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Alterations in X-linked gene dosage are suspected to contribute to female predominance in autoimmunity. A powerful example of X-linked dosage involvement comes from the<jats:italic>BXSB<\/jats:italic>murine lupus model, where the duplication of the X-linked<jats:italic>Toll-Like Receptor 7<\/jats:italic>(<jats:italic>Tlr7)<\/jats:italic>gene aggravates autoimmunity in male mice. Such alterations are possible in men with autoimmune diseases. Here we showed that a quarter to a third of men with rheumatoid arthritis (RA) had significantly increased copy numbers (CN) of<jats:italic>TLR7<\/jats:italic>gene and its paralog<jats:italic>TLR8<\/jats:italic>. Patients with high CN had an upregulated pro-inflammatory JNK\/p38 signaling pathway. By fluorescence<jats:italic>in situ<\/jats:italic>hybridization, we further demonstrated that the increase in X-linked genes CN was due to the presence of an extra X chromosome in some cells. Men with RA had a significant cellular mosaicism of female (46,XX) and\/or Klinefelter (47,XXY) cells among male (46,XY) cells, reaching up to 1.4% in peripheral blood. Our results present a new potential trigger for RA in men and opens a new field of investigation particularly relevant for gender-biased autoimmune diseases.<\/jats:p>","DOI":"10.1038\/s41598-019-49309-4","type":"journal-article","created":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T10:03:02Z","timestamp":1568023382000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Mosaicism of XX and XXY cells accounts for high copy number of Toll like Receptor 7 and 8 genes in peripheral blood of men with Rheumatoid Arthritis"],"prefix":"10.1038","volume":"9","author":[{"given":"Gabriel V.","family":"Martin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami B.","family":"Kanaan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie F.","family":"Hemon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doua F.","family":"Azzouz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"El Haddad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Balandraud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Mignon-Ravix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Picard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Arnoux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5435-8567","authenticated-orcid":false,"given":"Jean","family":"Roudier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Auger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie C.","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,9]]},"reference":[{"key":"49309_CR1","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1016\/j.autrev.2008.06.009","volume":"7","author":"A Lleo","year":"2008","unstructured":"Lleo, A., Battezzati, P. 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