Abstract
Endometriosis is an oestrogen-dependent chronic inflammatory process with primary symptoms including dysmenorrhea, chronic pelvic pain, and infertility. The immune environment of the endometrium is essential for successful embryo implantation and ongoing pregnancy. In this study, we assessed the composition, density, and distribution of infiltrating immune cells in the endometria of women with endometriosis. Gene expression profiles of endometrial samples were downloaded from the Gene Expression Omnibus (GEO) database. We found that the TNF signalling pathway, the IL-17 signalling pathway, and the MAPK signalling pathway were significantly enriched in the eutopic endometria of women with endometriosis. The fractions and proportion of infiltrating immune cells were estimated by the CIBERSORT, MCP-counter, and ImmuCellAI methods. We found that the proportions of CD8+ T cells, activated NK cells, and follicular helper T cells were significantly higher in the endometria of women with endometriosis than in the endometria of normal controls, while the proportions of M2 macrophages and resting mast cells were significantly lower in the eutopic endometria. In GSE120103 (n = 36), we found that elevated CD8+ T cells in endometriosis increased the risk of infertility (P = 0.0019). The area under the receiver operating characteristic (ROC) curve (AUC) of CD8+ T cells to distinguish fertile and infertile endometriosis was 0.914. In clinical samples (n = 40), we found that the proportions of CD8+ T cells and CD56+ NK cells were significantly higher in the eutopic endometria of women with endometriosis than in the endometria of normal controls, while the proportion of CD163+ macrophages were lower in the eutopic endometria. The AUCs of CD8+ T cells and CD163+ macrophages were 0.727 and 0.833, respectively, which indicated that CD8 and CD163 were potential diagnostic markers for endometriosis. In conclusion, our results demonstrated that increased CD8+ T cells and CD56+ NK cells and decreased CD163+ macrophages within the eutopic endometria of women with endometriosis reveal a proinflammatory feature in the endometrial immune environment and that elevated CD8+ T cells increase the risk of infertility in women with the disease.
Highlights
Endometriosis, a condition in which endometrial-like tissue aberrantly grows outside the uterus, is characterized by an oestrogen-dependent chronic inflammatory process and symptoms including dysmenorrhea, chronic pelvic pain, and infertility [1]
According to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) term enrichment analyses of the Differentially expressed genes (DEGs), the TNF signalling pathway, IL-17 signalling pathway, and MAPK signalling pathway were significantly enriched (Supplemental Figures 1C–F), which indicated that the eutopic endometria of women with endometriosis have prominent inflammatory features
We found that the proportions of CD8+ T cells and CD56+ NK cells were significantly higher in the eutopic endometria of women with endometriosis than in women with normal endometria (0.2292 ± 0.0591 vs 0.1790 ± 0.0562, P = 0.0132; 0.1686 ± 0.0745 vs 0.1163 ± 0.056, P = 0.0227; Figures 5A, B and Table 3), while CD163+ macrophages were lower in the eutopic endometria of women with endometriosis compared to their counterparts (0.1774 ± 0.0685 vs 0.2555 ± 0.0588, P = 0.0003; Figures 5A, B and Table 3)
Summary
Endometriosis, a condition in which endometrial-like tissue aberrantly grows outside the uterus, is characterized by an oestrogen-dependent chronic inflammatory process and symptoms including dysmenorrhea, chronic pelvic pain, and infertility [1]. Endometriosis affects nearly 10–15% of women of reproductive age [2], and 30–50% of women with endometriosis have infertility [3]. It is important to investigate the mechanism of endometriosis-associated infertility. Endometriosis affects the quality of embryos, the function of fallopian tubes and embryo transportation, and the endometrial receptivity and embryo implantation [4]; these abnormalities likely all impact fertility, which leads to infertility or pregnancy loss. The immune environment of the endometrium is a key factor for endometrial receptivity and is essential for successful embryo implantation and ongoing pregnancy. The eutopic endometria of women with endometriosis manifest progesterone resistance and oestrogen dominance, resulting in disturbed decidualization and aberrant inflammation [5, 6]
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