Discovery may help explain why women get autoimmune diseases far more often than men

Discovery may help explain why women get autoimmune diseases far more often than men
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). Credit: University of Michigan

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 .

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 than men.

Now, working in mice, they've discovered that having too much VGLL3 in skin cells pushes the 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 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 , including skin rash, and kidney injury."

Effects of excess VGLL3

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. 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.

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.

Lupus, which affects 1.5 million Americans, can cause debilitating symptoms, and current broad-based treatment with steroids can make patients far more vulnerable to infections and cancer.

Patients' role in future research

Their colleague and senior coauthor Michelle Kahlenberg, M.D., of the U-M Division of Rheumatology, is now recruiting patients with lupus for a study sponsored by U-M's A. Alfred Taubman Medical Research Institute that could provide answers to these questions and more.

Billi, a resident in dermatology, notes that when she speaks with patients who come to Michigan Medicine's dermatology clinics for treatment of the skin problems lupus can cause, she has to acknowledge the limits of current treatment. Even so, she says, patients are eager to take part in studies by contributing skin and DNA samples that could lead to new discoveries about their condition.

"Many patients are frustrated that they've had to try multiple therapies, and still nothing is working well," she says. "To be able to tell them that we're working on a mouse that has the same disease as them, and that we need their help, brings out their motivation and interest in research. They know that it's a long game, and they're in for it."

Explore further

'Master regulator' in genes may make women more susceptible to autoimmune diseases

More information: Allison C. Billi et al, The female-biased factor VGLL3 drives cutaneous and systemic autoimmunity, JCI Insight (2019). DOI: 10.1172/jci.insight.127291
Citation: Discovery may help explain why women get autoimmune diseases far more often than men (2019, April 19) retrieved 19 October 2019 from
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Apr 19, 2019
Maybe the converse helps explain why more boys have autism: Less VGLL3 leads to less active immune systems, which leads to less pruning of excess synapses.

Apr 19, 2019
Among other things, this can suggest that Todd Akin was right when he said that, when women are raped, their systems work together to prevent a pregnancy occurring. What could be called a form of autoimmune reaction could be responsible for this.
Which suggests that, maybe, in one way or another, women's bodies may be being insulted in many ways. Men's bodies can be being assaulted in the same way, but they work it off. Women's bodies, though, it can be said, have to try to remain as pure as possible to protect the ability to give birth. But this suggests that much of what's in the environment today, which largely if not mostly is the result of big business, may be effectively a contaminant for women that threatens successful pregnancy. Look, for example, to carrageenan.

Apr 21, 2019
Maybe the converse helps explain why more boys have autism: Less VGLL3 leads to less active immune systems, which leads to less pruning of excess synapses.

I don't know of a connection between synapse pruning and immune system, do you have any references? But even so, would a developed immune system be much active in the fairly bacterial free environment of the placenta? Above all, the neonatal immune system is undeveloped and primarily constituted bymaternal antibodies [ https://www.ncbi....4707740/ ], so the reverse of your hypothesis during early development, and the immune system identical between autistic and other children [ https://www.medic...3758.php ].

Autism is a consequence of development, and it is known [ibid] to be caused by variants of many genes (and perhaps other factors) together. Genetic and especially many-gene diseases are often more problematic in boys, since some of the genes may sit on the X chromosome.

May 01, 2019
I don't have references, I just have first-hand knowledge. My understanding is that the immune system is involved in memory formation with the specific role of pruning lower-value synapses during sleep. In autism, the synapses do not get pruned when they should, so you end up with too many and you can't distinguish what's important from what's not.

Your reference seems to be saying the immune systems are the same before 1 year of age. Autism symptoms first appear around 14 months, when the non-maternal immune system takes over. Most cases are diagnosed at age 7 or so.

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