CD4⁺CD25^highFoxp3⁺ Cells Increased in the Peritoneal Fluid of Patients with Endometriosis

Abstract

Problem To evaluate CD4+CD25highFoxp3+ cells and IL‐6, IL‐10, IL‐17, and TGF‐β in the peritoneal fluid of women with endometriosis. Method of study A total of ninety‐eight patients were studied: endometriosis (n = 70) and control (n = 28). First, peritoneal fluid lymphocytes were isolated, and CD4+CD25high cells were identified using flow cytometry. Then, RT‐PCR was performed to verify Foxp3 expression in these cells. Also, IL‐6, IL‐10, IL‐17, and TGF‐β concentration was determined. Results Of all the lymphocytes in the peritoneal fluid of women with endometriosis, 36.5% (median) were CD4+CD25high compared to only 1.15% (median) in the control group (P < 0.001). Foxp3 expression was similarly elevated in patients with the disease compared to those without (median, 50 versus 5; P < 0.001). IL‐6 and TGF‐β were higher in endometriosis group (IL‐6: 327.5 pg/mL versus 195.5 pg/mL; TGF‐β: 340 pg/mL versus 171.5 pg/mL; both P < 0.001). IL‐10 and IL‐17 showed no significant differences between the two groups. Conclusion The peritoneal fluid of patients with endometriosis had a higher percentage of CD4+CD25highFoxp3+ cells and also higher levels of IL‐6 and TGF‐β compared to women without the disease. These findings suggest that CD4+CD25highFoxp3+ cells may play a role in the pathogenesis of endometriosis.

Interplay between Misplaced Müllerian-Derived Stem Cells and Peritoneal Immune Dysregulation in the Pathogenesis of Endometriosis

“…It was proposed that the preserved Treg cells seen in women with endometriosis decrease the ability of newly recruited immune cell populations to effectively recognize and target endometrial antigens during menstruation, allowing survival and implantation of shed endometrial cells [72]. As proposed by Podgaec et al [84], the immune cells (macrophages, dendritic cells, NK, CD4 + , and CD8 + lymphocytes) responsible for local surveillance profile could have their activity suppressed by Treg cells, a fact that would prevent the ectopic endometrial cells from being removed from the peritoneal cavity. This, together with endometrial cells decreased apoptosis rate (see after), may cause perpetuation of disease growth.…”

“…Several researchers, in independent works, assessed the levels of cytokines involved in immune response patterns Th1 and Th2 in patients with endometriosis. Podgaec et al [84] noted an increase in the levels of IFN-gamma and IL-10 in patients with endometriosis, evidencing the coexistence of both responses. However, it a predominance of IL-4 and IL-10 was observed, thus reflecting a polarization toward Th2 immune response [106].…”

“…Some authors share the evidence that no significant differences were observed in the PF of endometriotic women in respect to controls, whereas others showed an elevation [112]. Contradiction can be explained by the velocity of production and consumption of inflammatory products, making comparisons difficult [84]. In particular, according to these latter authors, increased IL10 production may partially contribute to the disturbed immune regulation in patients with endometriosis, because it attenuates TNF- α -induced IL6 synthesis via NF-kappaB and MAPK pathways in endometriotic cells.…”

“…There is evidence that concentrations of this cytokine are ten times higher in peritoneal fluid of patients with endometriosis compared to those without the disease. In the inflammatory process, high levels of TGF β may occur in the regeneration process, inducing adhesion formation and the appearance of fibrotic tissue and stimulating Treg cells that are elevated to regulate the exacerbated immune response [84]. However, Meta-analyses of the available data showed that the association between TGF- β 1-509C/T polymorphism and susceptibility of endometriosis was not significant [114].…”

Endometriosis is an important cause of pelvic pain in adolescence

“…1,3 Its etiopathogenesis is still controversial and several theories have been proposed to justify the presence of the disease. 1,4,5 It can be classified as superficial, ovarian and deep, the latter being characterized by the infiltration of endometrial implants above a depth. 6,7 Endometriosis presents diverse clinical presentations.…”