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Study of the role of the X chromosome in sex differences in pediatric inflammatory diseases

par Lefevre, Nicolas
Président du jury Toungouz Nevessignsky, Michel
Promoteur Casimir, Georges
Co-Promoteur Corazza, Francis
Publication Non publié, 2017-10-30

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Résumé :

Sex influences the severity and evolution of various inflammatory conditions. Women exhibit better clinical courses and increased survival compared to men in acute inflammatory processes, yet worse prognosis in several chronic inflammatory diseases, probably due to the higher inflammation observed in females. This higher inflammation in females may contribute to better pathogen clearance during the early inflammatory response, but also to enhanced tissue damage during prolonged inflammatory response. Many X-linked genes are involved in the immune response and the mechanisms underlying these sex-dependent differences are multiple and probably involve both hormonal and genetic factors. To evaluate the sex differences in the immune response and the role of the X chromosome relatively to the sex hormones, we studied acute inflammatory response in prepubertal children, whose sex hormones levels are very low, as well as women at different phases of the menstrual cycle and subjects with various X/Y sex chromosome ratios. In children with severe sepsis, we observed, in vivo, higher inflammation and lower pH, in girls compared to boys. In vitro stimulation of certain immune functions depending on X-linked genes showed specific profiles of inflammatory cytokine production and leucocyte migration markers expression in males and subjects carrying only one X chromosome but phenotypically females (Turner patients), compared to females and subjects carrying two X chromosomes but phenotypically males (Klinefelter patients), in favor of a role for the X chromosome. Our work highlighted important sex differences in terms of in vivo acute inflammatory response and in vitro activation of certain X-linked genes. These differences cannot be explained by the sex steroid levels, thus supporting the hypothesis of a preponderant role of sex chromosomes in inflammatory response.