Natural Killer Cell Receptors and Endometriosis: A Systematic Review

Abstract

Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies correlate the immune system with endometriosis, particularly NK receptors (NKR), which have been suggested to play an essential role in the pathogenesis of the disease. This systematic review aims to enlighten the role of NKR in endometriosis. A literature search was performed independently by two reviewers, to identify studies assessing the role of NKR in endometriosis. In total, 17 studies were included. Endometriosis pathogenesis seems to be marked by the overexpression of NK inhibitor receptors (KIRS), namely, CD158a+, KIR2DL1, CD94/NKG2A, PD-1, NKB1, and EB6, and inhibiting ligands such as PD-L1, HLA-E, HLA-G, and HLA-I. Concurrently, there is a decrease in NK-activating receptors and natural cytotoxicity receptors (NCRs), such as NKp46, NKp30, and NKG2D. The immune shift from NK surveillance to NK suppression is also apparent in the greater relative number of ITIM domains compared with ITAM domains in NKRs. In conclusion, NK receptor activity seems to dictate the immunocompetency of women to clear endometriotic cells from the peritoneal cavity. Future research could explore NKRs as therapeutic targets, such as that which is now well established in cancer therapy through immunotherapy.

Killer Cell Immunoglobulin-like Receptor Genotypes and Reproductive Outcomes in a Group of Infertile Women: A Romanian Study

“…Most studies focusing on the KIR genotype of uterine NK cells examined its impact on pregnancy and found that it might be associated with pathologies such as preeclampsia, intrauterine growth restriction, and placenta acretta, providing consistent evidence towards the association of the KIR AA variant with pregnancy outcomes [19,33,34]. A few other studies reported results supporting the association between KIR variants and endometriosis [20,29,31]. Some authors reported changes in the number of NK cells in patients with chronic endometritis, but they did not document a correlation between these cells and the onset of the disease [35,36].…”

“…The arguments that sustain, at least in part, the association between the NK cell and these pathogenic pathways are given by its regulatory properties expressed by means of chemokines and cytokine production (e.g., IL-8, IL-1β, TNF-α, IFN-g, and VEGF) and its cytotoxic activity, on one hand, but also by its capacity to modulate the expression of endometrial cells or other cells that mediate the immune response (T lymphocytes), on the other hand [26,28]. The involvement of the NK cell in the development of endometriosis is strongly supported by scientific evidence that showed changes in its regulatory function, as well as in its cytotoxic potential [29]. The expression of inhibitory receptor CD94/NKG2A and NK cell expression was increased in patients with endometriosis.…”

TIM‐3 Expression in Endometriosis

“…The theory that the onset and growth of endometriosis are associated with immune dysfunction was first suggested in the 1990s [4]. Following this, numerous studies have supported this theory by illustrating the role of different immune cells at various stages in the immune response, resulting in compromised immune competence in women with endometriosis [1,14]. Despite the numerous studies conducted thus far, the precise mechanism detailing the role of the immune system in the advancement of endometriosis remains largely unknown.…”

Reproductive Immunology and Pregnancy 3.0

“…Dysfunctional natural killer (NK) cells may also contribute to the impaired recognition of ectopic foci in endometriosis and the lack of effective removal of endometrial cells by the immune system. Reis et al (2022) [21] reviewed, summarized, and updated the [17]. The activity of Foxp3 is a derivative of the degree of acetylation (Ac), which is directly related to the presence of sirtuin-1 (SIRT1).…”

“…Dysfunctional natural killer (NK) cells may also contribute to the impaired recognition of ectopic foci in endometriosis and the lack of effective removal of endometrial cells by the immune system. Reis et al (2022) [21] reviewed, summarized, and updated the previous literature on NK cells and endometriosis, focusing on the current state of knowledge about the role of NK receptors (NKRs).…”