Why Autoimmune Issues Plague Women
I’ve long wondered why women (particularly women of color—more about that in a bit) suffer autoimmune diseases at such high rates.
Autoimmune diseases occur when a person’s immune system is hyper-aroused, causing it to attack and damage the body’s own tissues.
There are more than 100 known autoimmune diseases; among the most common ae lupus, rheumatoid arthritis, Sjogren’s syndrome, inflammatory bowel disease (IBD), Grave’s disease, psoriasis, vasculitis, type 1 diabetes, Hashimoto’s thyroiditis, scleroderma, and multiple sclerosis.
Women account for approximately 80 percent of all cases of autoimmune diseases. In some cases, the discrepancy is even larger. In Sjogren’s syndrome, for example, women outnumber men by a factor of 16:1. In Hashimoto’s thyroiditis, it’s 9:1.
A note: Researchers in the fields and studies I cite here use the terms “women” and “female” to indicate humans with two X chromosomes and no Y chromosome. These terms are insufficient: The XX chromosomal makeup is not the only other “variation” of the XY type (we have XX, XYY, and XXX, for example). Moreover, chromosomal composition often differs from gender identity. For these reasons, I’ll most often use the term “people with at least two X chromosomes” in this article.
The striking disparity in autoimmune disease cannot be accounted for by hormonal differences alone.
In fact, a compelling study from October of 2023 on gender nonconforming people found that the risk of developing autoimmune disease in trans women who use gender-affirming hormones roughly equaled the risk of cisgender men. In contrast, trans men had a risk similar to that of cis women. This indicates that gender-affirming hormone therapy—and likely, female hormones in general—does not play a significant role in the development of autoimmune diseases.
Why, then, do people with at least two X chromosomes develop autoimmune disease at a whopping four times the rate of people with XY chromosomes?
The answer is complex. While I am decidedly not a geneticist, I’d like to share the broad strokes of an answer. And in the process, I’ll fill in what to my mind the research may not address adequately.
A Tiny Primer on Genetics
Researchers had long suspected that flawed regulation of genes on the X chromosome might drive the sex disparity in autoimmune diseases.
The X chromosome includes over 1,000 genes essential to cell viability and development.
However, people with two copies of the X chromosome (XX or XXY chromosomal makeup) have double the number of X-linked genes. This can spell trouble in terms of mutations. (This is even more true of the XXX chromosomal type.)
Nature has an answer for this dilemma. To address the excess genes, mammals with two X chromosomes silence one of the two X’s; this occurs in a process called X chromosome inactivation.
Ribonucleic Acid (RNA) plays a key part in the inactivation process. Two non-coding and complementary RNAs, called XIST and TSIX, manage the inactivation process. And the latest research homes in on XIST (pronounced “exist”). Picture long strands of XIST snaking around the extra X chromosome, attracting proteins that silence the genes inside.
This process renders the number of X-linked genes equal to that of humans with XY cells.
Yet sometimes, the XIST coating attracts the wrong kind of protein.
Rogue Antibodies Ignite Autoimmune Disease
Recently, a large collaborative of scientists joined forces to explore the mystery of the autoimmune disease inequity.
They came from a number of institutions and disciplines, including the Stanford School of Medicine, Stanford University, the Royal Institute of Technology in Sweden, Johns Hopkins School of Medicine, the Institute of Molecular Health Sciences in Zurich, and the Division of Immunology and Rheumatology at Stanford.
One of the lead researchers, Dr. Howard Chang of Stanford, observed almost a decade ago that many of the proteins that engage with XIST happen to be the targets of inflammatory immune molecules called autoantibodies.
Natural autoantibodies can provide a first line of defense against infections and contribute to the ecological balance of the immune system. But in many autoimmune disorders, some autoantibodies can injure tissues.
The latest study spearheaded by Dr. Chang, published in February of 2024, unveiled a new explanation for the autoimmune disparity.
The molecular coating typically found on half of women’s X chromosomes (but not usually in Y ones), the one called XIST, may ignite debilitating autoimmune responses.
As it turns out, the presence of these autoantibodies can precede the onset of disease, making it possible to use their presence to diagnose disease before it manifests.
Importantly, these same autoantibodies were also present in blood samples from people with lupus, scleroderma, and dermatomyositis (another autoimmune disorder.
And a study in late 2023 found that in women with lupus, XIST levels were elevated in white blood cells compared with controls, that they correlated with disease activity, and were higher in vesicles released from dying cells.
And yet, another factor kept coming to me as I reviewed the dense trove of genetic research on X chromosome inactivation: the social determinants of disease.
The Social Antecedents of Autoimmune Disease
We can’t separate out gene activity from social context. In fact, RNA is thought to be a primary factor in epigenetic trauma.
And let’s consider social location. Many doctors and researchers call lupus “the mother of all autoimmune diseases.”
Lupus is far more common in African American, African Caribbean, Latine, Asian American, Native (including Alaska Native and Pacific Islander women, who comprise a staggering 76 percent of those who have the disease. Furthermore, racial and ethnic minorities in the U.S. have dramatically worse outcomes with lupus than do their white counterparts.
Social determinants of health play a key role in the higher incidence of lupus in BIWOC.
Researchers already acknowledge that social factors have a significant impact on disease development. These factors include:
systemic racism
racial discrimination
trauma
violence
housing instability
poverty
health insurance disparities
reduced access to specialists
The social stress of racism and inequity impact both the immune and nervous systems. (The two are now referred to more often as the “neuroimmune system.”)
Paula S. Ramos, Ph.D. and Diane Kamen, M.D. collaborate to study not just the genetic but the social and epigenetic factors in lupus. They are collecting not only genetic data from blood samples but sociodemographic data, including information on experiences of racial discrimination and social support. And they are doing so with the participation of, communication with, and input from the people they study. More participatory interventions like this are sorely needed.
PTSD and Immune-Related Disease
I’d like to take a moment to double-click on the connection between trauma and autoimmune diseases.
People with PTSD often have elevated levels of inflammatory molecules such as c-reative protein, interleukin-6, and tumor necrosis factor-a. And PTSD often co-occurs with autoimmune disorders and cardiometabolic disorders. And factors such as lifetime burden of trauma, biological sex (there we go again with the X chromosome-related impact!), genetic background, metabolic conditions, epigenetic trauma, likely contribute to inflammation in PTSD.
A study conducted in 2020 explored the link between PTSD and autoimmune diseases in 120,572 active military personnel in the United States. They included lupus, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. The findings: People with PTSD had a 58 percent risk of the above autoimmune diseases than people with no PTSD history.
In reading the above study, alarm bells went off in my mind. After a quick Google search, I realized that, just as I’d thought, the 58 percent risk of autoimmune diseases in people with PTSD is likely much higher.
The study focused on active-duty U.S. military personnel. But in 2020, when the study took place, women made up only 17.2 percent of the active-duty force. So we might imagine that the link between PTSD and autoimmune disease is considerably north of 58%.
Another driver of PTSD is sexual violence, which is prevalent worldwide and, particularly among women, not showing signs of slowing.
We can acknowledge with little argument that patriarchy, white supremacy, and capitalism play pivotal roles in the high rates of autoimmune disease in women, particularly women of color.
And in my opinion, until we tackle these systemic forms of violence, we will be treating autoimmune disease in women without seeking to prevent the causes and conditions that help create it.
Sources:
Women account for approximately 80 percent of all cases of autoimmune diseases: Moyer, M. W. (2021, September 1). Why Nearly 80 Percent of Autoimmune Sufferers Are Female. Scientific American. https://www.scientificamerican.com/article/why-nearly-80-percent-of-autoimmune-sufferers-are-female/. See also: Fairweather, D., & Rose, N. R. (2004). Women and autoimmune diseases. Emerging infectious diseases, 10(11), 2005–2011. https://doi.org/10.3201/eid1011.040367.
In Sjogren’s syndrome, for example, women outnumber men by a factor of 16:1: Natri, H., Garcia, A. R., Buetow, K. H., Trumble, B. C., & Wilson, M. A. (2019). The Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases. Trends in genetics : TIG, 35(7), 478–488. https://doi.org/10.1016/j.tig.2019.04.008
In fact, a compelling study from October of 2023 on gender nonconforming people: Wiepjes, C., & Heijer, M. D. (2023). SAT416 The Incidence Of Autoimmune Disease In Transgender People After Initiation Of Gender-Affirming Hormone Therapy. Journal of the Endocrine Society, 7(Supplement_1), bvad114.2087. https://doi.org/10.1210/jendso/bvad114.2087
Ribonucleic Acid (RNA) plays a key part in the inactivation process: Two non-coding and X Chromosome Inactivation | Learn Science at Scitable. (n.d.). Retrieved April 9, 2024, from http://www.nature.com/scitable/topicpage/x-chromosome-x-inactivation-323
One of the lead researchers, Dr. Howard Chang of Stanford, observed almost a decade ago that many of the proteins that engage with XIST: Lu, Z., Carter, A. C., & Chang, H. Y. (2017). Mechanistic insights in X-chromosome inactivation. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 372(1733), 20160356. https://doi.org/10.1098/rstb.2016.0356
The latest study spearheaded by Dr. Chang, published in February of 2024, the unveiled: Dou, D. R., Zhao, Y., Belk, J. A., Zhao, Y., Casey, K. M., Chen, D. C., Li, R., Yu, B., Srinivasan, S., Abe, B. T., Kraft, K., Hellström, C., Sjöberg, R., Chang, S., Feng, A., Goldman, D. W., Shah, A. A., Petri, M., Chung, L. S., … Chang, H. Y. (2024). Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell, 187(3), 733-749.e16. https://doi.org/10.1016/j.cell.2023.12.037
Importantly, these same autoantibodies were also present in blood samples: Dolgin, E. (2024). Why autoimmune disease is more common in women: X chromosome holds clues. Nature, 626(7999), 466–466. https://doi.org/10.1038/d41586-024-00267-6
And a study in late 2023 found that in women with lupus: Crawford, J. D., Wang, H., Trejo-Zambrano, D., Cimbro, R., Talbot, C. C., Jr, Thomas, M. A., Curran, A. M., Girgis, A. A., Schroeder, J. T., Fava, A., Goldman, D. W., Petri, M., Rosen, A., Antiochos, B., & Darrah, E. (2023). The XIST lncRNA is a sex-specific reservoir of TLR7 ligands in SLE. JCI insight, 8(20), e169344. https://doi.org/10.1172/jci.insight.169344
Lupus is far more common in African American, African Caribbean, Latine: Starkman, E. (n.d.). Lupus Epidemiology: Sex, Race, and Ethnicity. WebMD. Retrieved April 10, 2024, from https://www.webmd.com/lupus/lupus-epidemiology-sex-race-ethnicity
Paula S. Ramos, Ph.D. and Diane Kamen, M.D. collaborate to study not just the genetic but the social and epigenetic: Starkman, E. (n.d.). Lupus Epidemiology: Sex, Race, and Ethnicity. WebMD. Retrieved April 10, 2024, from https://www.webmd.com/lupus/lupus-epidemiology-sex-race-ethnicity
People with PTSD often have elevated levels of inflammatory molecules such as: Katrinli, S., Oliveira, N. C. S., Felger, J. C., Michopoulos, V., & Smith, A. K. (2022). The role of the immune system in posttraumatic stress disorder. Translational Psychiatry, 12(1), 1–14. https://doi.org/10.1038/s41398-022-02094-7
But in 2020, when the study took place, women made up only 17.2 percent of the active-duty: Department of Defense Releases Annual Demographics Report—Upward Trend in Number of Wome. (n.d.). U.S. Department of Defense. Retrieved April 10, 2024, from https://www.defense.gov/News/Releases/Release/Article/3246268/department-of-defense-releases-annual-demographics-report-upward-trend-in-numbe/https%3A%2F%2Fwww.defense.gov%2FNews%2FReleases%2FRelease%2FArticle%2F3246268%2Fdepartment-of-defense-releases-annual-demographics-report-upward-trend-in-numbe%2F
Another driver of PTSD is sexual violence, which is prevalent worldwide and, particularly among women: Borumandnia, N., Khadembashi, N., Tabatabaei, M., & Alavi Majd, H. (2020). The prevalence rate of sexual violence worldwide: A trend analysis. BMC Public Health, 20(1), 1835. https://doi.org/10.1186/s12889-020-09926-5