1 Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, 310016 Hangzhou, Zhejiang, China
Abstract
Endometriosis is defined as a disorder in which the glands and stroma of the endometrium grow and shed periodically outside the uterine cavity. Highly prevalent in women of reproductive age, the most common clinical manifestations are chronic pelvic pain and infertility. The pathogenesis of endometriosis may be multifactorial, including factors of anatomy, immunity, inflammation, hormones (estrogen), oxidative stress, genetics, epigenetics, and environment. There are generally three types of endometriotic disease, namely peritoneal, ovarian, and deep infiltration. For the same patient, there may be a single or multiple types concurrently. The different manifestations of these types suggests that they each have their own etiology. Numerous studies have shown that the evasion of endometrial cells from peritoneal immune surveillance helps establish and maintain peritoneal endometriosis, but the specific mechanism is not well understood. Likewise, the molecular mechanisms of endometriosis-related infertility have not been clearly elucidated. This review attempts to identify the role of peritoneal immunity in peritoneal endometriosis and related infertility, especially in the aspects of molecular mechanisms.
Keywords
- peritoneum
- immune
- endometriosis
- lymphocyte
- macrophage
Endometriosis is defined as a disorder in which the glands and stroma of the endometrium periodically grow and shed outside the uterine cavity, resulting in severe chronic pelvic pain and infertility [1]. Generally, endometrial lesions contain the endometrial epithelium as well as stromal cells, blood vessels, and lymphocytes. Endometriosis affects more than 10% of women of reproductive age, whereas it occurs in 25–50% of infertile women. In turn, it has been reported that 35–50% of women with endometriosis suffer from infertility [2]. There are generally three types of endometriotic disease, namely, peritoneal, ovarian and deep infiltration, each with a different etiology. Of these, peritoneal endometriosis is the most common [3], hence our focus herein. The pathogenesis of endometriosis may be multifactorial, including factors of anatomy, immunity, inflammation, hormones (estrogen), oxidative stress, genetics, epigenetics and environment [4]. The two major theories about the etiology of peritoneal endometriosis are those of menstrual reflux and coelomic metaplasia [5]. The peritoneum is an important immune barrier, and the peritoneal cavity composed of it forms an immune microenvironment. Under the action of cytokines and chemokines, the peritoneum continuously recruits leucocytes from blood, of which monocytes and macrophages (MՓs) are the majority, accounting for more than 50% [6]. The peritoneum itself contains plentiful immune cells, including MՓs, mast cells (MCs), B1 cells, T cells, etc. [7, 8].
Under normal physiological conditions, peritoneal immunity tends to be in a balanced state. When it is stimulated by external stimuli, pro-inflammatory factors first initiate and promote inflammatory response. For body protection, anti-inflammatory factors then play a role to calm inflammation and begin tissue reconstruction to maintain body homeostasis. In patients with endometriosis, immune imbalance is manifested by reduced cytotoxicity of T lymphocytes, cytokines secreting by T helper (Th) cells, and autoantibody produced by B lymphocytes [9, 10]. While menstrual reflex occurs in almost all women of reproductive age, only 10% suffer from endometriosis. Many studies have confirmed that the number and activity of various immune cells in the peritoneal fluid of women with endometriosis, as well as the expression levels of secreted cytokines and inflammatory mediators, have changed. As the first site of broken endometrial fragments (also viewed as an exogenous stimulus) into the peritoneal cavity, what is the role of peritoneum in the occurrence and development of pelvic peritoneal endometriosis, and how does the local immune microenvironment of peritoneal cavity alter? What is the relationship between these alterations and endometriosis-related infertility? This review attempts to identify the role of peritoneal immunity in peritoneal endometriosis and related infertility, especially in the aspects of molecular mechanisms.
The peritoneum has approximately the same area as the surface
of the skin (1.8 m
The fluid in the peritoneal cavity is called peritoneal fluid. There are
different types of immune cells in peritoneal fluid [17]. This lays the
foundation for the peritoneum to participate in immune regulation of the body.
Studies have shown that there are ample stomata on peritoneal surfaces [13], that
are directly connected with the lymphatic system [18, 19, 20] and that facilitate
communication between the peritoneum and the lymphatic system by helping the
cells in the peritoneal cavity to absorb and migrate to the lymphatic system [20, 21]. These lymphatic portals located between the mesothelial cells, are usually
arranged around milky spots. Milky spots, on the other hand, are considered as
secondary lymphoid organs: an aggregation of immune cells, mainly composed of
MՓs, B cells, and T lymphocytes. Milky spots can respond to intraperitoneal
infection and play an antigen recognition role by amplifying the recruitment of B
cells and CD4
Normally, the peritoneum has an anti-inflammatory effect to prevent infectious peritonitis. The peritoneal inflammatory response is characterized by increased vascular perfusion, aggregated macrophages, and the release of pro- and anti-inflammatory factors [22]. Not only are MՓs abundant in the peritoneal fluid, but the stroma of the peritoneum also contains a certain number of MՓs that recognize and digest foreign material and subsequently recruit more inflammatory leukocytes such as monocytes, lymphocytes and neutrophils from blood. Influenced by these cells, mesothelial cells secrete inflammatory mediators [23, 24, 25, 26]. Moreover, adhesion molecules expressed on the surface of mesothelial cells interact with recruited leukocytes to reduce inflammation [27]. Interestingly, mesothelial cells of the peritoneum also act as antigen-presenting cells (APCs), displaying antigen fragments on their cell surface. Valle et al. [28] pointed out that mesothelial cells express major histocompatibility complex (MHC)-II molecules and present antigens to T cells, thus participating in T-cell activation together with resident MՓs, resulting in a cell-mediated immune response to pathogens. This complex peritoneal defense system works well against inflammation while an excessive immune response may lead to angiogenesis, fibrosis and injury of the peritoneum. When the inflammatory triggers remain, peritoneal inflammation does not stop, resulting in peritoneal scarring, impaired tissue function and eventual organ failure. Examples include autoimmune serositis caused by reactions to self-antigens, or peritoneal carcinomatosis and endometriosis caused by reactions to neoplastic or ectopic cells.
Pelvic peritoneal endometriosis refers to endometriosis located in the peritoneum around the uterus, fallopian tubes, and ovaries. Retrograde menstruation may cause this disease by activating the innate immune system in the pelvis, which induces local inflammation [29, 30]. Although menstrual reflux is common, peritoneal endometriosis does not exist in all women of reproductive ages [2]. In patients with endometriosis, the ability of endometrial cells and glands that flow into the peritoneal cavity with menstrual reflux to grow and survive depends on the specific pelvic environment. The decisive factor seems to be the large number of lymphocytes found in endometriotic lesions [31]. There is increasing evidence that immune disturbance is a major factor in the occurrence and evolution of endometriosis [32, 33, 34]. Individual peritoneal immune response promotes evolution of endometriosis [30]. This theory of immune system alterations and endometriosis suggests that changes in cellular and humoral immunity may promote development of the disease [35].
The most common immune cells in peritoneal cavity are MՓs [36]. Peritoneal MՓs (PMՓs) are divided into resident MՓs and monocyte-derived MՓs. The formers are representative of MՓs: they represent a strong phagocytic capacity, displaying longevity and self-renewal ability. Activated MՓs can not only remove damaged tissue, cellular debris and red blood cells via phagocytosis, but also regulate the peritoneal microenvironment with the help of their secreted cytokines, prostaglandins, enzymes and complement components [10]. In turn, those mediators secreted by MՓs promote themselves to induce inflammatory responses, tissue remodel, angiogenesis, and possibly recruitment of endothelial cells [37, 38]. Due to their phenotypic plasticity, activated MՓs can be divided into two types with different functions according to the altered microenvironments [39]. M1 type performs pro-inflammatory functions by secreting numerous inflammatory cytokines to specifically eliminate microorganisms and defective cells. M2 type plays the opposite role by secreting anti-inflammatory factor, participating in regulating adaptive immune responses, facilitating angiogenesis, tissue repair and the removal cell debris [40, 41, 42, 43].
Normally, the M1/M2 MՓs are in balance to keep the body in homeostasis. This
balance is skewed in favor of M1 type in the eutopic endometrium in women with
endometriosis [44], whereas it tends to be M2 type polarized in the peritoneum
and ectopic lesions [45]. Some scholars have proposed that the resident
M
Despite the number of activated PMՓs increasing significantly in women with endometriosis [10], their phagocytic capacity is considerably decreased, so that endometrial cells arriving in the pelvic cavity via retrograde menstruation cannot be cleared. Wu et al. [49] found that the content and activity of matrix metalloproteinases (MMPs) expressed by PMՓs in patients with endometriosis were inhibited, through which MՓs bind to extracellular matrix and play a phagocytic role. The downregulation of MMPs may be mediated by the overexpression of prostaglandin E2 (PEG2) in the peritoneal fluid. Other studies have found an increased proportion of free MՓs in the peritoneal cavity of women with endometriosis [50], suggesting that the decrease of conjugated MՓs implies a decrease in phagocytosis, thus sparing ectopic endometrial cells from phagocytosis and allowing them to plant and develop in the peritoneum. In conclusion, PMՓs may (1) regulate the dynamic changes of secreted proinflammatory factors and anti-inflammatory factors through the change of active phenotype; (2) reduce phagocytosis of the endometrium and stroma contained in reflex menstruation to promote the occurrence and development of peritoneal endometriosis.
NK cells, named for their cytotoxic properties, recognize and kill target cells, such as certain tumor cells, virus-infected cells, self-tissue cells (damaged cells), and parasites. They can also synthesize and secrete cytokines to play immune regulation. The regulation of NK cell activity depends on the interaction of two types of receptors expressed on the cell surface, namely activated receptor (KAR) and inhibitory receptor (KIR). KIR protects autologous cells by recognizing MHC-I molecules on their surface to generate inhibitory signals and block the activation of KAR. When the target cells lose MHC-I molecules, the inhibitory effect is relieved and KAR receptor activates NK cells to produce killing effect. KAR receptors, which mainly contain natural killer group 2 member D (NKG2D) and CD16, can bind to target cells coated with immunoglobulin G (IgG) and destroy target cells through an antibody-dependent cell-mediated cytotoxic mechanism. Thus, the increase of NKG2D ligand can trigger cytotoxic reactions of activated NK cells.
Oosterlynck et al. [51] first found reduced cytotoxicity of NK cells in both peritoneal cavity and peripheral blood of patients with endometriosis, confirmed by subsequent studies [52]. González-Foruria et al. [53] found that soluble NKG2D ligands were significantly increased in the peritoneal fluid of patients with endometriosis, implying that fewer NKG2D ligands were expressed on the surface of ectopic endometrial cells. This would make it easier for NK cells to evade recognition due to these soluble NKG2D ligands acting as bait receptors. Wu et al. [54] have found that the excessive expression of KIR in peritoneal NK cells of patients with endometriosis may also explain the decreased activity of NK cells. A recent study found that the chemotaxis (i.e., the ability to migrate to the site of immune response) of peritoneal NK cells decreases in patients with endometriosis, which may lead to the defect of NK cells’ cytotoxic function [55]. It is not clear whether this phenomenon is caused by differences in NK cell function per se or by differences in the peritoneal environment caused by retrograde menstruation, which warrants further exploration. Decreased cytotoxicity and chemotaxis of NK-cells in the peritoneal cavity reduce their ability to clear endometriotic cells and may be associated with the evolution of endometriosis.
Like MՓs, MCs usually reside in the mucosal epithelium of the lungs, digestive
tract, and reproductive tract, representing the first line of defense: in humans,
they are also positioned at mesothelium-covered cavities including the
peritoneal cavity [56]. MCs are degranulated when stimulated by allergens to
produce histamine and protease to participate in immunity [57]. MCs can be
divided into at least two populations depending on the protease they contain. MCs
containing only tryptase are called mucosal mast cells (MMCs) in mice and
MC
The main function of eosinophils is to regulate allergic reactions and to activate and attack pathogens during parasitic infections. Early studies found an indirect association between eosinophils and endometriosis. Hornung et al. [63] found that in both eutopic endometrium and ectopic endometrium in women with endometriosis, the expression of extaxin, a highly specific eosinophil chemotactic factor, is significantly elevated versus that in normal controls. Blumenthal et al. [64] found that the level of Eosinophil peroxidase (EPO), an enzyme released by degranulated eosinophils, was increased in ectopic lesions of patients with endometriosis. By establishing a mouse model of endometriosis, Uchiide et al. [65] found that the adherent peritoneal stroma showed the proliferation and infiltration of eosinophils related, which was thought to be the peritoneal manifestation in the early stage of endometriosis. A subsequent study found elevated eosinophil counts in the peritoneal fluid of patients with early endometriosis [66]. These studies suggest that eosinophils may be involved in the pathogenesis of endometriosis.
Neutrophils play a crucial role in the innate immune system as the second line of defense against microbial invasion, with strong chemotaxis and phagocytosis. The structure and metabolism of peripheral blood neutrophils in patients with endometriosis are changed [67], and the phagocytic function is decreased [68]. After surgical resection of endometriotic lesions, the phagocytic activity of peripheral blood neutrophils can be restored to normal temporarily, but only for a short time [68]. Conversely, the number of neutrophils is increased both in the peritoneal fluid and ectopic lesions of women with endometriosis, potentially secreting cytokines that promote angiogenesis [69, 70]. Co-culture with peritoneal fluid from patients with endometriosis induces neutrophils to release more vascular endothelial growth factor (VEGF), a factor that increases vascular permeability and promotes angiogenesis [71]. A recent study showed that granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6) regulate neutrophils through signal transducer and activator of transcription 3 (STAT3) pathway, altering the expression of angiogenesis-related genes, such as Mmp9, Bombina variegata 8 kDa protein (Bv8), and tumor necrosis factor-related apoptosis-inducing ligand (Trail) to promote the establishment of early endometriosis [72].
DCs, the most powerful specialized antigen-presenting cells discovered, can recognize and phagocytose antigens and present them to T lymphocytes. Generally, DCs are divided into two main groups: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs contain two subpopulations, namely cDC1 and cDC2, which can recognize and phagocyte antigens before maturing. After differentiation and maturation stimulated by inflammatory factors, mature DCs acquire the ability of migration, antigen presentation and T-cell differentiation. For example, cDC1 subgroup is also commonly referred to as Th1-inducing cells [73]. DCs control the differentiation of Th cells or regulatory T (Treg) cells; accordingly, researchers speculate that DCs could cause their functional abnormalities. Several studies have indicated that abnormal DC frequency in the uterus or peritoneal fluid may lead to endometriosis [74, 75, 76]. Unlike cDCs, pDCs detect the nucleic acid of pathogens and produce an abundance of interferons (IFNs), currently considered as a therapeutic target in endometriosis. According to Suen et al. [77], in the mouse model, IL-10 in endometriosis is mainly derived from pDC secretion; pDC was found to increase endometrial lesions, but this phenomenon was not observed in IL-10 knockout mice [78]. However, other researchers found that the frequency of pDCS in the peritoneal fluid of patients with endometriosis did not change [75]. Further studies on the function of peritoneal pDCs are needed to confirm whether they are associated with the establishment and evolution of endometriosis.
The complement system, a part of the innate immune system, consists of a series of proteins that undergo complex cascades upon activation and are highly effective in labeling the non-self (such as pathogens), altered self (such as apoptotic/necrotic cells and protein complex), and transformed self (such as tumor cells) [79, 80]. This is followed by lysis of target cells/pathogens, opsonization and subsequent enhancement of their uptake by immune phagocytes via complement receptors, and production of inflammatory mediators. Two anaphylatoxins, C3a and C5a, produced by activated complement, act as activators to stimulate peritoneal MCs and macrophages to produce mediators or cytokines; furthermore, increased endometrial vascular permeability causes inflammation and pain symptoms [81]. Numerous studies have found that the levels of various components of complement, such as C1q, C3a, C3c, C4, and sC5b-9 are significantly increased in the peritoneal fluid of patients with endometriosis. Accordingly, the complement system may also be a vital part of the pathogenesis of endometriosis [82, 83, 84].
Adaptive immunity refers to the process of activation, proliferation and
differentiation of antigen-specific T/B lymphocytes into effector cells and the
production of biological effects after being stimulated by antigens in
vivo. According to the different cell types and mechanisms involved in immune
response, adaptive immunity can be divided into T-cell-mediated cellular immunity
and B-cell-mediated humoral immunity. T lymphocytes, derived from bone marrow and
embryonic liver, migrate to thymus and mature into immunocompetent T lymphocytes.
According to the differences in their expressed glycoproteins CD4 and CD8, which
can bind to MHC-II and MHC-I molecules, respectively, T cells are divided into
two major categories [85, 86], namely, CD4
The concentration of Th2-type cytokines in peripheral blood and peritoneal fluid
was found to be elevated in women with endometriosis [90, 91]. Studies have found
that compared with normal endometrium, Th17 cells are more commonly present in
endometriotic lesions [92], and their content in peritoneal fluid is positively
correlated with disease grade [93]. IL-17A secreted by Th17 can stimulate
inflammatory response and promote the occurrence of endometriosis [94, 95].
Authors almost unanimously agree that increased Treg cells in the peritoneal
fluid are associated with local immune suppression, allowing ectopic endometrial
cells to escape clearance [96, 97]. CD8
B lymphocytes are derived from bone marrow and are released into peripheral lymphoid tissues after they develop into mature B cells, which are activated into plasma cells and begin to secrete antibodies, participating in humoral immunity [99, 100]. Excessive polyclonal activation of B cells has been found in patients with endometriosis via secretion of autoantibodies in endometriotic lesions, peritoneal fluid and blood [101, 102, 103]. Badawy et al. [104] found that the number of B cells was elevated in both the peripheral blood and peritoneal fluid of patients with endometriosis. Another study found that B1 lymphocytes (a subset of B lymphocytes, which do not have memory function but can produce antibodies to attack antigens) in the peritoneal fluid of patients with endometriosis and positive antinuclear antibodies (ANAs) are significantly increased, suggesting that this phenomenon may pertain to endometriosis-related infertility [105]. Others also found that the increase in the number of B cells in the follicular fluid of patients with endometriosis may damage the quality of eggs and cause infertility [106].
Levels of anti-endometrial antibodies and anti-ovarian antibodies have been
found to be significantly increased in patients with endometriosis, and elevated
levels of IgA and IgG-type antibodies in peritoneal fluid also have been
discovered [107, 108]. In addition to anti-tissue and anti-organ antibodies, B
lymphocytes also produce antibodies to cellular components, such as
antiphospholipid, anti-DNA and ANA, which are commonly seen in autoimmune
diseases [9]. An immunoregulatory B cell subtype, called B-reg cells, secretes
IL-10, which not only controls effector immune responses, but even controls the
progression of autoimmune diseases [97]. Animal experiments [98] suggest that
B-reg cells may help prevent the progression of endometrial lesions. An
immunoregulatory B-cell subtype, known as B reg cells, controls the progression
of autoimmune diseases by secreting IL-10 and TGF-
In conclusion, B cells may participate in the pathogenesis of endometriosis through their own activation and the production of antibodies and a small number of cytokines. However, their role in the microenvironment of endometriosis and their interaction with other immune cells need to be further explored.
Many studies have found that the increase in the number of various immune cells in the peritoneal fluid of women with endometriosis directly leads to elevated levels of soluble proteins, including certain cytokines, growth factors, enzymes and antibodies in the peritoneal fluid, lesions and peripheral blood [38, 115, 116, 117, 118, 119]. All the inflammatory factors and cytokines interact to regulate cellular and humoral immunity [17]. Their roles are shown in Table 1.
| Inflammatory factors and cytokines | The role in endometriosis |
| IL-1 | 1. affects the proliferation of ectopic endometrial cells |
| 2. regulates the expression of ICAM-1 on cell surface | |
| 3. stimulates the release of VEGF and IL-6 | |
| 4. has a negative effect on fertility | |
| IL-2 | unclear; more exploration is needed |
| IL-4 | 1. stimulates the proliferation of B and T lymphocytes |
| 2. promotes the differentiation of CD4 | |
| 3. induces the proliferation of its stroma cells | |
| IL-6 | 1. increases haptoglobin |
| 2. inhibits NK cell activity | |
| 3. regulates the growth of endometrial stromal cells | |
| IL-8 | 1. chemotaxis to neutrophils |
| 2. participates in neutrophil activation | |
| 3. proangiogenic effect | |
| 4. contributes to cell adhesion | |
| 5. promotes the proliferation of ovarian endometrioma-derived stromal cells | |
| IL-10 | decreases NK cell cytotoxicity |
| IL-13 | paradoxical; more exploration is needed |
| TNF- |
1. MՓs recruitment |
| 2. neutrophils recruitment | |
| 3. cell adhesion (endometrial cells and peritoneum) | |
| 4. stimulates the proliferation of stroma cells | |
| IFN- |
1. activates MՓs |
| 2. promotes development of T lymphocytes | |
| 3. interacts with IL-2 to shift the Th1/Th2 balance in favor of Th2 | |
| TGF- |
1. decreases NK cell cytotoxicity |
| 2. (TGF- | |
| 3. induces epithelial to mesenchymal transition (EMT) | |
| 4. increases VEGF-A secretion from the peritoneal mesothelium | |
| 5. promoting the vascularization of endometriosis lesions | |
| 6. enhances the migration, invasion and colonization potential of the endometriotic cells | |
| VEGF | 1. increases vascular permeability |
| 2. promotes the deformation of extracellular matrix | |
| 3. makes vascular endothelial cells migrate and proliferate, and promotes angiogenesis | |
| 4. formats new blood vessels around endometriotic lesions |
Abbreviations: IL, interleukin; ICAM, intercellular cell adhesion molecule; VEGF, vascular endothelial growth factor; NK, natural killer; TNF, tumor necrosis factor; IFN, interferon; TGF, transforming growth factor.
IL-1 family are pro-inflammatory and secreted into the peritoneal fluid by
activated macrophages [120]. They regulate immune and inflammatory responses by
controlling the expression of integrins in leukocytes and endothelial cells [33];
they further mediate the maturity and differentiation of various cells,
participating in angiogenesis together with other substances [120]. In this
family, IL-1
IL-2, a member of the chemokine family, is mainly produced by activated T lymphocytes and participates in cytotoxic cellular responses. Other functions include stimulating the proliferation and differentiation of lymphocytes, stimulating the proliferation and enhancing the killing activity of NK cells, inducing the production of lymphokine activated killers (LAKs), and activating monocytes and macrophages [125]. Different investigators have different views on the role of IL-2 in the development of endometriosis, as some studies have shown that the concentration of IL-2 in the peritoneal fluid of patients is reduced [126, 127, 128], while others have found the converse [93, 129]. A recent study showed that IL-2 is an independent protective factor against endometriosis [130]. In other words, the role of IL-2 in the pathogenesis of endometriosis is still unclear and more exploration is warranted.
IL-4 is a pleiotropic cytokine produced by Th2 cells [131]. Its biological
effects mainly include stimulating the proliferation of B and T lymphocytes and
promoting the differentiation of CD4
IL-6 is a multifunctional cytokine that is primarily produced in response to acute infection and tissue damage. It can regulate the growth and differentiation of a variety of cells, such as the induction of T lymphocyte activation and B lymphocyte differentiation [85]. While under normal circumstances, IL-6 expression is tightly regulated under pathological conditions, it may be continuously synthesized, affecting chronic inflammation and autoimmunity [138, 139]. It is well documented that the proliferation of MՓs in the peritoneal fluid of patients with endometriosis significantly increases IL-6 levels [140, 141, 142, 143, 144]. Elevated IL-6, by increasing haptoglobin, allows endometrial implants to evade peritoneal immune surveillance by reducing phagocytosis; NK cell activity can also be inhibited by IL-6 [140]. Other studies have found that endometrial stromal cells are resistant to IL-6 by reducing the expression of IL-6R [145, 146]. Elevated IL-6 in the peritoneal cavity not only facilitates the immune evasion of ectopic endometrial cells, but also regulates the growth of endometrial stromal cells.
IL-8, secreted by macrophages and monocytes, regulates
inflammatory response by chemotaxis to neutrophils. It can also participate in
neutrophil activation and have certain effects on eosinophils, basophils and
lymphocytes [147]. It also has a strong proangiogenic effect and can be regarded
as a potent angiogenic factor [85], contributing to cell adhesion [118]. IL-8
levels are increased in patients with endometriosis and may be positively
correlated with disease severity [148, 149]. IL-8 can promote the proliferation
of ovarian endometrioma-derived stromal cells, which may be enhanced by
TNF-
IL-10 is a Th2-type cytokine, also secreted by other cells, such as MՓs, keratinocytes and tumor cells [150]. IL-10 regulates cell growth and differentiation, participates in inflammation and immune response, and mainly plays an inhibitory role. Studies found elevated levels of IL-10 in the peritoneal fluid of patients with endometriosis [98], which may be related to the decrease of NK cytotoxicity [151]. Locally elevated IL10 is more conducive to the entry of endometrial debris into the abdominal cavity, facilitating the early stage of pelvic endometriosis [152].
IL-13, secreted by Th2 cells and MCs, can act on Th2 cells, B lymphocytes and MՓs, thereby stimulated B cell differentiation and inhibiting the production of inflammatory factors from MՓs. Researchers found significantly lower levels of IL-13 in the peritoneal fluid of patients with endometriosis [153]. Further study found that the decrease in concentration of IL-13 was not related to the severity of the disease [154]. On the contrary, other studies suggest that the expression of IL-13 in the peritoneal fluid and endometriosis lesions of patients with endometriosis is increased [155], possibly related to its impaired fertility [156]. Therefore, the role of IL-13 in promoting or inhibiting the pathogenesis of endometriosis remains to be determined.
TNF-
IFN-
TGF-
VEGF can not only increase vascular permeability and promote the deformation of extracellular matrix, but also make vascular endothelial cells migrate and proliferate, and promote angiogenesis. Endometriosis is characterized by the presence of numerous vascular proliferations in and around endometriotic lesions. It is generally believed that the formation of numerous new blood vessels is related to the etiology of endometriosis [162]. This is also confirmed by the increased VEGF levels found in the peritoneal fluid of patients with endometriosis [101], but it has yet to be verified whether these high concentrations of VEGF originate from the ectopic lesions themselves [172, 173] or from activated MՓs [37]. Thus, researchers speculate that the elevated level of VEGF in peritoneal fluid has notable clinical significance in the progression of the disease.
Endometriosis-related infertility may be attributed to both macro and micro aspects. The former includes mechanical deformation of fallopian tube caused by pelvic adhesion, and closure of fallopian tube and mechanical ovulation disorder. The latter is primarily related to follicle development, oocyte quality, sperm delivery, fertilization, embryo development, embryo delivery and embryo implantation. Studies have found that in donor IVF cycles, the pregnancy rate decreases if the donor is complicated with endometriosis, which may affect the quality of oocytes [174, 175]. High levels of inflammatory factors in peritoneal fluid of patients with endometriosis may lead to reproductive dysfunction through toxic effects on oocyte collection, fertilization, embryo development and implantation [85, 176]. Lachapelle et al. [106] found that the proportions of NK cells, B lymphocytes and monocytes in follicular fluid of patients with endometriosis-related infertility were higher than those with unexplained infertility and tubal infertility. Kolanska et al. [177] conducted a literature review by analyzing the levels of pro-inflammatory factors and autoantibodies in serum and peritoneal fluid of patients with endometriosis-related infertility, and concluded that inflammation and immune disorders may be tied to infertility. However, it is still controversial whether immunological changes in the eutopic endometrium of patients with endometriosis affect embryo implantation [178, 179].
The concentrations of various cytokines in the peritoneal fluid of women with
endometriosis are altered, and the levels of proinflammatory factors such as
TNF-
Autoantibodies are often associated with autoimmune diseases, but a variety of autoantibodies, including organ-specific and non-organ-specific antibodies, have been found in the peritoneal fluid and blood of women with endometriosis-related infertility, even if the patients do not have clinical manifestations of autoimmune disease [187]. Studies have found that non-organ-specific antibodies, including ANAs and antiphospholipid antibodies, are more common in patients with endometriosis [188]. Further studies have shown that the levels of these antibodies are significantly higher in patients with endometriosis-related infertility than in infertility patients without endometriosis [189]. However, organ-specific antibodies, such as anti-ovary, anti-theca, anti-granulosa cell, anti-zona pellucida, anti-sperm and anti-endometrial antibodies, have been detected in patients with endometriosis-related infertility, but their significance is not clear [107]. These autoantibodies may affect the fertility potential of endometriosis patients by interfering with oogenesis, sperm motility, embryo implantation and other processes [190, 191].
Endometriosis is defined as a disorder in which the glands and stroma of the endometrium periodically grow and shed outside the uterine cavity. It mostly appears on the surface of peritoneum and causes chronic pelvic pain and decreased fertility. The pathogenesis of endometriosis may be multifactorial, while the dysfunction of the immune system is a key factor in its occurrence and progression, including local immune regulation in the peritoneal cavity. Currently, Sampson’s theory of menstrual reflux is considered to be an accurate assessment of the basis of peritoneal endometriosis. It points out that the intimal debris entering the abdominal cavity interacts with the peritoneum, followed by a series of events such as adhesion, implantation, proliferation, vascularization and fibrosis. Endometrial cells adhere to the peritoneal mesothelium and acquire the ability to invade the matrix, which is a critical step in disease development. These endometrial cells escape peritoneal clearance and achieve adhesion through a mechanism called “immune evasion”. Whether the subsequent complex immune dysregulation in the peritoneal cavity is the cause of endometriosis or a consequence of the disease itself has yet to be determined. These immune dysregulations include innate and adaptive immune-involved cells, inflammatory factors, and the complement system. They interact with each other to form a complex immune network that promotes disease progression. Peritoneal immune cells and the cytokines they produce are critical in this process. In fact, the local immune changes in the peritoneal cavity of endometriosis are only a part of the body’s immunity, and such changes are difficult to study independently. Further research on the pathogenesis of endometriosis is required for the prevention and early detection of the disease.
JS and QH together conceptualized of the work. QH, YY, and WX screened and analyzed reliant literatures. QH integrated useful in formation and wrote the original draft. YZ and SL interpretated the data for the work, reviewed the work critically for important intellectual content, and edited the manuscript. JS investigated all aspects of the work and supervised the whole process of the work. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to its accuracy or integrity.
Not applicable.
We would like to apologize to colleagues whose work is not cited due to space constraints. And we also thank anonymous reviewers for excellent criticism of the article and all the authors in the reference list.
This work was funded by Department of Science and Technology of State Administration of Traditional Chinese Medicine—Zhejiang Provincial Administration of Traditional Chinese Medicine Co-construction Project 2023, grant number GZY-ZJ-KJ-23058 (Study on the improvement of oxidative stress in granulosa cells of endometriosis by Hedyoglossia and its active component MDHB) to JS.
The authors declare no conflict of interest.
References
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