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 far more women to develop autoimmune diseases such as lupus?
In a new study, researchers found that part of the answer may lie in the skin.
They found a key role for a molecular switch called VGLL3. women have more VGLL3 in their skin cells than men do.
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 research was conducted by a team of University of Michigan scientists
In the paper, the team describes how VGLL3 appears to set off a series of events in the skin that trigger the immune system to come running — even when there’s nothing to defend against.
According to them, 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.
In this study, the team found that overexpression of VGLL3 in the skin 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.
The expression of many of the same genes is altered in autoimmune diseases like lupus.
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.
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, which affects 1.5 million Americans, come with unwanted side effects from steroids, including increased infection risk and cancer.
The team hopes that finding the key factors downstream of VGLL3 may identify targets for new, and potentially safer, therapies that could benefit patients of both sexes.
The lead author of the study is Johann Gudjonsson, M.D., Ph.D.
The study is published in JCI Insight.
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