A mismatch — between the ancestral immune function changes induced by the placenta and fewer modern-day pregnancies — may help explain the greater risk for multiple sclerosis (MS) and other autoimmune diseases in women in industrialized societies, according to a new study.

The shift toward a sedentary lifestyle may further explain these gender differences.

The research with those findings, “The Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases,” was published in the journal Trends in Genetics.

While women are substantially more susceptible to develop autoimmune diseases such as MS and lupus, men are at a higher risk of cancers such as melanoma and colon cancer. Differences in treatment effectiveness also exist, with women responding more favorably to cancer immunotherapies.

Reproductive hormones or environmental exposures alone cannot explain this distinction between genders. Differences in genes on sex chromosomes are independent of reproductive hormones, and could be key contributing factors. Yet, these sex differences remain largely unexplained.

“We are proposing a new theory called the Pregnancy Compensation Hypothesis,” Melissa Wilson, PhD, the study’s senior author, said in a press release written by Sandra Leander.

Her team at Arizona State University hypothesized that women’s ancestral immune system was shaped to facilitate their survival in the presence of the placenta, which induces anti-inflammatory changes to tolerate fetal antigens, while still allowing protection from disease-causing parasites and pathogens.

Both reproductive hormones and heritable variations in sex chromosome content mediate these differences in immune function.

Scientists also propose that reduced pregnancy rates in industrialized societies aggravate the risk of autoimmune disease. This could help explain why autoimmune diseases are more common in industrialized than non-industrialized communities. Specifically, the team believes that the immune system has evolved to respond to a given amount of challenges, including the effects of the placenta. With a lesser load, the immune system attacks “self” targets, while also responding better to cancer.

“Now, in a modern, industrialized society, women are not pregnant all the time so they don’t have a placenta pushing back against the immune system. The changes in their reproductive ecology exacerbate the increased risk of autoimmune disease because immune surveillance is heightened. At the same time, we see a reduction in some diseases, like cancer,” Wilson said.

Angela Garcia, a co-author of the study, added: “There is a mismatch between the ancestral environment humans were adapted to, and the industrialized environment many people currently live in.” Garcia also pointed to the shift to a sedentary lifestyle, one in which the “overabundance of calories available,” that may lead to excessive levels of hormones such as estrogen and progesterone.

“Maintaining such high levels of hormones may increase the chance of triggering autoimmune diseases,” Garcia said.

Looking ahead, researchers proposed that sex differences in the immune system should be taken into account when developing treatments.

“Our goal is to actually make treatments better for everyone,” said Heini Natri, PhD, the study’s lead author. “Understanding the evolutionary origin of the sex bias in these diseases can help us better understand the mechanisms and particular pieces of the immune system we can target.”

“In the study of most cancers and other diseases, and so far in the development of cancer treatments, that has not really been taken into account,” Natri said.

Ken Buetow, PhD, also a study co-author, emphasized the importance of assessing immune differences between men and women, as well as their changes over time, to help find new ways to prevent cancer and autoimmune diseases.

“We think this is more than a hypothesis,” Buetow said. “We anticipate that the sex differences in immune function will, to some extent, contribute to sex differences in all human diseases,” the team wrote.

Evaluating unique gene regulation patterns in men and women, and assessing environmental variables such as the exposure to pathogens, levels of stress and reproductive hormones, are among other important aspects looking forward. “We have to understand these areas better,” Wilson concluded.