Endometriosis: Pathogenesis and Treatment 2014 Ed.

5. Role of NK Cells in Endometriosis

Nagamasa Maeda 

(1)

Department of Obstetrics and Gynecology, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city Kochi, 783-8505, Japan

Nagamasa Maeda

Email: maedan@kochi-u.ac.jp

Abstract

Impaired natural killer (NK) cell activity in women with endometriosis is thought to promote implantation and the progressive growth of endometrial tissue in accordance with Sampson’s hypothesis. However, the mechanisms responsible for decreased NK cell activity and the antigens recognized by NK cells in these women are not clear.

Decreased NK cell activity in the peripheral blood (PB) and peritoneal fluid (PF) of women with endometriosis was first reported by Oosterlynck et al. and subsequent investigators have identified the depression of NK cell function in women with this disorder. Decreased NK cell activity in women with endometriosis is thought to allow the implantation of endometrial tissue in the manner of a graft, but the mechanisms underlying the decline of NK cell activity remain uncertain.

We focused on the expression of HLA-G, a ligand of NK cell receptors, and its changes in eutopic endometrium during the menstrual cycle. HLA-G expression was only identified in eutopic endometrium during the menstrual phase, but not during the proliferative or secretory phases. HLA-G-expressing cells were also detected in peritoneal fluid during the menstrual phase.

Retrograde menstruation may allow HLA-G-expressing endometrial tissue to enter the peritoneal cavity, where it should be scavenged by the immune surveillance system. Because peritoneal NK cells play an important role in this system, impairment of their cytotoxicity via HLA-G could allow the survival and implantation of peritoneal endometrial cells.

In this article, we discuss the pathogenesis of endometriosis from the perspective of intraperitoneal interactions between NK cell receptors and their ligands (antigens) that enter the peritoneal cavity on cells shed from eutopic endometrium via retrograde menstruation.

Keywords

EndometriosisEndometriumHLA-GKIRNatural killer cellNK receptorRetrograde menstruationStress

5.1 Natural Killer (NK) Cells

NK cells are cytotoxic lymphocytes that constitute a major component of the innate immune system. Because these cells can attack target cells without requiring antigen sensitization, they are called “natural killer” cells [1]. NK cells participate in host defenses against infection [2], have antitumor activity [3], and are involved in graft rejection [4]. NK cells can also have an adverse influence on pregnancy [5].

These cells usually express the surface markers CD16 (FcγRIII) [6] and CD56 (neural cell adhesion molecule: NCAM) [7] in humans. In addition to killing target cells, NK cells secrete various cytokines, such as the antiviral cytokine interferon-γ (IFN-γ) [89] and the inflammatory and antitumor cytokine tumor necrosis factor-α (TNF-α) [10].

NK cell activity can be assessed by measuring cytotoxicity for NK-sensitive K562 cells (a chronic myelogenous leukemia cell line) [1112]. NK cells do not require activation in order to kill target cells that lack expression of major histocompatibility complex (MHC) class I antigens. Kärre et al. [1314] have proposed the “missing self” hypothesis, which states that NK cells act against target cells that do not express MHC determinants characteristic of “self,” while toxicity is inhibited when cells express these determinants.

This “missing self” hypothesis has been supported by the identification of killer cell immunoglobulin-like receptors (KIRs) on NK cells that recognize autologous MHC class I antigens [1516] and inhibit NK cytotoxicity against target cells bearing these determinants.

5.1.1 Activation of NK Cells

Because of their strong cytotoxicity and the potential for autoreactivity, the activity of NK cells is strictly regulated by several factors. Cytokines play a crucial role in the regulation of NK cells. Cytokines involved in the activation of these cells include interleukin (IL)-2 [8], IL-12 [17], IL-15 [18], IL-18 [19], IL-21 [20], IFN-γ [8], and granulocyte-macrophage colony-stimulating factor (GM-CSF) [21].

NK cells, as well as macrophages and several other cell types, express the Fc receptor (FcγRIII: CD16/Leu-11 antigen), an activating receptor that binds the Fc portion of antibodies and allows NK cells to lyse target cells through antibody-dependent cellular cytotoxicity (ADCC) [2223]. Thus, NK cells are fundamentally different from T cells in their lineage and mechanism of nonself recognition.

In addition to the Fc receptor, NK cells express various activating and inhibitory receptors, which maintain the balance of positive and negative signals that controls their cytolytic activity. The KIR family of receptors recognizes and binds both classical and nonclassical MHC class I molecules. Although receptors of this family can have activating or inhibitory cytoplasmic domains, most of these receptors mediate the inhibition of NK cell cytotoxicity. In addition, the nonclassical MHC I molecule HLA-E is recognized by the lectin-like CD94/NKG2 receptor family, which includes both activating and inhibitory receptors [2426]. Thus, NK cells can simultaneously express both activating and inhibitory receptors.

5.1.2 NK Cells and Endometriosis

In 1991 and 1992, Oosterlynck et al. reported that the NK cell activity against autologous endometrium in PB and PF was reduced in women with endometriosis [2728]. Impaired NK cell activity in women with this condition is thought to allow the implantation of endometrial tissue as a graft according to Sampson’s hypothesis [29].

The finding of decreased NK cell activity in women with endometriosis and the positive correlation of NK cell activity in both the PB and PF with the severity of this disease has led to consensus about its pathogenesis [3033].

After removal of endometriotic lesions, decreased NK cell activity and the impaired cytotoxicity of autologous and heterologous lymphocytes against the endometrium are unchanged, and cytotoxicity is still significantly decreased compared with that in women who do not have endometriosis. These findings suggest a primary deficiency of NK cell activity in women with endometriosis, which could explain its frequent relapse after treatment [34].

Survival of endometrial cells in the peritoneal cavity of women with endometriosis [35] is mainly due to decreased NK cell activity, but is also related to resistance of these cells to NK cytotoxicity [3638].

The “missing self” hypothesis has been supported by the identification of KIRs on NK cells that recognize self-determinants among MHC class I antigens andinhibit NK cell cytotoxicity against target cells bearing these determinants. In women with endometriosis, expression of inhibitory killer immunoglobulin-like receptors on NK cells from PB and PF is significantly upregulated compared with the level of expression in women without endometriosis [3941], indicating a decrease of NK cell activity and cytotoxicity for endometriotic cells.

5.2 NK Cell Receptors

5.2.1 Killer-Cell Immunoglobulin-Like Receptors (KIRs)

The KIR genes are polymorphic and highly homologous genes that are located in a cluster on chromosome 19q13.4 [25]. The KIR proteins are classified by the number of immunoglobulin (Ig)-like extracellular domain receptors (2 or 3) and by whether they have a long or short cytoplasmic tail. KIR proteins with a long cytoplasmic tail transduce inhibitory signals upon ligand binding via an immunoreceptor tyrosine-based inhibitory motif (ITIM) after binding tyrosine phosphatase SHP1/SHP2, while KIR proteins with a short cytoplasmic tail that lacks the ITIM associate with the tyrosine kinase-binding protein ZAP-70/Syk instead transduce activating signals via an immunoreceptor tyrosine-based activation motif (ITAM) [4244].

Most KIRs are inhibitory, indicating that recognition of MHC antigens by these receptors suppresses the cytotoxic activity of NK cells, while only a limited number of KIRs have the ability to activate these cells. The ligands for several KIRs are subsets of both classical HLA-Ia antigens (HLA-A, HLA-B, HLA-C) and also nonclassical HLA-Ib antigens (HLA-G) [4546].

5.2.1.1 KIR2DL1 and Endometriosis

In women with endometriosis, the decrease of NK cell activity may be related to the inhibitory KIRs expressed by NK cells.

The percentage of cells expressing KIR2DL1 among NK cells in PF and PB was reported to be significantly higher in women with endometriosis than in controls, suggesting that this receptor is probably related to suppression of NK cell activity in endometriosis [39]. The elevated percentage of KIR2DL1+ NK cells in PB from women with endometriosis was not reduced by laparoscopic surgery or by gonadotropin-releasing hormone agonist treatment. Thus, KIR2DL1 overexpression may be a primary event that represents a risk factor for both the development of endometriosis and its recurrence after treatment [40].

5.2.1.2 KIR2DL4 and Endometriosis

KIR2DL4-expressing NK cells have been identified in both the PB and PF [47]. Expression of HLA-G (a ligand for KIR2DL4), ILT-2, and ILT-4 by eutopic endometrium was only detected during the menstrual phase and was not found in either proliferative or secretory endometrium [47]. Because HLA-G-expressing cells were detected in PF during the menstrual phase, retrograde menstruation may allow eutopic endometrial cells bearing HLA-G to enter the peritoneal cavity and react locally with KIR2DL4.

Due to the innate immunological activity of KIR2DL4 targeting HLA-G, KIR2DL4-expressing NK cells in the PF may be cytotoxic for HLA-G-expressing endometrial cells that enter the peritoneal cavity through retrograde menstruation. Mutant (9A)/wild-type (10A) polymorphism would modulate the response of peritoneal NK cells to membrane-bound HLA-G on endometrial cells, and inhibitory ILT-2 and ILT-4 receptors may also influence the local immune response together with KIR2DL4. Thus, impaired cytotoxicity for endometrial cells could allow these cells to survive and result in ectopic implantation that produces peritoneal endometriosis.

5.2.2 CD94/NKG2A

CD94/NKG2A is a member of the C-type lectin receptor family composed of a CD94 chain covalently bound with a member of the NKG2 family. The ligand of CD94/NKG2A is HLA-E, a nonclassical HLA-Ib molecule. After binding of CD94 with NKG2A that has the ITIM, the resulting CD94/NKG2A heterodimer forms an inhibitory receptor, whereas association of CD94 with an NKG2 family member lacking the ITIM (NKG2C) may not form an inhibitory receptor.

5.2.2.1 CD94/NKG2A and Endometriosis

Despite its interesting inhibitory function, little has been reported concerning CD94/NKG2A and endometriosis. Women with stage III and stage IV endometriosis were found to have a significantly higher percentage of CD94/NKG2A+ peritoneal NK cells than control women [48], and HLA-E (the CD94/NKG2A ligand) has been identified in endometriotic tissues [48]. Because target cells expressing HLA-E show resistance to NK cell-mediated cytotoxicity in a CD94/NKG2A-dependent manner, the increased expression of CD94/NKG2A by peritoneal NK cells may mediate the resistance of endometriotic tissues to NK cell cytotoxicity and thus contribute to the progression of endometriosis [48].

5.2.3 Immunoglobulin-Like Transcript (ILT)

The immunoglobulin-like transcript (ILT) gene family has up to 11 members in humans. The extracellular part of each ILT molecule includes at least two and usually four immunoglobulin domains. ILT-2 through ILT-5 are all inhibitory members of this family with different numbers of cytoplasmic ITIM domains. ILT1, ILT7, and ILT8 have a short cytoplasmic tail and a charged amino acid residue in the transmembrane domain, and these family members deliver an activating signal through the cytoplasmic ITAM of the associated common g chain of Fc receptor (FcRg).

5.2.3.1 Immunoglobulin-Like Transcript (ILT) and Endometriosis

ILT-2 and ILT-4 bind to HLA-G with a three- to fourfold higher affinity than that for classical MHC class Ia [49], suggesting that ILT/HLA-G recognition may play a dominant role in regulating the activation of NK cells, T cells, and monocytes. Although ILT is thus thought to have a role in the pathogenesis of endometriosis, surprisingly, there has been no report concerning its interaction with this disease.

5.3 NK Receptor Ligands on Endometrial Cells

5.3.1 HLA Class Ia

In 1990, expression of HLA class I molecules was identified on human endometrial and endocervical epithelial cells [50]. This suggests that KIRs expressed on NK cells can respond to their HLA class I ligands on eutopic endometrium [3941]. It was also reported that progesterone induces HLA class I mRNA expression by cultured cells from secretory endometrium [51].

In women with endometriosis, HLA class I expression by both glandular cells and stromal cells is significantly elevated compared with that in controls [52]. Furthermore, women with endometriosis show significantly higher expression of HLA class I molecules by eutopic endometrial cells compared with controls [52].

Our investigations have suggested that HLA-C-expressing endometrial cells may enter the peritoneal cavity via retrograde menstruation and react with peritoneal NK cells expressing KIR2DL1 [3941]. Impaired KIR2DL1 expression by peritoneal NK cells could allow endometrial cells to survive in the peritoneal cavity and undergo ectopic implantation, favoring the onset and progression of endometriosis.

5.3.2 HLA Class Ib

5.3.2.1 HLA-E

HLA-E is one of a family of molecules known as HLA class Ib and it has a very specialized role in the recognition of other cells by NK cells. HLA-E is very highly conserved and presents a small repertoire of peptides of various origins [53]. NK cells recognize the HLA-E/peptide complex via the heterodimeric inhibitory receptor CD94/NKG2A or the activating receptor CD94/NKG2C. When CD94/NKG2A is stimulated, it has an inhibitory effect on NK cell cytotoxic activity and prevents target cell lysis [54].

Expression of HLA-E, the ligand of CD94/NKG2A, has been detected in endometriotic tissues. Target cells bearing HLA-E show resistance to NK cell cytotoxicity in a CD94/NKG2A-dependent manner. Therefore, increased expression of CD94/NKG2A by peritoneal NK cells may mediate the resistance of endometriotic tissue to NK cell cytotoxicity, thus contributing to the progression of endometriosis [48].

5.3.2.2 HLA-G

5.3.2.2.1 Receptors for HLA-G

HLA-G appears to be mainly recognized by ILT-2 and ILT-4 receptors, which are expressed by T and B lymphocytes, as well as NK cells and monocytes, and inhibit the activating signals received by these cells. In addition to ILT, HLA-G can also react with KIR2DL4 expressed on NK cells and T cells. Although the expression of ILT2, ILT3, ILT4, and KIR2DL4 is known to be upregulated by HLA-G in antigen-presenting cells, NK cells, and T cells [55], whether the HLA-G/KIR2DL4 interaction leads to activation or inhibition of NK cells remains a complicated and controversial issue.

5.3.2.2.2 HLA-G and Endometriosis

Hornung et al. reported that HLA-G was not expressed by eutopic endometrium or endometriotic tissue [56] and HLA-G protein was not detectable in peritoneal fluid from endometriosis patients or controls. Moreover, ectopic and normal endometrial tissues and stromal cells did not express HLA-G during the proliferative phase. Accordingly, they concluded that immune cell inhibition in endometriosis is mediated by factors other than HLA-G.

In another study, HLA-G expression was identified in the glandular epithelium of peritoneal endometriotic implants, but not in eutopic endometrium [57]. The authors concluded that differential expression of HLA-G suggests peritoneal inflammation or cellular stress may upregulate mechanisms promoting the survival of ectopic endometrium.

According to our recent findings, KIR2DL4-expressing NK cells can be identified in both the PB and PF. Interestingly, we found that HLA-G (a ligand of KIR2DL4) was only expressed by eutopic endometrium during the menstrual phase and not during the proliferative or secretory phases [47]. In addition, we detected HLA-G-expressing cells in PF during the menstrual phase [47]. This suggests that cells bearing HLA-G may enter the peritoneal cavity through retrograde menstruation, allowing the antigen to react locally with KIR2DL4.

In 2000, Ibrahim et al. reported that stress, including heat shock and arsenite treatment, induces an increase in the expression of various HLA-G alternative transcripts without affecting other MHC class I transcripts (HLA-A, HLA-B, HLA-E, and HLA-F) [58].

A heat shock element (HSE) that binds to heat shock factor 1 (HSF1) trimers under stress conditions has been identified within the HLA-G promoter. When stresses such as heat shock, bacterial infection, and poisons (including arsenite) affect cells, cytoplasmic heat shock factor (HSF)-1, which is usually regulated by HSF-2 and HSF-4, undergoes translocation into the nucleus where it forms trimers and binds with the HSE located in the promoter region of the heat shock protein (Hsp) and HLA-G genes (37), resulting in the induction of hsp70 and HLA-G [58].

We detected HLA-G expression by eutopic endometrial cells during menstruation [47], which presumably reflects the stressful intrauterine environment at this time.

In the normal menstrual cycle, a decrease of the serum progesterone level induces uterine smooth muscle contraction and spiral artery spasm, resulting in menstruation [59]. Transient bacterial invasion and inflammation may also affect the eutopic endometrium during menstruation, and increased expression of Hsp70 and HLA-G by the endometrium may result from such “physiological” stress. Hsp70- and HLA-G-expressing endometrial cells that enter the peritoneal cavity via retrograde menstruation may react with immunocompetent cells such as NK cells in the PF and be eliminated. However, an impaired NK cell response to these antigens could lead to endometrial cell survival in the PF and implantation with subsequent development of endometriosis (Fig. 5.1).

A313895_1_En_5_Fig1_HTML.gif

Fig. 5.1

In the usual menstrual cycle, “physiological” stresses such as progesterone withdraw, smooth muscle contraction, spasm of spiral artery, ischemia-reperfusion, oxidative stress, and transient bacterial infection may occur in the uterus. Increased expression of Hsp70 and HLA-G in the endometrium during menstruation may result from such stress pathway. Hsp70- and HLA-G-expressing endometrial cells in the retrograde menstruation may react with immunocompetent cells such as NK cells in PF and finally disappear from peritoneal cavity or survive and develop to endometriosis. HSF heat shock factor, HSE heat shock element, HSP heat shock protein, KIR killer immunoglobulin-like receptor, ILT immunoglobulin-like transcript

5.4 Conclusions

We demonstrated that HLA-G was expressed in the eutopic endometrium during menstruation, suggesting the existence of physiological stress during the menstrual phase. HLA-G-expressing endometrial cells may enter the peritoneal cavity via retrograde menstruation and react with immunocompetent cells, particularly NK cells. Retrograde menstruation involves the backflow of menstrual discharge from the uterine cavity through the fallopian tubes into the peritoneal cavity. It is a physiological phenomenon that is observed in women with patent tubes.

There is probably a physiological system that removes displaced tissues or debris from the peritoneal cavity and peritoneal NK cells presumably play an important role in this system. Expression of HLA-G by endometrial cells during the menstrual phase and entry of such cells into the peritoneal cavity may induce a local immune response from immunocompetent cells including KIR2DL4-expressing NK cells, while impaired NK cell activity could allow the survival and ectopic implantation of endometrial cells.

Impairment of the physiological immune surveillance system (particularly NK cell function) may favor endometrial cell implantation and thus trigger the onset of endometriosis. Further investigation of the molecular mechanisms leading to expression of antigens during menstruation and the role of immunocompetent responder cells in the PF may contribute to better understanding of the pathogenesis of endometriosis.

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