Study of the Sex Differences in Inflammatory Diseases in Children

Brief Summary

Detailed Description

Many studies demonstrated immune differences between men and women suffering from acute and chronic inflammatory processes. In cases of acute inflammatory diseases, such as sepsis, females have better prognosis comparing to males (1,24-28). On the contrary, worse prognosis for women is observed in chronic inflammatory diseases such as asthma or cystic fibrosis (8-10,12,13,29). Sex-depended inflammatory response was attributed to the influence of sex hormones on the immune system. (2,15-18). However recent studies revealed differences in the clinical outcome but also in inflammatory markers between boys and girls suffering from acute and chronic inflammatory diseases (19-23). Sex hormone levels in prepubertal children are particularly low and insufficient to explain the gender differences observed in inflammatory conditions from neonates to the elderly, suggesting the contribution of another mechanism, such as the influence of genes situated on the sex chromosomes and involved in the inflammatory response. The aim of this work is to identify the potential X-linked mechanisms responsible for some of the differences between boys and girls in the inflammatory response, making the girls more at risk of developing complications in chronic inflammatory diseases and the boys more at risk of lethal complications in severe acute inflammatory diseases like sepsis. Several genes coding for innate immunity components are linked to the X chromosome such as diapedesis molecule CD99 or TLR pathway proteins genes. (30-33). X chromosome is also highly enriched in genes encoding micro RNAs (miRNAs) involved in the post-transcriptional regulation of gene expression which play a critical role in immune inflammatory response (34-36). Thus, in order to discriminate more precisely the role of the X chromosome relatively to the sex steroids in the sex-specific inflammatory response, some innate immune functions related to X-linked genes will be evaluated in whole blood from prepubertal children of both sexes, suffering from acute inflammatory processes such as pyelonephritis caused by Escherichia coli, pneumonia with pleural effusion caused by Streptococcus pneumoniae or sepsis. We will also study the correlations between inflammatory and clinical markers of the disease activity to identify prognosis indicators depending on the sex. Additionally, to delineate microbiome contribution, we will study the gut microbiota in stool samples obtained from the recruited patients.

Primary Outcomes

Secondary Outcomes

• Intracellular quantity of the phosphorylated forms of NF-κB p65 in leukocyte population.(within 24 hours of hospital admission (Day 0))
• Intracellular quantity of the phosphorylated forms of ERK1/2 in leukocyte population.(within 24 hours of hospital admission (Day 0))
• Whole blood production of cytokine TNF-α(within 24 hours of hospital admission (Day 0))
• Whole blood production of cytokine IL-8(within 24 hours of hospital admission (Day 0))
• Whole blood production of cytokine interferon-α(within 24 hours of hospital admission (Day 0))
• Whole blood production of cytokine IL-10(within 24 hours of hospital admission (Day 0))
• Whole blood production of cytokine IL-1β(within 24 hours of hospital admission (Day 0))
• Intracellular quantity of the phosphorylated forms of p38 MAPK in leukocyte population.(within 24 hours of hospital admission (Day 0))
• Expression of the cell diapedesis receptor CD99 on monocytes(within 24 hours of hospital admission (Day 0))
• IGF1(within 24 hours of hospital admission (Day 0))
• Expression of the cell diapedesis receptor CD99 on PMNs(within 24 hours of hospital admission (Day 0))
• Expression of TLR2 on monocytes(within 24 hours of hospital admission (Day 0))
• BTK gene expression(within 24 hours of hospital admission (Day 0))
• Expression of X-linked miRNAs in leucocytes(within 24 hours of hospital admission (Day 0))
• Expression of X-linked miRNAs in plasma(within 24 hours of hospital admission (Day 0))
• Leukocyte population(Day 3)
• Total 17β-estradiol(within 24 hours of hospital admission (Day 0))
• Expression of the cell diapedesis receptor CD99 on lymphocytes(within 24 hours of hospital admission (Day 0))
• Expression of TLR2 on PMNs(within 24 hours of hospital admission (Day 0))
• Expression of TLR4 on monocytes(within 24 hours of hospital admission (Day 0))
• Expression of TLR4 on lymphocytes(within 24 hours of hospital admission (Day 0))
• NEMO gene expression(within 24 hours of hospital admission (Day 0))
• Expression of TLR2 on lymphocytes(within 24 hours of hospital admission (Day 0))
• Expression of TLR4 on PMNs(within 24 hours of hospital admission (Day 0))
• IRAK1 gene expression(within 24 hours of hospital admission (Day 0))
• CRP(Day 3)
• Testosterone(within 24 hours of hospital admission (Day 0))
• pSOFA score(Day 3)
• Microbiome analysis(During subject hospitalisation)