Study Explores Cause for Higher Autoimmune Disease Prevalence Among Women

A molecular switch in the skin cells may cause increased susceptibility to autoimmunity in women.

Women are 4 times more likely to develop autoimmune disease than men. In systemic lupus erythematosus (SLE), the prevalence of the disease is 9 times higher among women; however, the cause of this disparity is largely unknown, a recent study indicates.

The study, published in JCI Insight, examined the potential mechanisms promoting increased likelihood of autoimmunity in women as opposed to men. The study pointed to a skin-targeted overexpression of the female-biased transcription cofactor vestigial like family member 3 (VGLL3) as a potential contributor to autoimmunity. Previous research has indicated that women have more VGLL3 in their skin cells than men.

According to the study, the researchers found that in mice, having too much VGLL3 in skin cells promoted an autoimmune response that extended beyond the skin. In the mouse model, overexpression of VGLL3 drove an autoimmunity-prone transcriptional signature similar to that observed in female skin, causing inflammation and activation of type I IFN signaling that mimics cutaneous lupus, according to the researchers.

Additionally, the researchers noted that extra VGLL3 in the skin cells appeared to change expression levels of a number of genes important to the immune system, including many of the same genes altered in autoimmune diseases. In mice with excess VGLL3, their skin became scaly and raw and they produced antibodies against their own tissues.

“VGLL3 appears to regulate immune response genes that have been implicated as important to autoimmune diseases that are more common in women, but that don’t appear to be regulated by sex hormones,” lead study author Johann Gudjonsson, MD, PhD, professor of dermatology at the University of Michigan Medical School, said in a press release. “Now, we have shown that overexpression of VGLL3 in the skin of transgenic mice is by itself sufficient to drive a phenotype that has striking similarities to systemic lupus erythematosus, including skin rash, and kidney injury.”

The researchers concluded that the data support the assertion that overexpression of VGLL3 in female skin primes women for autoimmunity. However, they do not know what triggers may set off overexpression of VGLL3 activity.

Current treatments for lupus carry a serious risk of infection and malignancy that can contribute to morbidity and mortality. Further research can help identify targets for new and potentially safer therapies, according to the study.

“As VGLL3 appears to be not only constitutively active in women but also turned on in men with SLE, targeting VGLL3 may prove beneficial in patients of both sexes,” the researchers wrote.

Reference

Billi AC, Gharaee-Kermani M, Fullmer J, et al. The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity. JCI Insight. 2019. Doi: 10.1172/jci.insight.127291