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

JC Guéry
University of Toulouse
C Chizzolini
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.

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.

Publications

  • 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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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.