One of the great mysteries of medicine and also one that affects the lives of millions of people is why the immune systems of women gang up on them far more than men's do which causes nine times more women to develop autoimmune diseases such as lupus.
It turns out that part of the answer may lie in the skin!
New discovery points to a vital role for a molecular switch called VGLL3. About three years ago, a team of researchers at the University of Michigan showed that women have more VGLL3 in their skin cells than men.
The team is now working in mice, and they have found out that having too much VGLL3 in skin cells pushes the immune system into overdrive and it can lead to a 'self-attacking' autoimmune response. It is also surprising enough that this response extends beyond the skin; it also attacks internal organs as well.
The researchers published their study in JCI Insight where they 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 against which to defend.
A professor of dermatology at the U-M Medical School and the leader of the research team, Johann Gudjonsson, M.D., Ph.D., said that VGLL3 appears to regulate immune response genes that have been implicated as essential to autoimmune diseases that are more common in women, but that doesn't seem to be controlled by sex hormones.
Gudjonsson explained further that since they have now 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.
The researchers discovered that extra VGLL3 in skin cells changed expression levels of several genes relevant to the immune system. Expression of many of the same genes is altered in autoimmune diseases like lupus.
In the mice, the gene expression changes caused by excess VGLL3 wreaked havoc. Their skin becomes scaly and raw, immune cells abound, filling the skin and lymph nodes. The mice also produce antibodies against their tissues, including the same antibodies that can destroy the kidneys of lupus patients.
To begin with, it is not yet clear to the researchers what causes female skin cells to have more VGLL3. It is likely 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.
Also, what is not clear to them is what triggers might set off extra VGLL3 activity. But the researchers know that in men with lupus, the same VGLL3 pathway seen in women with lupus is activated.