by wayne persky
Founder and President of the Microscopic Colitis Foundation
As an online article published on the MedicalNewsToday website points out, 80% of patients who have an autoimmune disease are women (Pratt, 2024, February 1).1 The reason for this gender bias has been unexplained until recently, when researchers discovered a connection with a genetic process unique to women, that occurs because of the DNA configuration that defines the difference between mammalian males and females.
As an online article published on the MedicalNewsToday website points out, 80% of patients who have an autoimmune disease are women (Pratt, 2024, February 1).1 The reason for this gender bias has been unexplained until recently, when researchers discovered a connection with a genetic process unique to women, that occurs because of the DNA configuration that defines the difference between mammalian males and females.
As an online article published on the MedicalNewsToday website points out, 80% of patients who have an autoimmune disease are women (Pratt, 2024, February 1).1 The reason for this gender bias has been unexplained until recently, when researchers discovered a connection with a genetic process unique to women, that occurs because of the DNA configuration that defines the difference between mammalian males and females.
Women autoimmune disease patients, outnumber men 4 to 1.
As the article points out, not only human females, but every biologically female mammal has two X chromosomes, while men have one X and one Y chromosome. Although it's obviously possible to live without a Y chromosome, as females do, it's not possible to live without an X chromosome, because the X chromosome contains the coding for hundreds of genes that define the production of critical proteins that are essential for the proper operation of our body.
Sex is determined at conception.
As we're all aware, during conception, the sex of a baby is determined by the combination of X and Y sex chromosomes that it receives from the egg and the sperm. While sperm can contain either an X or a Y chromosome, the egg contains only two X chromosomes, so it can only contribute an X chromosome. Most of us are well aware that each cell in our body carries our genetic code in the form of 23 pairs of chromosomes, and the final pair of chromosomes determines biological sex. As mentioned above, men have one X and one Y chromosome, while women have two X chromosomes.
The researchers focused on that duplicate X chromosomes arrangement.
Apparently this gender bias issue that's unique to women can be blamed on that extra X chromosome in women's DNA. An online article recently published by MedPageToday describes how researchers at Stanford University were able to pinpoint the problem (Associated Press, 2024, February 1).2
What happens to that duplicate X chromosome?
Most of us are not familiar with the events surrounding that extra X chromosome that's present in the DNA of women. As the MedPageToday article points out, every female cell must switch off one of its X chromosomes, because a double copy would have a toxic effect (due to the excess production of all the redundant proteins). As an article published in the journal Nature points out, females inherit an X chromosome from each parent, whereas males inherit only a single X chromosome from their mother, and a Y chromosome from their father (Ross, et al., 2005).3
As the article states, normally, one of the two X chromosomes is randomly, and permanently inactivated in all of the cells in the bodies of females, other than egg cells This occurs in the early stages of embryonic development, leaving only one functional copy of the X chromosome in each cell of the female body(Ross, et al., 2005).
As the article states, normally, one of the two X chromosomes is randomly, and permanently inactivated in all of the cells in the bodies of females, other than egg cells This occurs in the early stages of embryonic development, leaving only one functional copy of the X chromosome in each cell of the female body(Ross, et al., 2005).
The inactivation of one of the X chromosomes is encoded in the Xist gene.
Because the Xist gene is found in all X chromosomes, every cell of both males and females contains this gene. But as the original research article, published in the prestigious journal Cell, points out, Xist long non-coding RNA (lncRNA) is expressed only in females, and it's expressed solely for the purpose of inactivating one of the two X chromosomes. (Dou, et al., 2024).4 In order to verify that the expression of the Xist gene is responsible for the autoimmune disease gender bias, the researchers developed a group of male mice that were genetically modified to express Xist. And the mice were also predisposed to the development of a condition similar to lupus that can be triggered by a chemical agent.
The researchers found that (similar to females), the modified male mice produced a Xist ribonucleoprotein (RNP) complex of numerous antigenic components that are associated with the development of autoimmune diseases, and when chemically triggered, the genetically modified mice developed a lupus-like autoimmunity at a level similar to females. The researchers noted that human patients also display significant autoantibodies to multiple components of Xist RNP.
The researchers found that (similar to females), the modified male mice produced a Xist ribonucleoprotein (RNP) complex of numerous antigenic components that are associated with the development of autoimmune diseases, and when chemically triggered, the genetically modified mice developed a lupus-like autoimmunity at a level similar to females. The researchers noted that human patients also display significant autoantibodies to multiple components of Xist RNP.
Reflecting on the research findings,
inactivation of the duplicate X chromosomes in every cell of the female body takes place in the early stages of embryonic development. But as mentioned in the MedPageToday article, the researchers point out that in order for autoimmune disease to actually develop, an environmental trigger is needed, and it's necessary for Xist RNA to leak out of a cell so that the immune system is able to detect it (Associated Press, 2024, February 1). And although it typically takes decades for an autoimmune disease to develop, interestingly, various autoimmune diseases typically show up during specific time ranges that are unique to each particular autoimmune disease (Angum, Khan, Kaler, Siddiqui, and Hussain, 2020).5 For example, the average age of onset for:
Systemic lupus erythematosus (SLE) is 15 to 55
Systemic sclerosis is 20 to 50
Rheumatoid arthritis is 30 to 60
Psoriasis is 15 to 35
Systemic lupus erythematosus (SLE) is 15 to 55
Systemic sclerosis is 20 to 50
Rheumatoid arthritis is 30 to 60
Psoriasis is 15 to 35
Why do women have two X chromosomes in the first place?
As pointed out in paragraph number four, above, while males inherit one Y chromosome from their father, and one X chromosome from their mother, females inherit an X chromosome from each parent, making the inactivation of one of the X chromosomes necessary, in order for every cell in the female body to function properly. One would hope that inactivating this duplicate X chromosome would proceed flawlessly, but alas, expression of the Xist gene RNA is associated with 81 unique binding proteins that form the RNP complex, and unfortunately, many autoantibodies tend to be associated with nuclear RNA binding proteins. Research shows that the specific associations of those autoantibodies with the targeted proteins determine the status of both the type of autoimmune disease that might develop, and the severity (if the disease develops).
It's possible that because we're living in an increasingly toxic environment as a result of accumulating industrial waste and contaminated food, water, and air, the expression of the Xist gene might result in an increased risk of the development of autoimmune disease in today's environment, but that's strictly speculation, of course, as there's no medical research available to either confirm or dispute it. The take-home message appears to be that apparently, the gender bias associated with autoimmune disease is associated with the inactivation of that duplicate X chromosome.
It's possible that because we're living in an increasingly toxic environment as a result of accumulating industrial waste and contaminated food, water, and air, the expression of the Xist gene might result in an increased risk of the development of autoimmune disease in today's environment, but that's strictly speculation, of course, as there's no medical research available to either confirm or dispute it. The take-home message appears to be that apparently, the gender bias associated with autoimmune disease is associated with the inactivation of that duplicate X chromosome.
References
1. Pratt, E. (2024, February 1). How a type of molecule may be the reason women have a higher risk of autoimmune disease. MedicalNewsToday, Retrieved from https://www.medicalnewstoday.com/articles/how-a-type-of-molecule-may-be-the-reason-women-have-a-higher-risk-of-autoimmune-disease
2. Associated Press. (2024, February 1). A Clue on Why Lupus, Other Autoimmune Diseases Strike Far More Women Than Men. MedPageToday, Retrieved from https://www.medpagetoday.com/rheumatology/lupus/108531?xid=nl_mpt_DHE_2024-02-01&eun=g443580d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%20Evening%202024-02-01&utm_term=NL_Daily_DHE_dual-gmail-definition
3. Ross, M. T., Grafham, D. V., Coffey, A. J., Scherer, S., McLay, K., Muzny, D., . . . Bentley, D. R. (2005). The DNA sequence of the human X chromosome. Nature, 434(7031), pp325–337. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665286/?_ga=2.264390607.1507444215.1706977167-906493032.1706977167
4. 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), pp733–749. E16. Retrieved from https://www.cell.com/cell/fulltext/S0092-8674(24)00002-3#%20
5. Angum. F., Khan, T., Kaler, J., Siddiqui, L., and Hussain, A. (2020). The Prevalence of Autoimmune Disorders in Women: A Narrative Review. Cureus, 12(5), e8094. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292717/
