals who develop lupus are women. Also, XXY individuals have increased incidence of lupus, suggesting that X chromosome dosage could be an important risk factor. Now researchers have found that the gene, TLR7, escapes silencing in lupus and may be a potent drug target for the disease.
Patients of systemic lupus erythematosus (SLE), an autoimmune disease, produce antibodies to their own body tissues rather foreign proteins. The result is chronic inflammation of a few or many body tissues, including the heart, lungs, nervous system, skin, kidneys, or joints. Viruses, some medications, ultraviolet light, and specific genes are thought to contribute to development of SLE. Lupus also occurs more frequently in Japanese and Chinese populations and in blacks.
The study carried out by researchers at the French National Institute of Health and Medical Research (INSERM), now demonstrates that Toll-like receptor 7 (TLR7) that is encoded from the X chromosome escapes X inactivation in B cells and myeloid cells in females and Klinefelter individuals (47,XXY).
Examination of blood cells led the researchers to find that the 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.
“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.
