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
JC Guéry
University of Toulouse
jean-charles.guery@inserm.fr
Meet the Team
University of Geneva
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
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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.
Read more - 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
- 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
- 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.
- Chizzolini C, Hughes S., Ribi C. Pourquoi le LES touche-t’il préférentiellement les femmes ? Magazine Lupus 2020 N°1: p6-10.
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.