Study finds why women get autoimmune diseases far more often than men

A research conducted on mice discovered that having too much molecular switch called VGLL3, which regulates immune response genes in skin cells, lead to autoimmune diseases.

The study published in 'JCI Insight' pointed a key role for VGLL3. Three years ago, a team of University of Michigan researchers showed that women have more VGLL3 in their skin cells than men.

"VGLL3 appears to regulate immune response genes that have been implicated as important to autoimmune diseases that are more common in women, but that doesn't appear to be regulated by sex hormones," said Johann Gudjonsson, the lead author.

"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," added Gudjonsson.

Now, working in mice, researchers have 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.

The team described how VGLL3 appears to set off a series of events in the skin that trigger the immune system to come running - even when there is nothing to defend against

The researchers 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. 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. 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.

The researchers 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.

Many of the current therapies for lupus, like steroids, come with unwanted side effects, from increased infection risk to cancer. Finding the key factors downstream of VGLL3 may identify targets for new, and potentially safer, therapies that could benefit patients of both sexes.