Peritoneal Fluid from Patients with Ovarian Endometriosis Displays Immunosuppressive Potential and Stimulates Th2 Response

Abstract

Endometriosis is a common gynaecological disorder characterized by the ectopic growth of endometrial tissue outside the uterine cavity. It is associated with chronic pelvic inflammation and autoimmune reactivity manifesting by autoantibody production and abrogated cellular immune responses. Endometriotic peritoneal fluid contains various infiltrating leucocyte populations and a bulk of proinflammatory and immunoregulatory cytokines. However, the nature and significance of the peritoneal milieu in women with endometriosis still remains obscure. Therefore, the aim of the present study was to investigate the immunoregulatory activity of the peritoneal fluid (PF) from women with endometriosis. The peritoneal fluid samples were collected during laparoscopic surgery from 30 women with and without endometriosis. Immunoregulatory cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ and TNF) and chemokines (CCL2, CCL5, CXCL8 and CXCL9) were evaluated in PF and culture supernatants generated by unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells cultured in the presence of PF. The effect of PF on the generation of Treg and Th17 cells in CD4+ T cell cultures, as well as the natural cytotoxic activity of peripheral blood mononuclear cells, was also investigated. Concentrations of IL-6, IL-10, CCL2, CXCL8 and CXCL9 were significantly upregulated in the PF from women with endometriosis when compared to control women, whereas concentrations of other cytokines and chemokines were unaffected. The culturing of unstimulated and CD3/CD28/IL-2-stimulated CD4+ T cells in the presence of endometriotic PF resulted in the downregulation of their IL-2, IFN-γ, IL-17A and TNF production as compared to culture medium alone. On the other side, endometriotic PF significantly stimulated the production of IL-4 and IL-10. Endometriotic PF also stimulated the release of CCL2 and CXCL8, whereas the production of CCL5 and CXCL9 was downregulated. Endometriotic PF stimulated the generation of Treg cells and had an inhibitory effect on the generation of Th17 cells in cultures of CD4+ T cells. It also inhibited the NK cell cytotoxic activity of the peripheral blood lymphocytes. These results strongly imply that the PF from patients with endometriosis has immunoregulatory/immunosuppressive activity and shifts the Th1/Th2 cytokine balance toward the Th2 response, which may account for deviation of local and systemic immune responses. However, a similar trend, albeit not a statistically significant one, was also observed in case of PF from women without endometriosis, thus suggesting that peritoneal milieu may in general display some immunoregulatory/immunosuppressive properties. It should be stressed, however, that our present observations were made on a relatively small number of PF samples and further studies are needed to reveal possible mechanism(s) responsible for this phenomenon.

Molecular analysis suggests oligoclonality and metastasis of endometriosis lesions across anatomically defined subtypes

“…This work also showed that ovarian endometriomas had the highest potential for oligoclonality, whereas deep infiltrating endometriosis lesions were associated with a wider range of mutations. Considering previous work in the field (46)(47)(48)(49), this is consistent with the concept that distinct microenvironments are important for the forming and spreading of lesions. The ovarian microenvironment may provide permissive conditions for the expansion of multiple clones, which could be associated with a higher risk of malignant transformation (50).…”

Understanding the molecular mechanisms of macrophage polarization and metabolic reprogramming in endometriosis: A narrative review

“… 5 , 22 As shown in Figure 3 , with a few exceptions, 23 , 24 studies showed that levels of typical Th2 cytokines (e.g., IL‐4, IL10, IL‐13, or TGF‐β) in serum, peritoneal fluid, and ectopic lesions of patients with endometriosis were higher than those of normal patients, whereas levels of typical Th1 cytokines (e.g., interferon‐γ [IFN‐γ] or IL‐12) were suppressed. 18 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 Indeed, in vivo experimental animal models revealed that pharmacological depletion of peritoneal macrophage suppressed peritoneal fluid MCP‐1 levels, thereby attenuating the initiation and growth of endometriosis implants. 38 …”

Interleukin-33 Derived from Endometriotic Lesions Promotes Fibrogenesis through Inducing the Production of Profibrotic Cytokines by Regulatory T Cells

“…Regulatory T cells (Tregs) are the primary regulators in the immune system [ 1 ]. We and others have previously reported the involvement of Tregs in endometriosis [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ] in general and the promotion of the development of endometriosis through the transforming growth factor β1 (TGF-β1) and platelet-derived growth factor (PDGF) signaling pathways in particular [ 18 ]. TGF-β1 is highly expressed in both peritoneal fluid [ 19 ] and eutopic endometrium of women with endometriosis, and the activation of the TGF-β1 signaling pathway results in stromal cell proliferation [ 20 ].…”

“…Increased PDGF-B gene expression has also been observed in the peritoneal fluid of patients with endometriosis [ 21 ]. Hyperactive TGF-β signaling induces fibrogenesis by stimulating stromal fibroblasts to produce collagen [ 22 ], which is a vital component of the extracellular matrix [ 23 ].It has been widely believed that the local immunological milieu is type 2 T helper (Th2)-cell-skewed, and Th2 lymphocytes are reported to be involved in endometriosis [ 14 , 16 , 17 , 18 , 24 , 25 , 26 ].…”