The nature and the strength of the immune response differ between women and men. While women show more vigorous immune responses to infections, they also suffer more from autoimmunity (such as Systemic Lupus Erythematosus (SLE)). It is becoming clear that not only sex hormones but also sex-chromosome associated loci regulate biological pathways common to autoimmune and infectious diseases. This is particularly clear for TLR7, a single-stranded RNA receptor encoded by a gene located on the X-chromosome. While the innate immune response initiated by TLR7 is essential for the defense against RNA viruses, TLR7 can also respond to endogenous ssRNA, potentially leading to autoimmunity if not properly controlled. Escape from X-chromosome inactivation (XCI) could contribute to this sexual dimorphism. Indeed, although XCI is stably established at an early stage of female embryogenesis, around 20% of X-linked human genes escape XCI in certain tissues, and are thus expressed from both female X chromosomes. It has been shown using transgenic mice that expressing 2 copies of the Tlr7 gene is enough to induce SLE. In collaboration with Dr JC Guéry (Infinity, Toulouse, France) we have demonstrated that TLR7 escapes XCI in a fraction of female immune cells. XCI-escape of TLR7 may thus impact the innate and adaptive immune response. As a collaborative project, we are investigating the mechanisms of TLR7 escape from XCI in immune cells.

Project

In collaboration with Dr JC Guéry (Infinity, Toulouse, France), we have demonstrated that the X-linked gene TLR7, coding a single-stranded RNA receptor, can escape XCI in a fraction of woman immune cells (1,2). Strikingly, B cells expressing TLR7 biallelically were more responsive than monoallelic cells at specific checkpoints of B cell differentiation that involve signaling through TLR7. Athough this overexpression of TLR7 gives to women a direct benefit with greater innate and adaptive immunity against selected pathogens or self-components containing ssRNA, it may also explain the higher susceptibility of women to TLR7-driven antibody mediated autoimmune diseases, such as SLE. We wish now to understand the mechanisms of TLR7-escape in immune cells.

  1. Souyris M, et al, Chaumeil J, Mejia JE, Guéry JC. Science Immunol 2018;3: pii: eaap8855.
  2. Souyris M, Mejia JE, Chaumeil J, Guéry JC. Semin Immunopathol 2018;41:153.

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