Pregnancy Compensation Hypothesis May Explain Sex-based Differences in Autoimmune Diseases, Study Says

The idea that the female immune system adapts to accommodate pregnancy could explain why biological females are more likely than males to develop lupus and other autoimmune diseases, a study suggests.

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

Females (with two X chromosomes) are more likely than males (with one X and one Y chromosome) to develop autoimmune diseases, but are less likely to get non-reproductive tumors, with the exception of thyroid cancer.

The reason for this dichotomy has long been a puzzle to scientists but they have now proposed an answer: the Pregnancy Compensation Hypothesis.

This hypothesis basically states that the female immune system has evolved in order to deal with two opposing pressures. On the one hand, the immune system needs to do its job of repelling invaders and parasites to keep the person healthy. But on the other hand, the immune system must not attack a fetus during pregnancy.

From an immunological perspective, a fetus and placenta — both of which are genetically distinct from the person they’re in — aren’t that much different from an infecting parasite. This means that the female immune system has had to evolve so that it doesn’t respond to fetuses in the same way it does to parasites, while still responding appropriately to actual parasites.

In pre-industrialized societies, this may have been particularly important because it was common for women to spend most of their reproductive years either pregnant or lactating.

“But now, in modern, industrialized societies, women are not pregnant all the time, so they don’t have a placenta pushing back against the immune system,” Melissa Wilson, PhD, a professor at Arizona State University and co-author of the study, said in a press release. “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.”

This idea isn’t dissimilar to how people infected with parasitic worms are less likely to have allergies and asthma. The concept behind the Pregnancy Compensation Hypothesis is that the immune system has evolved to deal with a particular pressure (many pregnancies over a lifetime) that no longer exists in the industrialized world, which causes the immune system to be overactive.

Mechanistically, the researchers think that this sex-based bias in disease development stem from differences in how genes are packaged on the X and Y chromosomes, as well as hormonal differences. Although still a theory, the Pregnancy Compensation Hypothesis is supported by a few lines of evidence, beyond the known gender differences in frequency of autoimmune diseases and cancer.

For example, the hormone estriol is produced almost exclusively during pregnancy, and one of its known effects is “putting the brakes” on the immune system, which supports the notion that, without pregnancy, the immune system might be overactive.

Additionally, people with Klinefelter syndrome — who are born with two X chromosomes and one Y chromosome — generally develop externally as males, but they are more likely to develop autoimmune diseases than males with one X chromosome.

On the flip side, patients with Turner syndrome — who have one X chromosome and develop as females — are more likely to develop autoimmune diseases than females with two X chromosomes. However, these diseases are common in biological males. These data support the idea that the differences in immune-related diseases are linked to genetic differences due to the presence of different sex chromosomes.

This may also explain why thyroid cancer is the only non-reproductive cancer that’s more common in females than males because the thyroid plays a critical role in hormone regulation.

For now, the Pregnancy Compensation Hypothesis proposes an answer to a question that has long confused scientists, but it may also have implications for how immune-related diseases are treated.

Heini Natri, PhD, another study co-author, said: “Going forward, 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.”