Depiction of immune response to X chomosome inactivation (Emily Moskal/Stanford Medicine News Center)
By Mindy Sim ’27
Eighty percent of patients diagnosed with an autoimmune disease are females.1 What is the cause for this strikingly disproportionate distribution of autoimmune disease cases in females? This is the question that many scientists have set out to answer, and scientists have recently been coming back to a similar answer: the X chromosome.
Of the 23 chromosomes that make up the human genome, the 23rd pair of chromosomes are the sex chromosomes. The presence of both an X and Y chromosome in this 23rd pair result in a biological male; the presence of two X chromosomes result in a biological female. While it may seem that biological males have an element that females do not have—the Y chromosome—the Y chromosome actually carries much less genetic information than a single X chromosome.2 Thus, a male with XY sex chromosomes has roughly half of the genetic material than a female with XX sex chromosomes.
In order to match the amount of genetic material present in males, cells in a female body repress one of the X sex chromosomes through a process known as X chromosome dosage compensation or X chromosome inactivation (XCI). In mammals, including humans, X inactivation is achieved through the formation of a ribonucleoprotein called Xist (X-inactive specific transcript) which coats one of the X chromosomes, preventing the genetic material from this chromosome from being accessed. Xist works as a sort of locker for the X chromosome; by coating the chromosome, Xist blocks other molecules like DNA polymerase or transcription factors in the cell from getting access to the chromosome. Down the line, this ultimately prevents the production of proteins. Because Xist is only produced in females with two X chromosomes, Xist has been a target of study by scientists to explain the female-biased prevalence of autoimmune diseases.
Previous studies on the XCI by Xist have focused on the actual genes that are repressed by Xist. In a 2019 study, researchers found that in systemic lupus erythematosus (SLE), an autoimmune disease where nine out of every ten patients are female,1 Xist was susceptible to faulty regulation in T cells, a type of white blood cell crucial to the body’s immunity.3 Similarly, a 2021 study focused on Xist regulation in B cells (another type of white blood cell) and found that faulty regulation resulted in the production of RNA from the X chromosome that should have been repressed by Xist.4 The implication behind this faulty Xist regulation is that cells in individuals with XX sex chromosomes are producing double the amount of certain proteins compared to individuals with XY sex chromosomes.
A 2020 review assesses the implications of certain genes being produced in double doses in XX individuals with faulty Xist regulation. While the researchers note that some genes in double doses can be helpful to pregnancy, they also note five specific double dosed genes that may contribute to greater prevalence of autoimmune diseases, specifically SLE, in female patients.5
However, a study published in the peer-reviewed scientific journal Cell Press in February of 2024 shifts the focus away from genes regulated by Xist to the Xist molecule itself. Stanford Medicine scientists, alongside colleagues at partner institutions, set out to study if the presence of the Xist ribonucleoprotein may be implicated in the greater development of autoimmune diseases in XX individuals.
In order to test this hypothesis, the researchers produced a modified version of the Xist gene to introduce to male mice. This modified version of Xist gene still allowed for the production of the Xist ribonucleoprotein and its coating of the X chromosome, but prevented Xist from actually silencing the X chromosome. This ensured that in XY individuals, the one X chromosome would still function normally. Using this modified Xist gene, the researchers conducted a set of experiments comparing the male mice with the modified Xist gene and induced SLE to a set of control mice. The treatment group (male mice with Xist and induced SLE) was compared to female mice with induced SLE, male mice with no modified Xist with induced SLE, male mice with the modified Xist with no induced SLE, and male mice with no modified Xist and no induced SLE.
After creating these various cohorts of mice, the researchers ran a series of tests and analyses to assess how the presence of the Xist ribonucleoprotein impacted the mice’s autoimmunity. These tests included assessments of chromatin accessibility through ATAC-seq, determining the presence of specific RNAs using RNA-seq, tissue staining, and antibody profiling in blood samples using antigen arrays. Furthermore, results from antibody profiling from the mouse cohorts were compared to antibodies present in both autoimmune and non-autoimmune human blood samples.
The results from these tests indicate that the male mice with modified Xist and induced SLE show pathological trends similar to (but at overall lower levels than) the control female mice with induced SLE. Interestingly, this trend was only present for male mice with modified Xist with induced SLE and not for male mice with modified Xist but not with induced SLE. These results suggest that the presence of the Xist ribonucleoprotein and the presence of damaged tissue (induced in this study by SLE) are both important to autoimmunity. Additionally, the overall higher level of pathology in female mice indicates that previous studies implicating the double dosage from faulty Xist regulation may also be a factor contributing to higher female autoimmunity. Finally, antibodies found in autoimmune human blood samples were also found in the female mice and the male mice with modified Xist and induced SLE, showing that the results from this mouse model has relevance to understanding and treating human autoimmune diseases.
Therefore, this study marks an important advancement in our understanding of human autoimmune diseases, and especially the female-biased prevalence of these diseases. In a larger scale, this study also marks a shift towards advancing scientific and medical knowledge of populations who have historically been understudied. In an interview for the Stanford Medicine News Center, the study’s lead contact Howard Chang stated that the historical use of only male cell lines as the standard in biological studies has prevented the study of Xist and at large, female autoimmunity.6 Thus, this study and its predecessors studying Xist are important contributions to the scientific community not only because they advance scientific knowledge, but also because they recognize and address the gaps in research that have prevented medical advances for non-mainstream populations.
Mindy Sim ’27 is an staff writer at The Princeton Medical Review. She can be reached at ms5683@princeton.edu.
References:
- Dou, D. R. et al. (2024). Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell, 187(3), 733–749.e16. https://doi.org/10.1016/j.cell.2023.12.037
- Ercan S. (2015). Mechanisms of x chromosome dosage compensation. Journal of genomics, 3, 1–19. https://doi.org/10.7150/jgen.10404
- Syrett, C. M. et al. (2019). Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseases. JCI insight, 4(7), e126751. https://doi.org/10.1172/jci.insight.126751
- Yu, B. et al. (2021). B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells. Cell, 184(7), 1790–1803.e17. https://doi.org/10.1016/j.cell.2021.02.015
- Youness, A., Miquel, C. H., & Guéry, J. C. (2021). Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases. International journal of molecular sciences, 22(3), 1114. https://doi.org/10.3390/ijms22031114
- Goldman, B. (2024, February 1). Stanford Medicine-led study shows why women are at greater risk of autoimmune disease. Stanford Medicine News Center. https://med.stanford.edu/news/all-news/2024/02/women-autoimmune.html
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