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 Lupus and other autoimmune diseases affect many more women than men. Now there’s a clue  

why

More than 24 million Americans, and an estimated as many as 50 million, suffer from an autoimmune disease — diseases such as 

lupus, rheumatoid arthritis, multiple sclerosis, and dozens more. About four out of five patients are women a conundrum that has puzzled scientists for decades.

One theory is that the X chromosome could be the culprit. Finally, women have two X chromosomes, while men have one X and one Y chromosome. The new research, published in the journal Cell, shows that additional X is involved, but in an unexpected way.

Our DNA is carried in every cell on 23 pairs of chromosomes, including the last pair that determines biological sex. The X chromosome is packed with hundreds of genes, many more than the much smaller Y chromosome in men.

Each female cell must deactivate one of its copies of the X chromosome to avoid receiving the toxic double dose of all these genes. The so-called inactivation of the X chromosome occurs by a special type of RNA called Xist, which is pronounced: “exist”. This long stretch of RNA parks at points along a cell’s extra X chromosome, attracting proteins that bind to it in strange clusters and silencing the chromosome.

Stanford dermatologist Dr. Howard Chang was studying how Xist does its job when his lab identified nearly 100 such bound proteins. Chang acknowledged that many of these are related to skin-related autoimmune diseases: Patients may have “autoantibodies” that mistakenly attack these normal proteins.” That got us thinking: These are the well-known ones.

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What about the other proteins in Xist?” Chang said. Perhaps this molecule, found only in women, could “somehow organize proteins to activate the immune system.

” If this is true, Xist alone could not cause autoimmune diseases, otherwise all women would be affected. Scientists have long thought that it takes a combination of genetic susceptibility and an environmental trigger, such as an infection or injury, for the immune system to spiral out of control. For example, the Epstein-Barr virus is associated with multiple sclerosis. Chang’s team decided to engineer male lab mice to artificially produce Xist without silencing their single X chromosome and see what happened.

The researchers also specifically bred mice that were susceptible to a lupus-like disease that can be triggered by a chemical irritant. The mice that produced Xist formed their characteristic protein clusters and, when activated, developed lupus-like autoimmunity to a similar extent as the mice, the team said.” We believe it is important that the Xist RNA gets out of the cell to where the immune system can see it.

 Beyond the mice, the researchers also examined blood samples from 100 patients and discovered autoantibodies against Xist-associated proteins, which scientists had not previously linked to autoimmune diseases. Chang suggests one possible reason: standard autoimmunity tests were performed on male cells.