Seminars in Immunopathology

, Volume 41, Issue 2, pp 153–164 | Cite as

Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation

  • Mélanie Souyris
  • José E. Mejía
  • Julie Chaumeil
  • Jean-Charles GuéryEmail author


Women develop stronger immune responses than men, with positive effects on the resistance to viral or bacterial infections but magnifying also the susceptibility to autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, the dosage of the endosomal Toll-like receptor 7 (TLR7) is crucial. Murine models have shown that TLR7 overexpression suffices to induce spontaneous lupus-like disease. Conversely, suppressing TLR7 in lupus-prone mice abolishes SLE development. TLR7 is encoded by a gene on the X chromosome gene, denoted TLR7 in humans and Tlr7 in the mouse, and expressed in plasmacytoid dendritic cells (pDC), monocytes/macrophages, and B cells. The receptor recognizes single-stranded RNA, and its engagement promotes B cell maturation and the production of pro-inflammatory cytokines and antibodies. In female mammals, each cell randomly inactivates one of its two X chromosomes to equalize gene dosage with XY males. However, 15 to 23% of X-linked human genes escape X chromosome inactivation so that both alleles can be expressed simultaneously. It has been hypothesized that biallelic expression of X-linked genes could occur in female immune cells, hence fostering harmful autoreactive and inflammatory responses. We review here the current knowledge of the role of TLR7 in SLE, and recent evidence demonstrating that TLR7 escapes from X chromosome inactivation in pDCs, monocytes, and B lymphocytes from women and Klinefelter syndrome men. Female B cells where TLR7 is thus biallelically expressed display higher TLR7-driven functional responses, connecting the presence of two X chromosomes with the enhanced immunity of women and their increased susceptibility to TLR7-dependent autoimmune syndromes.


Sexual dimorphism Systemic lupus erythematosus Toll-like receptor 7 X chromosome dosage X chromosome inactivation escape 


Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


This work was supported by grants from Fondation pour la Recherche Médicale (DEQ20131029169 and DEQ20180339187), Fonds de Dotation CSL Behring, Fondation Arthritis, SIDACTION and Fondation ARC.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, INSERM, CNRS, Université Paul SabatierToulouseFrance
  2. 2.Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris-DescartesParisFrance
  3. 3.INSERM UMR1043, Centre Hospitalier Universitaire PurpanToulouse Cedex 3France

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