子宫内膜异位症的免疫学相关研究进展

高 涵，张 萍

上海交通大学医学院附属新华医院妇产科，上海200092

Endometriosis is an estrogen-dependent, benign gynecologic disease that involves the growth of endometrial glands and stroma in various locations outside the endometrium. It has been observed among the women of all ethnic and social groups, and has afflicted approximately 10%-15% of the women at the reproductive age[1]. The locations most commonly happened are the ovaries, fallopian tubes, bladder, recto sigmoid colon and uterine myometrium (adenomyosis). The primary clinical symptoms of endometriosis are chronic local inflammatory process, poor oocyte development, dysmorphology of the fallopian tubes, and intense abdominal pain from ectopic lesion growth.

Endometriosis was first described almost 400 years ago. Although several theories have been proposed, none of these could fully explain the etiology. At present, there are three main theories on endometrial lesion establishment: retrograde menstruation, coelomic metaplasia and stem cell. The most widely accepted theory is the retrograde menstruation theory of Sampson, which proposes that viable endometrial tissues are disseminated into the peritoneal cavity via the fallopian tubes during menstruation, and subsequently implants into the peritoneal tissue or pelvic organs[2]. The evidence for Sampson's theory comes from the women with cervical stenosis and other congenital outflow obstructions. The intraperitoneal injection of menstrual endometrium to induce peritoneal endometriosis in a baboon model also confirmed this theory[3]. However, for cases of endometriosis in premenarchal girls, newborns and males, other explanations are need. The coelomic metaplasia theory postulates that endometriosis arises from the metaplasia of cells that line the visceral and abdominal peritoneum, following various hormonal, environmental, or infectious stimuli. In addition, the stem cell theory considers that endometrial stem/progenitor cells from the basalis layer of the endometrium can travel via retrograde menstruation and lymphatic or vascular dissemination into the peritoneal cavity to develop into endometriotic lesions.

Although supported by the theories above, the incidence of endometriosis is low, when compared to the existence of retrograde menstruation, coelomic metaplasia and stem cell development, which are experienced by most women. One hypothesis is that some kind of “eraser” scrubs the endometrial fragments as these enter the wrong cavity, and these become invalid in some individuals, leading the morbidity. In other words, endometriosis is essentially a heterogeneous inflammatory disorder, and the concept of immunological dysfunction has garnered much attention in recent years. To date, adequate contexts have proven the significantly different microenvironment that consists of endometrium tissues, hormones, and innate [macrophages, neutrophils, dendritic cells (DCs) and natural killer (NK) cells] and adaptive (T and B cells) immune cells between the ectopic and eutopic endometrium. In virtue of the transcriptomic profiling, the elevated expression of genes associated with immune cell recruitment, cytokine-cytokine receptor interactions, cellular adhesion and apoptosis in ectopic lesions, when compared to eutopic and control endometrial specimens, have been revealed[4]. Present studies have summarized the changes in immune systems, and attempted to determine whether there is an accompanying or causal relationship between endometriosis and immune events. Since hormones play an important role in pathogenesis and therapy, this is also briefly mentioned in the last part of the article.

1 Immune cells and endometriosis

Immune cells and their products are key to the detection and clearance of abnormal cells. Immune cells, such as T and NK cells, have been recently found to be significantly implicated in determining the acceptance or rejection of survival, implantation, and proliferation of endometrial and endometriotic cells. In this section, the main changes in innate (neutrophils, DCs and NK cells) and adaptive (T and B cells) immune cells that occur during endometriosis were analyzed.

1.1 NK cells

NK cells, which are a component of the innate immune system, have ability to kill malignant or infected cells without prior sensitization. This killing mechanism involves both the production of interferon-γ (IFN-γ), which is a molecule that modulates the function of other immune cells such as macrophages, and the release of cytotoxic granule components such as perforin. Uterine natural killer (uNK) cells are the predominant leukocyte population in the normal human endometrium. Activated uNK cells can produce angiogenic factors [vascular endothelial growth factor (VEGF), angiopoietin 2 (ANG2)] that promote spiral artery remodeling and secrete cytokines [granulocytemacrophage colony stimulating factor (GM-CSF), colony stimulating factor-1 (CSF-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), leukemia inhibitory factor (LIF), interleukin-2 (IL-2), C-X-C motif chemokine ligand 12 (CXCL12)], and direct the migration and invasion of the trophoblast. Giuliani et al[5]reported that women, with or without endometriosis, who had larger populations of cytotoxic CD16+uNK cells and/or higher populations of NKp46+CD56+cells, may have a greater risk for infertility disorders that result from inflammatory environments that occur during implantation or after decidualization. The present study may be correlated to endometriosis, since endometriosis is also characterized by inflammatory manifestations. However, there is no further evidence that clearly defines the role of uNK in endometriosis. A number of studies have focused on peripheral blood NK (pNK) cells, and most of them have not made headway on the pNK cell number[6]. However, a reduced cytotoxic phenotype in pNK cells was confirmed, and the analysis of pNK cell surface markers revealed the elevated expression of the inhibitory receptor domain and immunorecepter tyrosine-based activation motifs (ITAM)-killer immunoglobulin-like receptor (KIR) in endometriosis patients. For example, the best known CD158a, which is an inhibitory KIR, was significantly upregulated in women with endometriosis, when compared to women without the disease[7-9]. As for NK cells in the peritoneal cavity, several chemokines have been found at a low level in the peritoneal fluid (PF) of the women with endometriosis, which implies the changes in NK cell activity. For example, CXCL12, which is an NK cell chemo-attractant, is significantly higher in the PF and ectopic endometrium of women with endometriosis, suggesting the potential recruitment of NK cells into the peritoneal cavity[10]. Meanwhile, the PF from women with endometriosis has been shown to have higher levels of Fas ligand (FasL), when compared to controls. Furthermore, the peritoneal NK cells in the women with mild endometriosis expressed significantly higher levels of CD95 that bound to FasL[11]. Both IL-6 and TGF-β1 in the PF of the women with endometriosis decreased the NK cell cytolytic activity[12-13]. In addition, Montenegro et al[14]reported that both endogenous and exogenous IL-2-activated NK cells are able to track, migrate and infiltrate endometriosis lesions. For the mentioned progress, the aberrant expression of various activating and inhibitory receptors on the NK cell surface in both endometriosis lesions, the peritoneal cavity and peripheral blood have been well-established. Although increased NK cell chemo-attractants and increased NK cell death may lead to counterbalance, in terms of total number, the decrease in NK cell cytotoxicity in endometriosis plays a crucial role in the pathogenesis of endometriosis.

1.2 DCs

DCs, which are a type of antigen presenting cells, are paramount in the activation of adaptive immunity through antigen presentation to naive T cells. Immature DCs are nonexistent in the peritoneal membrane of healthy women, while these are found within endometriotic lesions and the surrounding peritoneal membrane of the women with endometriosis. Elevated mannose receptor-expressing blood DC antigen 1-positive (BDCA1+) myeloid DCs in endometriosis patient PF are capable of phagocytosing dead endometrial stromal cell (ESC) debris. Thus, these may contribute to the inflammatory profile observed in patients through the secretion of IL-6 and IL-1β[15]. A study conducted by Fainaru et al[16]revealed that DCs that infiltrate surgically induce endometriotic lesions in mice, and predominate around the vasculature of the lesion. In addition, the further adoptive transfer of bone marrow-derived DCs in mice resulted in enhanced lesion growth and vascularization. Some experimental results are inconsistent[17]. Stanic et al[17]reported on the depletion of DCs, which led to the growth of endometriotic lesions, while Pencovich et al[18]offered an opposite opinion, that is, the depletion of DCs attenuated the development of endometriosis. Since there is a lack of literatures pertaining to DC function in vivo and inconsistent results in vitro, further attempts should be made to determine whether DCs promote or repress lesion formation, and identify the specific mechanisms.

1.3 Neutrophils

Few studies have focused on the neutrophil phenotype and functions in endometriosis. A study[19]evaluated human neutrophil peptides 1, 2 and 3 in the PF of 67 patients with endometriosis and 16 healthy control women, and compared these to the peritoneal leukocyte subpopulation (neutrophils, T cells and macrophages). This clearly indicated that endometriosis is associated with the increase in concentration of peritoneal neutrophils. This was likely the result of the elevated concentration of potent neutrophil chemo-attractants, such as IL-8, which are present in endometriosis patient plasma and PF[20]. Berkes et al[7]evaluated and described the presence of neutrophil extracellular traps (NETs) in the PF of endometriosis patients. It was demonstrated that NETs may be involved in the complex pathophysiology of endometriosis. Chung et al[21]reported that estrogen functions to support the neutrophil infiltration and neutrophil-mediated establishment of a pro-tumor microenvironment in mammary involution, which enlightens a new frontier on the cooperation between neutrophils and hormones.

1.4 T lymphocytes

T cells are a diverse population of lymphocytes identified by the absence/presence of specific CD markers, transcription factors, cytokine production and cytotoxic capacity. Takamura et al[22]analyzed the proportion of CD4+T lymphocytes, Th1, Th2, Th17 and regulatory T cells (Tregs) in endometriosis lesions and peripheral blood, and found that the T lymphocyte profile was altered, when compared with the healthy contrast. The recent research hotspot Tregs, which is often identified by the expression of the transcription factor forkhead box P3 (FoxP3), secrete immunosuppressive cytokines that promote a state of immune tolerance. Budiu et al[23]reported higher levels of FoxP3+cells in the ectopic endometrium, when compared to the eutopic endometrium from healthy controls. Similarly, Parkin et al[24]used baboon models, and suggested that FoxP3+cells and FoxP3 mRNA are maximums in the ectopic endometrium. In contrast, a decrease was observed in FoxP3+cells and FoxP3 mRNA in the endometrium after the induction of endometriosis in baboons[25]. Furthermore, other studies revealed the establishment of an immunotolerant (Th2/Treg) environment, which appeared to be replaced by an inflammatory Th1/Th17 immune response associated with recurrent pregnancy loss and pre-eclampsia in endometriosis[26-27].

1.5 B lymphocyte

A meta-analysis[28]revealed the role of B cells and antibodies in endometriosis. Among the 22 cases, 14 studies demonstrated the increase in number and/or activation of B cells, seven studies found no difference, and two studies reported a decrease in number of B cells[28]. The increase in B lymphocytes and excessive production of autoantibodies have been described in the literature, but their role in the development of the disease remains not well-understood. In addition to producing antibodies, B lymphocytes also produce cytokines, such as IL-6, granulocyte-macrophage colonystimulating factor and IL-17, leading to perpetuate chronic inflammatory diseases (Section 3, below)[29].

2 Cytokines and chemokines in endometriosis

As it is known, cytokines and chemokines are the main mediators and communicators of the immune system, and cytokine dysregulation has been recognized as an important aspect of the pathogenesis of numerous conditions, including endometriosis. Several pro- or anti-inflammatory cytokines and chemokines for monocytes, macrophages and granulocytes have been identified in the endometrial tissues or PF of the women with endometriosis.

2.1 Interleukin

Among this family, proinflammatory cytokines such as IL-1, and anti-inflammatory cytokines such as IL-4, IL-6, IL-10 and chemokine IL-8 (CXCL8) are very famous members in terms of inflammatory reaction, and several of these have a compact relationship with endometriosis. Sikora et al[30]assessed IL-1β, IL-18 and IL-1 converting enzyme (ICE) in the PF from endometriosis patients, and noted the impairment of the secretion of the IL-1 cytokine family in endometriosis. Invalid IL-1β and IL-18 maturation by ICE may be an important pathogenic factor in endometriosis. Another conclusion from the same study revealed that the levels of IL-1 and IL-6 in serum were the lowest in women who used estrogen and progestin[30]. In contrast, the highest concentrations of both interleukins were found in the serum of women with endometriosis. Similarly, Kang et al[31]reported the increased levels of IL-6 in the PF of patients with endometriosis, and noted that IL-6 levels were negatively correlated with the cytolytic activity of NK cells. Furthermore, IL-6 reduced the cytolytic activity of NK cells, suggesting that IL-6 plays a crucial role in the reduction in NK cell activity in the PF of patients with endometriosis. IL-8 can enhance the invasion and proliferation of ESCs through the focal adhesion kinase (FAK) signal pathway, and its secretion is stimulated by Toll like receptor 4 (TLR4) activation. However, the study conducted by Luo et al[32]has proven the higher expression of TLR4 in the eutopic endometrium, when compared to the normal endometrium, and that ectopic tissues had the highest level of expression. In addition, endometriotic lesions produce IL-17A, and the removal of the lesion via laparoscopic surgery leads to the significant reduction in systemic levels of IL-17A. This shows the likely important role of IL-17A in promoting angiogenesis and the pro-inflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions[33].

2.2 TNF-α

TNF-α is the most studied protein in the TNF family, and is primarily produced by activated macrophages, NK cells and Th1 cells. TNF-α appears to act synergistically with IL-1, since both activate the canonical nuclear factor-κB (NF-κB) inflammatory pathway. Taniguchi et al[34]measured the TNFα-induced inhibitor of apoptosis (IAP) protein expression in ESCs, and supported that TNF-α markedly enhances cellular IAP 2 (cIAP-2) protein expression in ESCs. An antagonist of IAPs abrogated the TNF-α-induced cIAP-2 protein expression, and exhibited a decrease in TNF-α-induced IL-8 protein expression and bromodeoxyuridine (BrdU) incorporation in ESCs. Furthermore, the data reported by Chen et al[35]highlighted the crucial role of TNF-α in CH-PF (PF from patients with chocolate cysts)-induced embryotoxicity, and suggested that TNF-α inhibitors may be potential therapeutic agents for treating endometriosis-induced infertility.

2.3 Other cytokines

Due to the alteration of macrophages and mast cells on the microenvironment, VEGF takes a profound effect as the downstream molecule. For the in vitro culture of isolated peritoneal macrophages and neutrophils, and in the presence of IL-6, TNF-α, lipopolysaccharide (LPS) and estrogen enhanced the VEGF released by these cells[36]. The surgical removal of endometriotic lesions was shown to decrease the serum VEGF in patients, suggesting that lesion presence in the peritoneum has a profound effect on the microenvironment[37]. Other cytokines, such as CSF-1, have been proven to be expressed higher in endometriotic tissue formations and progression, according to the study conducted by Budrys's group[38]. The elevation in CSF-1 after the co-culture of endometrial cells with peritoneal mesothelial cells (PMCs) suggests that endometrial tissues may be a source of peritoneal CSF-1. Hepatocyte growth factor (HGF) secretion facilitates epithelial cell growth and development in the female reproductive tract (FRT), and may contribute to pathological conditions, such as cancer and endometriosis. Treating uterine fibroblasts with estradiol would significantly increase the HGF secretion[39].

3 Associations between endometriosis and autoimmune diseases

Although the pathogenesis of endometriosis remains obscure, there is a consensus among specialists that the basis of its pathophysiology would be multifactorial, and that endometriosis does have a systemic effect that varies with the distance to the end organ. At present, many researchers have aimed to associate autoimmunity and endometriosis, since endometriosis fulfills most of the classification criteria for autoimmune diseases, including polyclonal B cell activation, immunological abnormalities in T and B cell functions, increased apoptosis, tissue damage, and multiorgan involvement. There is also a familial occurrence with a possible genetic preference, a female preponderance, and an increased likelihood of some autoimmune diseases. Overall, the production of many autoantibodies, such as those against endometrial antigens, anti-laminin-l (aLN-1) auto-antibodies and others (e.g. anti-phospholipid antibody) in patients with endometriosis is a serologic characteristic that also supports the theory[40-41]. For example, antinuclear antibodies were found to be present in 18% of patients with endometriosis, 0 of normal controls, and 93% of patients with systemic lupus erythematosus (SLE)[42]. Evidence for the potential link between endometriosis and autoimmune diseases, such as allergies and hypothyroidism, were found in several studies, regardless of whether these cited common clinical elements or reported common serologic factors[41]. The conclusive evidences on the mechanism on how endometriosis triggers autoimmunity due to the presence of autoantibodies in endometriosis patients were further complicated by various comorbidities. More research is needed not only to arrive at an answer to this condition, but also to improve these present approaches for its treatment.

4 Immune and endocrine pathways in endometriosis

Apart from autoimmune disease, endometriosis is known as a hormone-dependent response. The local biosynthesis of estradiol by endometriotic lesions in concert with pronounced inflammation in the aberrant immune-endocrine microenvironment inspire the growth and survival of ectopic lesions. Estradiol (E2), which is a biologically active form of estrogen that interacts with its nuclear receptors, estrogen receptor α (ER-α) and ER-β, plays a critical role in the reconstruction of the endometrium after menstruation. The E2/ER-α/IL-6 immune-mediated signaling axis reported by Burns's team[43]was also implicated in the early endometriosis development in a mouse model. Another research revealed the critical role of ER-β in the activation of innate NOD-like receptor pyrin domain-containing 3 inflammasome, which perpetuates IL-1β production and lesion growth[44].

5 Conclusion

Endometriosis is one of the most investigated disorders in gynecology. However, this still remains enigmatic. This is presently treated medically, surgically, or in the combination of both approaches. Surgical treatments are usually used for large lesions in severe degree, while other endometriosis suppressions includes estrogen-progesterone combinations, progesterone-only modalities, and other novel therapeutics, such as cIAP-2, and CSF-1 inhibitors, such as imatinib[37,40]. The present literature shows that immunological factors are significantly involved in the pathogenesis of endometriosis, and the crosstalk among the stromal, epithelial and immune compartments mentioned above provides challenges that needs to be puzzled out. Understanding the pathogenesis of endometriosis may help to develop more effective and safer medication, which can inhibit disease development, and alleviate pain or infertility, without the inhibition of ovulation and menstruation. The potential use of immunomodulators should be further investigated.

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