It’s one of the great mysteries of medicine, and one that affects the lives of millions of people: Why do women’s immune systems gang up on them far more than men’s do, causing nine times more women to develop autoimmune diseases such as lupus Part of the answer, it turns out, may lie in the skin.
New evidence points to a key role for a molecular switch called VGLL3. Three years ago, a team of University of Michigan researchers showed that women have more VGLL3 in their skin cells than men. Now; working in mice, they’ve discovered that having too much VGLL3 in skin cells pushes the immune system into overdrive; leading to a “self-attacking” autoimmune response. Surprisingly; this response extends beyond the skin, attacking internal organs too.
Writing in JCI Insight; the team describes how VGLL3 appears to set off a series of events in skin that trigger the immune system to come running – even when there’s nothing to defend against. “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;” says Johann Gudjonsson, M.D., Ph.D., who led the research team and is a professor of dermatology at the U-M Medical School.
“Now, we have shown that over-expression 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.” Gudjonsson worked with co-first authors Allison Billi, M.D., Ph.D., and Mehrnaz Gharaee-Kermani, Ph.D., and colleagues from several U-M departments, to trace VGLL3’s effects.
They found that extra VGLL3 in skin cells changed expression levels of a number of genes important to the immune system. Expression of many of the same genes is altered in autoimmune diseases like lupus. The gene expression changes caused by excess VGLL3 wreaked havoc in the mice. Their skin becomes scaly and raw. Immune cells abound, filling the skin and lymph nodes.
Changed expression levels
The mice also produce antibodies against their own tissues, including the same antibodies that can destroy the kidneys of lupus patients. The researchers don’t yet know what causes female skin cells to have more VGLL3 to begin with. It may be that over evolutionary time females have developed stronger immune systems to fight off infections – but at the cost of increased risk for autoimmune disease if the body mistakes itself for an invader.