An overlooked sex bias: Women disproportionately suffer from autoimmune diseases

When you hear sex bias, what initially comes to mind?

In society, we often associate sex bias with the unequal treatment of an individual or group of individuals based on their sex. Historically, females have been negatively impacted by the effects of sex bias, facing discrimination, underrepresentation and inequality within different areas of society, particularly within the workforce.

Unfortunately, women in STEM are not immune to the negative effects of sex bias. A 2019 article published by Charlesworth and Banaji in the Journal of Neuroscience highlighted three major areas that women in STEM deal with sex bias: representation, compensation and recognition.

As if it wasn’t already difficult for women in STEM to navigate and overcome these extrinsic biases, women face an additional bias that is internal and often overlooked: disease bias.

Sex bias in the context of disease is when an individual’s biological sex puts them at an increased risk of developing a particular disease. Sex differences have been shown to play a role in many well-known diseases including Alzheimer’s, cardiovascular and mental health diseases. However, one of the most striking examples of sex bias in disease is seen in autoimmune diseases.

The normal function of the body’s immune system is to provide a defense from infection by attacking foreign agents that enter the body. However, in autoimmune diseases the body’s immune system shifts into overdrive and begins attacking the body’s own cells which can lead to severe, irreversible damage.

"Increasing awareness that women in STEM not only face extrinsic, but also intrinsic, biases may help to cultivate a greater appreciation for the challenges that women have to overcome to allow women to have a greater opportunity for success within STEM."

-- Nadia St. Thomas

Over 100 autoimmune diseases have been identified including type-1 diabetes, celiac disease, multiple sclerosis and lupus. Researchers continue to strive for a better understanding of what exactly causes individuals to develop these diseases. Interestingly, biological sex appears to be a major contributing factor, with 80% of autoimmune diseases affecting females according to the American Autoimmune Association.

What exactly makes females so much more susceptible to developing autoimmune diseases?

To answer this question, scientists have investigated two biological factors contributing to sex: DNA and hormones.

Within a cell, DNA is the key factor that distinguishes males and females. Males possess an X chromosome inherited from their mother and a Y chromosome inherited from their father, while females possess two X chromosomes, one copy inherited from each parent. Under normal biological conditions, the second X chromosome in females is usually inactivated to prevent an excess production of proteins encoded by the DNA found on that chromosome.

Interestingly, researchers have found that defective inactivation of the second X chromosome in females can contribute to the development of autoimmunity through the excess production of proteins involved in the body’s immune response. Further evidence supporting the role of X chromosome “dosing” in autoimmunity is that men who have an extra X chromosome (XXY), a condition known as Kleinfelter syndrome, are as likely to develop an autoimmune disorder as females.

While this finding certainly provides valuable knowledge about the genetic mechanisms that may contribute to the female sex bias in autoimmunity, it only explains one piece of the puzzle. The onset and severity of autoimmune diseases appears to be linked with age and reproductive state, which cannot be explained by only looking at chromosomal differences between males and females.

On a larger biological scale, another factor that distinguishes males and females is the composition of their hormones. Hormones are molecules produced by the body that regulate a wide variety of processes involved in growth and development, metabolism and reproduction. Sex hormones, such as estrogen, testosterone and progesterone, are present at different levels in males and females; males typically have higher levels of testosterone while females typically have higher levels of estrogen.

Researchers have found that these sex hormones play unique roles in the body’s immune response. They can bind to proteins found on the surface of immune cells and trigger a series of reactions that alter the function of these cells.

Curiously, progesterone and testosterone act mainly to suppress the immune response and have been shown to provide protection against the development of autoimmune disorders in laboratory mouse models. On the other hand, the effects of estrogen on the immune response were found to be more complex, with evidence demonstrating activating or suppressive roles depending on the immune cell type and amount of estrogen. Despite its ambiguous effect on the immune response, estrogen’s role in modulating autoimmunity remains an area of ongoing research.

Based on these numerous studies, it is clear that both DNA and hormones are important biological factors that influence the body’s immune response and contribute to the female sex bias in the development of autoimmunity. However, autoimmune diseases are complex and it is unlikely that a single factor is responsible for the inherent female sex bias.

While much remains to be discovered about how autoimmune diseases develop and why females seem to be at such a higher risk of developing them, recognizing the inherent sex bias in autoimmunity has opened a door for researchers and clinicians to better understand and treat these diseases.

Increasing awareness that women in STEM not only face extrinsic, but also intrinsic, biases may help to cultivate a greater appreciation for the challenges that women have to overcome as well as invigorate systemic changes that aim to alleviate some of the extrinsic biases to allow women to have a greater opportunity for success within STEM.