A recent study conducted by scientists at Stanford Medicine has revealed why women are at a greater risk of developing autoimmune diseases compared to men. Autoimmune diseases occur when the immune system mistakenly attacks the body’s own tissues. It is estimated that between 24 and 50 million Americans suffer from an autoimmune disease, with women comprising as many as four out of five of those affected.
Autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and scleroderma demonstrate imbalanced female-to-male ratios. For instance, lupus has a ratio of 9:1, whereas Sjogren’s syndrome presents a ratio of 19:1. In order to understand the cause behind this disparity, researchers investigated the fundamental difference between biological female mammals and males.
Dr. Howard Chang, a professor of dermatology and genetics, as well as a Howard Hughes Medical Institute investigator, stated that as a physician, he frequently encounters patients with lupus and scleroderma, which predominantly affect women. To shed light on the issue, the team analyzed the presence of two X chromosomes in female mammals, as biological sex is determined by the presence of these chromosomes in every female cell.
While male cells possess one X chromosome and a shorter Y chromosome, female cells contain two X chromosomes. Having two X chromosomes poses the risk of overproduction of proteins specified by the X chromosome in each female cell. To counteract this potential problem, mammals have evolved a mechanism known as X-chromosome inactivation. During embryogenesis, cells in a female mammal decide to deactivate one of the two X chromosomes. This decision is then passed down to the progeny of these cells in the developing fetus, ensuring that the same amount of protein is produced as in male cells.
The researchers discovered that X-chromosome inactivation may lead to autoimmune disorders; however, other factors can also contribute to their occurrence, explaining why men can also develop these conditions. X-chromosome inactivation is facilitated by a molecule called Xist, which is found on all X chromosomes. However, Xist is only produced when a matched XX pair of chromosomes is present and is active on only one member of that pair.
Xist is a long noncoding RNA (lncRNA) molecule, which does not encode proteins but has other regulatory functions. When activated, Xist covers long sections of one of the female mammalian cell’s X chromosomes, effectively silencing its output. The other X chromosome remains active and produces enough RNA-encoded instructions to maintain normal cellular functioning.
However, the presence of Xist and the resulting combinations of lncRNA, proteins, and DNA can trigger an immune response, as observed by the researchers. In 2015, Dr. Chang’s team identified nearly 100 proteins that interacted with Xist or were associated with the complex formed during X-chromosome inactivation. Many of these proteins are known to be linked to autoimmune disorders.
Upon further examination, the team realized that the RNA-protein-DNA complexes created during X-chromosome inactivation could be responsible for the higher prevalence of autoimmune diseases in women compared to men. This finding provides valuable insights into the underlying causes of autoimmune disorders and potentially opens doors for improved prediction and management of these conditions.
In conclusion, the study conducted by Stanford Medicine scientists has shed light on why women are more susceptible to autoimmune diseases. The research highlights the role of X-chromosome inactivation and the resulting interactions between Xist, lncRNA, proteins, and DNA, which may contribute to the higher prevalence of autoimmune disorders in women. Understanding these mechanisms can potentially lead to advancements in the diagnosis and treatment of autoimmune diseases.
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