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‘Master Regulator’ in genes may make women more susceptible to autoimmune diseases

Researchers at the University of Michigan (U-M) Ann Arbor, recently published a study in Nature Immunology that was aimed at exploring why women are disproportionately more susceptible to autoimmune diseases.

“[Through research], our team identified a gene expression difference between the sexes that is associated with susceptibility to autoimmune disease,” says senior author Dr. Johann Gudjonsson, an assistant professor of dermatology at the University of Michigan Ann Arbor.

Finding clues in skin Because Dr. Gudjonsson’s lab has focused on autoimmune diseases of the skin, the researchers decided to take a broader approach to this study by investigating gene expression in the skin of healthy subjects—including biopsy samples from 31 females and 51 males.

“It’s important to examine changes to the skin in diagnosis and treatment of autoimmune disease,” Dr. Gudjonsson says. For example, he notes, four of 11 criteria for a lupus diagnosis relate to the skin, with signifying features such as rashes.

The gender breakdown, meanwhile, revealed additional clues.

“We found some striking differences in gene expression between the women and men,” says first author Yun Liang, PhD, a U-M dermatology research investigator. In total, 661 genes were expressed differently between the sexes.

“Many of those genes had an immune function, and overlapped with genetic pathways and risk genes that related to autoimmune diseases,” added Dr. Liang, who was quoted in a press release.

That led the team to identify what they’re calling VGLL3, a “master regulator” of the female-biased immune network.

“This previously unknown inflammatory pathway promotes autoimmunity in women,” says Dr. Gudjonsson.

VGLL3 was also active in men with autoimmune diseases, though, to a much smaller degree, the authors wrote.

The role of sex hormones Much of the existing work on gender differences in autoimmune diseases focuses on sex hormones by investigating the effects of hormones on women’s immune systems to explain the disparity.

However, the novel inflammatory pathway U-M researchers identified as VGLL3 is not hormonally regulated.

“We found no evidence of the involvement of estrogen or testosterone in the immune differences we observed between women and men,” Dr. Gudjonsson said. “Identifying a separate regulatory mechanism could be a huge advance in gender-focused autoimmune research.”

The study, Dr. Gudjonsson noted, provides direction for future investigations into the identified pathway and how it is regulated.

It also might put greater focus on women’s unique biology. According to the researchers, this is one of the first studies to conclusively demonstrate that it is critical for immunological research to study and analyze female and male samples differently.

“Learning more about these disease processes in each gender will provide opportunities for therapeutic interventions we did not imagine before, including both prevention and treatment,” concluded Dr. Gudjonsson.

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