Endometriosis and Natural Killer Cell Immunity

Natural killer cells in pelvic endometriosis

Key Points

Highlight:

• Dr. Shibahara group reviews the role of abnormal Natural Killer cell activity on the development of pelvic endometriosis.

Background:

• Thirty to fifty percent of women with endometriosis suffer from infertility and immunological abnormality is one of the causes.
• Women suffering from endometriosis have abnormal NK cell activity as well as their inhibitory receptors, suggesting immunological changes play a critical role in infertility or reproductive failure.

Key points:

• In endometriosis, reduced NK cell activity was reported in the peritoneal fluid and peripheral blood NK cells.
• NKp46 (one of the NK cell-activating receptors) in the peritoneal fluid was significantly lower, and the expression of CD158a (one of the inhibitory receptors) was significantly higher in women with severe endometriosis.
• These reports suggested that reduced NK cell cytotoxicity is involved in the development and progression of endometriosis.
• Recently, the function of the platelets on NK cell cytotoxicity found to be also important in the development of endometriosis.
• Platelet-derived transforming growth factor-beta1 (TGF-beta1) suppresses the expression of NKG2D on NK cells, resulting in reduced cytotoxicity in women with endometriosis.
• Decreased NKG2D and IFN-γ production by NK cells cause reduced NK cell cytotoxicity, and the percentage of IFN-γ- and TNF-α-producing NK cells are positively correlated with the endometriosis stage.

Conclusions:

• Abnormal expressions of NK cell receptors and cytokines production by NK cells are involved in the development of pelvic endometriosis.
• The effect of the oral contraceptive pills, hormones, and dienogest on the NK cell abnormalities should also be investigated for endometriosis treatment.
• However, further analysis is needed to clarify the roles of NK cells in women with endometriosis, and new forms of treatment should be developed.

Lay Summary

It is known that approximately 25 to 50% of infertile women have endometriosis, and 30% to 50% of the women with endometriosis have infertility and recurrent pregnancy loss. Previous studies have shown that women suffering endometriosis have abnormal NK cell activity and abnormal expression of inhibitory receptors, suggesting immunological changes play a critical role in infertility or reproductive failure.

Although several factors including retrograde menstruation, bacterial infections, and epigenetic factors play role in the development of endometriosis, one important factor is the immune system and the immune cell alterations in the peritoneal cavity. Normally immunological cells such as the NK cells, T cells, and macrophages eliminate endometrial cells from the peritoneal cavity, however, due to the changes in the characteristics of these immune cells, the endometrial cells may be able to locate and grow in the peritoneal space.

In this review, which includes the group's own data, Dr. Shibahara group from Japan focuses on the role of natural killer (NK) cells in pelvic endometriosis, and was recently published in the “American Journal of Reproductive Immunology”.

In endometriosis, reduced NK cell activity was reported in the peritoneal fluid and peripheral blood NK cells. The expression of NKp46, one of the activating receptors, on the peritoneal fluid NK cells was significantly lower, and the expression of CD158a, one of the inhibitory receptors, was significantly higher in women with severe endometriosis. These reports suggested that reduced NK cell cytotoxicity should be involved in the development and progression of endometriosis.

Recently, the function of a platelet on NK cell cytotoxicity found to be very important to the development of endometriosis. Platelet-derived transforming growth factor-beta1 suppresses the expression of NKG2D on NK cells, resulting in reduced cytotoxicity in women with endometriosis. As a result, decreased NKG2D and IFN-γ production by NK cells cause reduced NK cell cytotoxicity. The percentages of IFN-γ- and TNF-α-producing NK cells are positively correlated with the revised American Society for Reproductive Medicine stage of endometriosis. Taken together, abnormal expressions of NK cell receptors and cytokines production by NK cells are involved in the development of pelvic endometriosis.

The authors suggest that the effect of oral contraceptive pills and dienogest should be evaluated whether they normalize the NK cell abnormalities in endometriosis. However, further analysis is needed to clarify the roles of NK cells in women with endometriosis, and new forms of treatment should be developed.

Research Source: https://pubmed.ncbi.nlm.nih.gov/32896016/