One of the great mysteries of medicine is this: Why are autoimmune diseases so much more prevalent in women than in men? In fact, women are nine-times more likely than men to develop lupus. New evidence, published yesterday in JCI Insight, points to a key role for a molecular switch in the skin 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, using mice, the same researchers have discovered that too much VGLL3 in skin cells pushes the immune system into overdrive, leading to an autoimmune response. Surprisingly, this response extends beyond the skin, attacking internal organs too.
“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 senior author Johann Gudjonsson. “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.”
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 became scaly and raw. Immune cells abounded, filling the skin and lymph nodes. The mice also produced 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. They also don’t know what triggers might set off extra VGLL3 activity. But they do know that in men with lupus, the same VGLL3 pathway seen in women with lupus is activated.
Image: Stark differences in the presence of autoimmune antibodies and immune factors in the blood (top) and kidneys (bottom) of mice that produced excess VGLL3 (left column) compared with healthy mice (right column). Image courtesy of University of Michigan.