Why Women Get More Autoimmune Diseases than Men (it's not what you think)

What Causes Autoimmune Disorders?

Autoimmunity occurs when the immune cells of the body, whose job it is to attack invaders such as viruses and bacteria, damage the body’s own tissues instead. Multiple sclerosis, rheumatoid arthritis, Hashimoto’s thyroiditis and lupus are examples of common autoimmune diseases. The specific symptoms experienced depend on which human molecule is the target of the immune system. Virtually any cell type or tissue can be the target of rogue immune cells. There are over 100 different autoimmune diseases.

What would cause the immune system to turn on itself? It’s thought to be due to something called “molecular mimicry.” This occurs when toxins or pathogens entering the body look so similar to human molecules that the immune system gets confused and attacks the human molecules by mistake. Mistakes also occur when human molecules are damaged and look different than usual. In autoimmune diseases, the body’s tissues become collateral damage in our immune system’s efforts to keep us safe.

Are All Autoimmune Diseases More Common in Women?

YES! Gender is a huge risk for autoimmunity. All autoimmune diseases are much more common in women than in men. Why this is the case has been puzzling medical researchers for decades. Those in the chronic complex disease community are particularly interested in this puzzle because all chronic complex diseases—such as myalgic encephalomyelitis (ME), fibromyalgia (FM), sensitivities of all kinds, chronic pain, and long COVID—are more common in women.

Why Are Chronic Complex Diseases More Common in Women?

Many people assume that myalgic encephalomyelitis and fibromyalgia are autoimmune in nature because these conditions mostly affect women, similar to autoimmune diseases. Several small studies in ME and FM have reported elevated levels of autoantibodies, but no studies have been conducted in large or diverse enough populations to prove that autoimmunity is at the core of these chronic complex conditions.

The answer to the puzzle of why more women than men get autoimmune diseases has just been discovered. Maybe this discovery will also shed some light on the triggers and causes of chronic complex diseases.

The authors of a recently published study explain why women are more likely than men to develop autoimmune diseases. Their results show that it is not hormonal, as many people have suggested, but is genetic. Epigenetic, actually. Epigenetics is what controls which genes are turned on and off at any moment.

All humans have 46 chromosomes in each cell, 23 from our mother and 23 from our father. Chromosomes are basically bundles of DNA, wrapped tightly so the long strands don’t get tangled. Among the 46 bundles are two chromosomes that determine our sex. Men have one X and one Y chromosome. Women have two X chromosomes.

As you can see in the image, X chromosomes are much larger than Y chromosomes. Because they’re larger, Xs produce many more proteins. To avoid producing too many critical proteins and throwing off the delicate balance of the body, one X chromosome is inactivated in females. While still at the embryo stage, each cell makes its own decision about which X chromosome to inactivate. The coloration of calico cats (all of whom are female) is a result of this random deactivation of one X chromosome in different parts of the body.

Autoimmunity Is All about Epigenetics

The body couldn’t function if all genes were turned on and were producing protein at the same time. Many proteins would work against each other. So, it’s necessary to have a way to turn genes on and off as needed for the body to function. This is the role of epigenetics—molecules that mark which genes to turn on and which to turn off. The challenge of turning off an entire X chromosome is a big one and requires a big molecule—in fact, a whole complex of molecules which have been named XIST. The XIST complex is relatively stable most of the time, but when cells die, the complex breaks down and is released outside the cell where it is spotted by the immune system.

Unfortunately, the immune system can mistake the XIST complex as foreign. Over time, the immune cells become sensitized and produce antibodies against the XIST complex. And there is often some collateral damage when antibodies are produced. Since only women have the XIST complex, women are at higher risk of collateral damage

 How Did the Researchers Find the Smoking Gun (XIST)?

The researchers genetically modified male mice by adding the Xist gene to their DNA. The genetically modified male mice expressed the XIST complex just like female mice usually do. Then the mice were given an injection that typically triggers a lupus-like autoimmune reaction, and sure enough, these male mice developed autoantibodies at the same rate as female mice.  This proved that the XIST complex was the cause of autoimmunity.

Why Did We Not Learn of This Important Finding Before now?

The researchers report that even though autoimmunity is more common in females, “for several decades, we’ve used a male cell line as the standard of reference.” Hard to believe! Luckily, times are changing, and most funding agencies now mandate that all grant holders use male and female cells, animals, and humans in their research.

The risk of autoimmunity depends on many factors, including sex, genetic risk, and environmental triggers. We can’t change our sex, but we can modify environmental triggers. Diet is a key trigger. In the sister blog to this one called How to Reduce Inflammation Through Diet, I share an eating plan called the Autoimmune Protocol (AIP) that is showing evidence of helping people with autoimmunity decrease inflammation and symptoms.

 Join my live online sessions called Live! with Dr. Stein.  Held every two weeks, these sessions provide some new information and then I open up the session to questions from the attendees. I will also be featuring many guest experts on a variety of topics related to your health.

References

Dou, D. R., Zhao, Y., Belk, J. A., Zhao, Y., Casey, K. M., Chen, D. C., . . . Chang, H. Y. (2024). Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell, 187(3), 733-749.e716. doi:10.1016/j.cell.2023.12.037