New research on the X chromosome from the School of Veterinary Medicine points to an abnormality in the immune system\u2019s T cells as a possible contributing factor in lupus and other autoimmune diseases.
\nThe autoimmune disease lupus, which can cause fatigue, a facial rash, and joint pain, strikes females far more often than males. Eight-five percent of people with lupus are female, and their second X chromosome seems partly to blame. According to a new study by Penn researchers, females with lupus don\u2019t fully \u201csilence\u201d their second X chromosome in the immune system\u2019s T cells, leading to abnormal expression of genes linked to that chromosome.
\nThe work, led by Montserrat Anguera of the School of Veterinary Medicine is the first to connect disruptions in maintaining X chromosome inactivation in T cells to lupus. It also suggests that changes to the nuclear structure in the inactive X chromosome of T cells may play a part in the genetic missteps that can arise in lupus\u2014the first time that nuclear organization has been noted as a feature of this disease.
\n\u201cIn normal circumstances, the inactive X should be silenced, and what we show is, in lupus, it\u2019s not,\u201d says Anguera, a biologist at Penn Vet. \u201cAnd it\u2019s ultimately affecting gene expression.\u201d
\nAnguera\u2019s lab has paid close attention to the link between X chromosome inactivation, an epigenetic process that balances gene expression between males and females, and autoimmune disease. In earlier studies, the team found that, in females, both T cells and B cells have incomplete inactivation of the second X chromosome due to changes in the patterns of Xist, an RNA molecule that is necessary for X inactivation.
\nIn the new work, Anguera and colleagues wanted to more closely examine this process in T cells and specifically in the context of an autoimmune disease, in this case, lupus.
\nThey first tracked the process of X inactivation in T cells from healthy mice. Their observations revealed that, as T cells develop, Xist temporarily diffuses away from the inactive X chromosome. But when a T cell is activated, as it would be upon encountering a potential pathogen, for example, then Xist RNA returns to this chromosome.
\nTo see what happens in autoimmune disease, the researchers used a mouse model that spontaneously develops lupus in a female-biased manner, similar to the human disease. All female mice of this strain develop the disease, while only 40 percent of males do. Examining the animals\u2019 T cells, the researchers discovered that those at early stages of disease resembled healthy controls in their patterns of Xist localization. But those in the later stages of disease had a dramatically different pattern.
\nThe only differences we detected happened at late stages of disease,\u201d Anguera says. \u201cWhat this means is that abnormal X inactivation is a consequence of the disease; it\u2019s not predisposing the animal to develop the disease.\u201d
\nInterestingly, when the researchers looked at T cells from paediatric lupus patients, provided by study co-author Edward M. Behrens of the Perelman School of Medicine and Children\u2019s Hospital of Philadelphia, they found the same mislocalization of Xist that they had seen in the mice with lupus, even though the children were in remission from their disease.
\nEven stimulating those patients\u2019 cells in vitro wasn\u2019t enough to coax Xist into the normal pattern. \u201cEven though they don\u2019t have active disease, there\u2019s something missing that\u2019s preventing the RNA from staying targeted at that inactive X chromosome,\u201d Anguera says.
\n University of Pennsylvania\nhttps:\/\/tinyurl.com\/y3nsrssw<\/link>\n","protected":false},"excerpt":{"rendered":"
New research on the X chromosome from the School of Veterinary Medicine points to an abnormality in the immune system\u2019s T cells as a possible contributing factor in lupus and other autoimmune diseases. The autoimmune disease lupus, which can cause fatigue, a facial rash, and joint pain, strikes females far more often than males. Eight-five […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[35],"tags":[],"_links":{"self":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/771"}],"collection":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/comments?post=771"}],"version-history":[{"count":0,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/771\/revisions"}],"wp:attachment":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/media?parent=771"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/categories?post=771"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/tags?post=771"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}