Changes in the number and activity of natural killer cells and its clinical association with endometriosis: systematic review and meta-analysis

Objective

To pool all available data from literature and compare the differences in cell percentages and cytotoxicity of peripheral blood, peritoneal fluid, and uterine natural killer (NK) cells (pNK, pfNK, uNK) between individuals with endometriosis and those without. In addition, we examined the differences in NK cells between early and advanced stages of endometriosis.

Evidence review

International databases such as PubMed, Web of Science, Scopus, Google Scholar, and EMBASE through OVID were searched. Meta-analysis was conducted according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol) and PICO (Population, Intervention, Comparison, and Outcome) frame. STATA 17 was used to analyze the data. T² and I² Statistics were calculated to check heterogeneity. Meta-analysis was performed to compare the percentage and cytotoxic activity of NK cells between different groups. A random effect model was used to pool all the available data. Subgroup and sensitivity analysis were used to identify the source of heterogeneity.

Results

We included 29 case control and 2 cross-sectional studies across 13 countries that met our inclusion criteria. There was no significant difference in the percentage of pNK cells (mean difference [MD] 1.94, 95% confidence interval [CI] −0.52, 4.39; I² 94.52%; total of 915 women), and pfNK cells (MD 2.12, 95% CI −5.26, 9.5; I² 96.59%; total 397 women) between women with endometriosis and controls. However, the percentage of uNK cells (MD 3.91, 95% CI 1.63, 6.19; I² 0%; a total of 149 women) was significantly higher in women with endometriosis compared with controls. The study also found that the cytotoxic activity of pNK cells (MD −8.01, 95% CI −13, −3.02; I² 40.27%; total of 187 women), pfNK cells (MD −9.94, 95% C: −13.53, −6.34; I² 0%; total 110 women), and uNK cells (MD −12.1, 95% CI −17.95, −6.27; I² 16.75%; total 104 women) were significantly lower in women with endometriosis compared with the control group. Similarly, the pooled mean lytic unit of pNK cell cytotoxicity in women with endometriosis (MD −2.77, 95% CI −3.91, −1.63; I² 0%; total of 74 women) was significantly lower than controls. However, there was no significant difference in the NK cell cytotoxicity between the early and advanced stages of endometriosis.

Conclusion

The consistent reduction of NK cell cytotoxicity across different samples (peripheral blood, peritoneal fluid, and endometrial tissue) may provide insights into the pathogenesis of endometriosis. Establishing standardized references for the cytotoxicity of uNK, pfNK, and pNK cells, as well as the percentage of uNK cells, is a prerequisite to determining their potential values in clinical diagnosis and treatments.