Science and Technology Daily, Beijing, February 4 (Reporter Zhang Mengran) Why are women more likely to suffer from autoimmune diseases such as lupus erythematosus than men? A new explanation for the difference has emerged: A molecular coating typically found on half of women's X chromosomes may cause unwanted immune responses. The research is published in a new issue of the journal Cell.
Women account for about 80% of all autoimmune cases, which include diseases such as lupus and rheumatoid arthritis. However, this "gender bias" has always been a mystery that scientists cannot explain.
One prime suspect is the X chromosome. X chromosome inactivation masks the activity of one X chromosome in most female XX cells, making their "dose" of X-linked genes equal to that of typical XY cells in men. The process is highly physical: Long strands of RNA called XIST coil around chromosomes, attracting dozens of proteins to form complexes that effectively kill the genes inside.
However, not all genes remain silent, and those that escape X chromosome inactivation are thought to underlie some autoimmune diseases. In addition, the XIST molecule itself can initiate an inflammatory immune response.
About 10 years ago, research at Stanford University School of Medicine found that many proteins that interact with XIST become targets of autoantibodies. This results in the chronic inflammation and damage seen in autoimmune diseases. Because XIST is typically expressed only in XX cells, it is thought that autoantibodies that attack XIST-related proteins may be more severe in women than in men.
To test this idea, the team bioengineered male mice (which do not normally express XIST) to produce a form of XIST that does not silence gene expression but does form a characteristic RNA-protein complex. A lupus-like disease was then induced in mice and found that animals expressing XIST had higher levels of autoantibodies than animals that did not express XIST. Their immune cells are also on higher alert, a sign of susceptibility to autoimmune attack.
Notably, the same autoantibodies were found in blood samples from patients with lupus, scleroderma and dermatomyositis. This proves that XIST and its related proteins are difficult for the human immune system to ignore. Human data validate that the XIST-related mechanisms observed in mice are directly relevant to human autoimmune disease. Diagnostics targeting these autoantibodies can help clinicians detect and monitor various autoimmune diseases. (Science and Technology Daily)