Exploring the X-linked determinant implicated in the female susceptibility to rheumatic diseases

Our objective was to investigate the mechanisms underlying the female predominance in SLE/SSc, and more specifically the contribution of X chromosome-linked genetic mechanisms. In a cohort of women with SLE we profiled the B cell compartment and discovered that a subset of CD11c-CXCR5-DN B cells was strongly associated with clinical signs of SLE. Whether this DN3 cells are also found in male SLE will warrant further investigation. We also provided multiple evidences that dysregulated X chromosome inactivation, targeting the TLR7/8 locus, can be associated with enhanced expression of TLR7 in immune cells involved in the pathogenesis of SLE and SSc, such as Age-associated B cells and plasmacytoid dendritic cells, both in mouse and in human, including patients with SSc. In mouse, we discovered a new subset of B cells with biallelic expression of Tlr7 poised for immediate activation/differentiation into plasmablasts. Constitutive elimination of these cells prevents lupus-like syndrome.

The incidence of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is markedly increased in women and Klinefelter syndrome men bearing at least two X chromosomes. This observation led to the hypothesis that the dosage of X chromosomes might contribute to this sex bias. The dosage of X-linked genes is equilibrated between men and women due to the inactivation of one X chromosome (XCI) in female cells. However, XCI is incomplete, leading to increased expression of some X-linked genes. TLR7 and TLR8, are candidate genes as they are important activators of the immune system and increased dosage of Tlr7or Tlr8 is sufficient to trigger autoimmunity in mice. We made the seminal observation that the innate receptors TLR7 and TLR8 escape X chromosome inactivation in a fraction of immune cells from females but also from Klinefelter males (47XXY) whose susceptibility to develop SLE/SSc is equivalent to that of females, and we provided evidence for enhanced functional responses of female immune cells stimulated through those TLRs. During the course of this project, we also identified a subset of CD11c-CXCR5- B cells, called DN3 B cells, was strongly associated with clinical signs of SLE in women. We also provided multiple evidences that dysregulated X chromosome inactivation, targeting the TLR7/8 locus, can be associated with enhanced expression of TLR7 in immune cells involved in the pathogenesis of SLE and SSc, both in mouse and in human, including patients with SSc. Understanding further the underlying mechanisms responsible for the emergence of immune cells with bi-allelic expression of these TLRs may provide a powerful leverage point for therapeutic intervention in female autoimmune diseases.

• Cenac C, Ducatez M, Guéry JC. Hydroxychloroquine inhibits proteolytic processing of endogenous TLR7 protein in human primary plasmacytoid dendritic cells. European Journal of Immunology 2022 52(1): 54-61. doi: 10.1002/eji.202149361. PMID: 34580855
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• Youness A, Miquel CH, and Guéry JC. Escape from X chromosome inactivation and the female predominance in autoimmune diseases. International Journal of Molecular Sciences 2021 23;22(3): 1114. doi: 10.3390/ijms22031114.
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• Miquel CH, Youness A, Guéry JC. Prédominance féminine des maladies auto-immunes: les lymphocytes ont-ils un sexe? Revue du rhumatisme 2021 88: 3-7.
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• Pietraforte I, Butera A, Gaddini L, Mennella A, Palazzo R, Campanile D, Stefanantoni K, Riccieri V, Lande R, Frasca L. CXCL4-RNA Complexes Circulate in Systemic Sclerosis and Amplify Inflammatory/Pro-Fibrotic Responses by Myeloid Dendritic Cells. Int J Mol Sci. 2022 Dec 30;24(1):653. doi: 10.3390/ijms24010653. PMID: 36614095
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• Heparin-Independent and Heparin-Dependent Anti-CXCL4 Antibodies Have a Reciprocal Expression in a Systemic Sclerosis Patients' Cohort. Palazzo R, Stefanantoni K, Cadar M, Butera A, Riccieri V, Lande R, Frasca L. Antibodies (Basel). 2022 Dec 15;11(4):77. doi: 10.3390/antib11040077.PMID: 36546902
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• Miquel CH, Faz-Lopez B, and Guéry JC. Influence of X chromosome in sex-biased autoimmune diseases. J. Autoimmun. 2023 Jan 12:102992. doi: 10.1016/j.jaut.2023.102992. Online ahead of print. PMID: 36641351.
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• Chizzolini C, Hughes S., Ribi C. Pourquoi le LES touche-t’il préférentiellement les femmes ? Magazine Lupus 2020 N°1: p6-10.
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• Huret C, Férrayé L, David A, Mohamed M, Valentin N, Charlotte F, Savignac M, Goodhardt M, Guéry JC, Rougeulle C* and Morey C*. *co-corresponding authors. Altered X-chromosome inactivation predisposes to autoimmunity. Science Advances (in press) 
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• JC Guéry. L’immunité a-t-elle un sexe ? Chromosome X et biais de sexe dans le lupus systémique. Réflexions Rhumatologiques. 2023 (251) 27:8-11.
• Youness A, Cenac C, Faz-López B, Grunenwald S, Barrat FJ, Chaumeil J, Mejía JE, Guéry JC. TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells. Biol Sex Differ. 2023 Sep 18;14(1):60. doi: 10.1186/s13293-023-00544-5. PMID: 37723501
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• Anesi N, Miquel CH, Laffont S, Guéry JC. The Influence of Sex Hormones and X Chromosome in Immune Responses. Curr Top Microbiol Immunol. 2023;441:21-59. doi: 10.1007/978-3-031-35139-6_2. PMID: 37695424
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• Du Y, Faz-Lopez B, Ah Kioon MD, Cenac C, Pierides M, Lakin KS, Spiera RF, Chaumeil J, Truchetet ME, Gordon JK, Guéry JC, Barrat FJ. Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis. J Exp Med. 2025 Mar 3;222(3):e20231809. doi: 10.1084/jem.20231809. Epub 2024 Dec 13. PMID: 39670995; PMCID: PMC11639950.
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