The Battle of the Sexes in Autoimmune Disease

You know the stereotype of men never asking for directions? Well, I recently learned more about the basis for this, and other traits that differ between males and females, while watching “Battle of the Sexes,” an episode of the National Geographic television series Brain Games. This show is a favorite of my two kids, thanks to its cool science facts and the clever antics of its host.

“Battle of the Sexes” got me thinking about another difference between men and women; namely, the striking female-bias of autoimmune diseases. Nearly 80 percent of people affected by autoimmune diseases are women. In fact, being female is the strongest risk factor for developing autoimmune disease, dwarfing the risk posed by known autoimmune disease risk genes. But why?

To solve this puzzle, you might think scientists would want to look for differences between men and women with an autoimmune disease. However, in patients, active disease and the effects of medications might create too much noise, hiding any real clues. The solution? Use samples from healthy people, as investigators did in a study recently published in the journal Nature Immunology.

The authors hoped to identify patterns of gene expression, or “signatures,” that differ between healthy men and women. The results were striking – even among healthy people, gene signatures involved in inflammation and autoimmunity were much more common in women than men. Furthermore, many of the female-biased genes are known risk genes for SLE and systemic sclerosis, another female-dominant autoimmune disease. These findings all suggest that healthy women have higher levels of potentially autoimmune-provoking gene signatures compared to healthy men. But again, why?

One prediction is that sex hormones control these gene signatures; however, the authors tested that idea and found no evidence to support it. By looking more broadly at other types of gene regulators, they zeroed in on a gene called VGLL3. This gene did control the expression of the female-biased, autoimmune-related signatures they had observed. And VGLL3 itself is found at higher levels in women than men. All together, their findings suggest that VGLL3 is a gene regulator that might tip the balance towards autoimmune disease in women.

More work is required to confirm the findings and to translate this knowledge into ideas for new treatments or ways to identify people at risk for developing SLE. While this study didn’t fully solve autoimmunity’s “Battle of the Sexes,” it did provide a new set of directions scientists can follow in navigating toward a solution to this puzzle.

Emily Gillespie

About the Author:

Emily Gillespie, Ph.D., is a 2014 and 2015 LFM Lupus Clinical Research Grant recipient whose studies have focused on cardiovascular disease in SLE as well as the relationship between lupus and women, particularly African-American women. She has been researching lupus for over 10 years and enjoys the challenge of trying to understand such a complicated disease. Dr. Gillespie works as a Principal Clinical Evidence Specialist in the Restorative Therapies Group at Medtronic.
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