Inflammation is our body's defense mechanism against phenomena it recognizes as foreign. However, as with any complicated system, an error may arise. Inflammation helps our body fight off bacteria, viruses, and other toxins.
But suppose our immune response continues after the threat has passed. In that case, it can cause damage to your healthy tissue or precipitate an autoimmune disorder that occurs when the body's immune system attacks and destroys healthy body tissue because it misinterprets it as an invader.
Women have up to four times more autoimmune disorders than men. Many explanations are proposed for this difference, including sex hormones, women's extra X chromosome, environmental factors, and differences in our gut environment. Understanding the mechanism for this difference is essential because autoimmune disorders are a leading cause of morbidity and mortality in young and middle‐aged women.
Women have higher levels of circulating antibodies than men. Women's antibody levels spike after giving birth, and this is also a time when more autoimmune disorders are diagnosed. Women produce much more estrogen than men, and estrogen increases antibody production, while androgens (like testosterone) decrease it.
The exception is men who have a condition called Klinefelter's syndrome. Men born with this condition have an extra copy of the X chromosome, and they, too, have higher levels of antibodies. In addition, their prevalence for autoimmune disorders is like that of women.
Researchers at the Mayo Clinic and the University of Alabama published an article investigating this question from an evolutionary perspective. They wondered why nature would preserve excess antibody production in women during the prime child-bearing years and hypothesized that the answer is related to infections.
Historically, infections are a leading cause of death for infants and adults. Even in the modern world, almost 70% of infant deaths are attributed to infections. So, from an evolutionary perspective, women having higher antibodies means they are more likely to fight off infections, and if breastfed, their infants have the same advantage.
Women have two X chromosomes, while men are XY. The X chromosome contains more genetic material than the Y and carries more immune-related genes. Because of this, the X chromosome has a greater possibility of gene-related mutations.
A study at the University of California, Los Angeles (UCLA) discovered that a gene located on the X chromosome might help to explain why women are more prone to develop multiple sclerosis (MS) than men. They found a gene called Kdm6a that is more frequently expressed in women's immune cells. When scientists conducted an animal study using female mice without the Kdm6a gene bred to mimic a disease like MS, the animals experienced reduced inflammation and less damage to their spinal cords.
A Stanford University study published earlier this month supports the theory behind women's extra X chromosome as the reason for women's increased risk of autoimmune disorders. They reported on a molecule called Xist found on X chromosomes, which is only transcribed into RNA proteins when two XX chromosomes are present. The job of this molecule is to shut down the extra X chromosome in a process called X-chromosome inactivation.
The study's lead author, Howard Chang, found that sometimes Xist can generate odd RNA combinations that bind to other proteins, creating complexes that can trigger a robust immune response. Chang learned that some proteins associated with Xist are linked to autoimmune disorders.
To eliminate the sex difference, his group studied male mice genetically altered with an Xist protein and bred for susceptibility to autoimmune disorders. Once the researchers chemically activated the Xist complex in those animals, they developed symptoms like human lupus, an autoimmune disorder. When the researchers stimulated the Xist molecule in male mice bred to be resistant to autoimmunity, they did not have the same result. This supports the evidence in humans. Women are more susceptible to autoimmune disorders, but not every woman develops one.
It means that genetics are but one element that, in combination with others, can cause an autoimmune disorder. Like most medical conditions, the causes of autoimmune disease are multifactorial.
In addition to genetics, other factors shown to contribute to this disease class are environmental such as diet, smoking, exercise, or lack thereof, stress, poor sleep, pollutants, infections such as COVID-19, and increased alcohol use. There are, however, ways to minimize your risk of developing one of these disorders.
The bottom line is that if you are born a genetic female, you are more likely than your male counterpart to develop an autoimmune disorder. However, genes are not the sole cause of this class of disease. Several modifiable environmental factors can be practiced to decrease your overall risk.
References
Bertagnolli, Monica. “Study Offers New Clues to Why Most People with Autoimmune Diseases Are Women.” NIH Directors Blog, National Institutes of Health, 15 Feb. 2024.
Dolgin, Elie. “Why Autoimmune Disease Is More Common in Women: X Chromosome Holds Clues.” Nature, no. 7999, Springer Science and Business Media LLC, Feb. 2024, pp. 466–466.
Itoh, Yuichiro, et al. “The X-Linked Histone Demethylase Kdm6a in CD4+ T Lymphocytes Modulates Autoimmunity.” Journal of Clinical Investigation, no. 9, American Society for Clinical Investigation, Aug. 2019, pp. 3852–63.
Jiang, Xia, and Lars Alfredsson. “Modifiable Environmental Exposure and Risk of Rheumatoid Arthritis—Current Evidence from Genetic Studies.” Arthritis Res Ther, June 2020,
Kronzer, Vanessa L., et al. “Why Women Have More Autoimmune Diseases than Men: An Evolutionary Perspective.” Evolutionary Applications, no. 3, Wiley, Dec. 2020, pp. 629–33.
Levy, Brandon. “Exercise Energizes Patients With Autoimmune Disease.” NIH Intramural Research Program, Our Research Changes Lives, USA.gov, 7 Feb. 2023.
Sciarra, Francesca, et al. “Gender-Specific Impact of Sex Hormones on the Immune System.” International Journal of Molecular Sciences, no. 7, MDPI AG, Mar. 2023.
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