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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

Gabriel Martin 1 Sami Kanaan 1 Marie Hemon 2, 1 Doua Azzouz 1 Marina El Haddad 1 Nathalie Balandraud 3, 1 Cecile Mignon-Ravix 2, 4 Christophe Picard 5, 6 Fanny Arnoux 1 Marielle Martin 1 Jean Roudier 3, 1 Isabelle Auger 1 Nathalie Lambert 1
1 AA - Arthrites autoimmunes
2 Arthritis R&D [Neuilly-Sur-Seine]
3 Service de Rhumatologie, Hôpital Sainte-Marguerite, Aix Marseille
4 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
5 EFS - Alpes-Méditerranée - Etablissement Français du Sang - Alpes-Méditerranée
6 ADES - Anthropologie bio-culturelle, Droit, Ethique et Santé
Abstract : The X chromosome, hemizygous in males, contains numerous genes important to immunological and hormonal function. 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 BXSB murine lupus model, where the duplication of the X-linked Toll-Like Receptor 7 (Tlr7) 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 TLR7 gene and its paralog TLR8. Patients with high CN had an upregulated pro-inflammatory JNK/p38 signaling pathway. By fluorescence in situ 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.
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Journal articles
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https://www.hal.inserm.fr/inserm-02440863
Contributor : Isabelle Auger <>
Submitted on : Wednesday, January 15, 2020 - 2:44:53 PM
Last modification on : Thursday, February 6, 2020 - 9:55:58 AM

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ANTHROPO-MARSEILLE | UNIV-AMU | MMG | CNRS

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Gabriel Martin, Sami Kanaan, Marie Hemon, Doua Azzouz, Marina El Haddad, et al.. 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. Scientific Reports, Nature Publishing Group, 2019, 9 (1), pp.12880. ⟨10.1038/s41598-019-49309-4⟩. ⟨inserm-02440863⟩

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