Chapter 1: Evolutionary Insights into Autoimmune Diseases

Approximately 65 million years ago, shortly after the age of dinosaurs, a small creature emerged in the evolutionary timeline. Often described as a "scampering animal," this early mammal likely resembled a particularly fierce rat and possessed a placenta—an organ that embeds deeply in the maternal body to nourish a developing fetus during gestation. This rodent-like ancestor gave rise to all placental mammals, including humans, and may hold the key to understanding why women are disproportionately affected by autoimmune diseases.

Autoimmune disorders occur when an individual's immune system mistakenly attacks its own body. In the U.S., a staggering 80% of those diagnosed with autoimmune diseases are women. For instance, women are 16 times more prone to Sjögren’s syndrome, a condition targeting tear and saliva-producing glands, and nine times more likely to develop Hashimoto’s thyroiditis, which impacts the thyroid gland. Notably, high-profile cases like Venus Williams’ withdrawal from the 2011 U.S. Open due to Sjögren’s and Selena Gomez's kidney transplant stemming from lupus underscore the severity of these diseases, which are significantly more common in females.

Recent research suggests that the placenta could be a contributing factor to this gender disparity. In a study published in Trends in Genetics, evolutionary biologist Melissa Wilson and her colleagues proposed the "pregnancy-compensation hypothesis." This theory posits that women’s immune systems are in a perpetual state of adjustment due to the evolutionary pressures of pregnancy, even when not pregnant.

The crux of the theory is as follows: Women, like all placental mammals, have evolved to be pregnant for a considerable portion of their lives. Historically, before the development of birth control, many women bore between eight to twelve children. While this may sound taxing, women's physiology has adapted to manage such demands. During pregnancy, the placenta emits signals that modulate the immune response, preventing the mother’s body from rejecting the placenta and fetus. This adaptation often results in a temporary dampening of the immune system.

However, in contemporary society, where women typically have fewer than two children on average, this evolutionary balancing act becomes problematic. Without the regular immune modulation that occurs during pregnancy, Wilson suggests that the immune system may become overly aggressive. It can begin to misidentify harmless substances as threats, resulting in autoimmune diseases.

Wilson likens this to an analogy of pulling on a heavy object. If the object suddenly disappears, the sudden absence can lead to chaos. For millennia, women’s immune systems have anticipated the presence of a placenta. With fewer pregnancies today, the immune system may overreact, leading to increased susceptibility to autoimmune conditions.

This hypothesis is not the first to attempt to explain the gender disparity in autoimmune diseases. Other theories have focused on specific proteins or the genetic differences between the sexes, such as women possessing two X chromosomes. Wilson’s theory, however, offers a comprehensive framework that integrates these previous ideas. She asserts that while each theory holds merit, her hypothesis provides a cohesive evolutionary context.

Experts in the field have expressed cautious optimism about the implications of Wilson's theory. Nikolaos Patsopoulos, a neurology professor, highlights that no single theory can explain all autoimmune diseases, yet Wilson's perspective aligns well with existing knowledge. Similarly, Johann E. Gudjonsson from the University of Michigan found that women have higher levels of a molecular switch called VGLL3 in their skin, which may enhance immune responses. This suggests that while VGLL3 could explain the heightened immune activity, the pregnancy-compensation hypothesis may elucidate the underlying reasons for this response.

Despite the excitement surrounding Wilson's theory, some skeptics, like David Hafler from Yale, emphasize the need for empirical validation. Theories are intriguing, but they require rigorous testing and data to support their claims.

Opportunities for research abound, including investigating whether a woman's number of pregnancies correlates with her autoimmune disease risk. If Wilson's hypothesis is accurate, one would expect women with more pregnancies to have a reduced risk of such conditions. Another avenue could involve comparing the immune functions of wild mammals versus those in controlled environments, where factors like birth control come into play.

While some may misinterpret Wilson's findings as a recommendation for constant pregnancy, it is crucial to recognize that pregnancy carries significant health risks. Furthermore, women's immune systems may offer protective benefits in other areas, such as a lower incidence of certain cancers.

Ultimately, Wilson aims to identify the specific immune responses associated with the placenta, potentially leading to targeted vaccines or treatments for autoimmune diseases. She expresses her enthusiasm for the future: “I’ve never been more excited about an idea than I am about this,” she states. “This is the first time that I can see my work having a direct impact in the next 10 years on human health.”

Chapter 2: Understanding Autoimmune Disparities in Women

This video delves into the reasons behind the higher prevalence of autoimmune diseases in women, offering insights from experts in the field.

In this discussion, researchers explore why women experience a greater number of autoimmune issues compared to men, shedding light on underlying biological factors.