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

Concept

The incidence of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is markedly increased in women. Both sex hormones and 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.

Facts and Figures

Project Lead
JC Guéry
University of Toulouse
jean-charles.guery@inserm.fr
FOREUM research grant: € 600.000
2020–2023

Meet the Team

Project Lead

JC Guéry
University of Toulouse
jean-charles.guery@inserm.fr
S Hugues
University of Geneva
L Frasca
Istituto Superiore di Sanità

Objectives

It will be investigated whether higher levels of TLR7 expression, arising from the escape of X-chromosome inactivation (XCI) are linked to increased risk of developing autoimmunity specifically in women. This will be achieved by exploring the relevance of TLR7 XCl escape to the pathophysiology of SLE and SSc by assessing the functions of key human immune cell subsets implicated in disease development, in relationship to the dose of TLR7 (one copy or two copies) expressed in each cell subset.

Goals/Milestones

  • Year 1 and 2: Collect PBMCs from patients
  • Year 1 and 2: Provide functional relationship between TLR7 biallelism and ABC development, sex-bias in TLR7-responsiveness using cells from healthy donors. 
  • Year 2 and 3: Provide the first proof of concept regarding the clinical associations between ABC cells, monocytes and pDC in relationship to XCI-escape of TLR7 genes and frequency of monoallelic vs biallelic cells in SLE and SSc patients.
  • Year 1-3: Functional relationship between Tlr7 biallelism, ABC development and SLE pathogenesis in a mouse model of spontaneous lupus.

Publications

  • 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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Patient Voice

Representative of the Swiss SLE (Lupus-Suisse.ch) and SSc (sclerodermie.ch) patient organizations have reviewed the present proposal and have provided a feedback. It is foreseen that the results will be discussed annually with these representative and upon completion, the study results will be presented at meetings of interested patients’ organizations.

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