Significant differences in gene expression between women and men diagnosed with autoimmune diseases have been uncovered by researchers from the University of Michigan.

Almost 80% of people with autoimmune diseases are women. The disproportionate statistics are well known, but scientists are still trying to figure out why women’s immune systems are more likely to become overactive and attack their own healthy cells.

The new finding sends the research, and ultimate goal of finding a treatment, in a different direction from the existing work on sex hormones.

Gene Expression Difference

Senior author Johann Gudjonsson, M.D., Ph.D., U-M assistant professor of dermatology, says:

“We found a completely new angle. Our team identified a gene expression difference between the sexes that is associated with susceptibility to autoimmune disease."

Autoimmune diseases take many forms across the body, from psoriasis patches on the skin to lupus throughout the body to rheumatoid arthritis in the joints, yet all conditions affect women at a higher rate.

It often takes years to get a correct diagnosis for these chronic diseases. There are no cures for the estimated 7.5 percent of people in the U.S. dealing with them, and current treatments come with devastating side effects.

Autoimmune Disease Treatment

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

It is important to look at changes to the skin in diagnosis and treatment of autoimmune disease, Gudjonsson says. For example, four of 11 criteria for a lupus diagnosis relate to the skin, with features like rashes.

First author Yun Liang, Ph.D., a U-M dermatology research investigator, said:

“We found some striking differences in gene expression between the women and men. Many of those genes had immune function, and overlapped with genetic pathways and risk genes that related to autoimmune diseases."

In total, 661 genes were expressed differently between the sexes.

Following that finding, the team was able to identify what they are calling VGLL3, a master regulator of the female-biased immune network.

“This previously unknown inflammatory pathway promotes autoimmunity in women,"

says Gudjonsson, also the Frances and Kenneth Eisenberg Emerging Scholar in the Taubman Emerging Scholars Program. VGLL3 was also active in men with autoimmune diseases.

Master Regulation

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

But the novel inflammatory pathway the team identified as VGLL3 is not hormonally regulated.

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

This study, according to Gudjonsson, provides direction for future investigation into the identified pathway and how it is regulated.

The work was funded by the National Institutes of Health, Doris Duke Charitable Foundation, Pfizer Aspire Award, and A. Alfred Taubman Medical Research Institute - Kenneth and Frances Eisenberg Emerging Scholar Award.

Liang Y, Tsoi LC, Xing X, Beamer MA, Swindell WR, Sarkar MK, Berthier CC, Stuart PE, Harms PW, Nair RP, Elder JT, Voorhees JJ, Kahlenberg JM, Gudjonsson JE A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases Nature Immunology (2016) doi:10.1038/ni.3643

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