Abstract: Endometriosis is a common benign clinical gynecological disease, the etiology and pathogenesis of which are still unclear. A large number of studies have shown that the occurrence of endometriosis is closely related to abnormalities in the immune response system of the body. Research on the abdominal microenvironment and immune mechanisms in patients with endometriosis has become a current hot topic, and this paper provides a brief overview of the studies on the role of immune abnormalities in the pathogenesis of endometriosis in recent years.
Keywords: endometriosis; cellular immunity; humoral immunity; cytokines
Endometriosis (EMs) is a common and frequent disease in women of reproductive age, and the mechanism of its occurrence is still unclear. A large number of studies have shown that the occurrence of EMs is related to the abnormal immune response of the body. Patients with EMs often have abnormalities in local or systemic cellular and humoral immune functions, especially in relation to the defective immune surveillance and defense functions that maintain the body’s own stability, mainly manifested by the abnormal number and function of immune cells, the production of autoantibodies, and changes in the content and activity of cytokines. The progress of immunological research on this disease in recent years is reviewed as follows.
1. EMs and cellular immunity
1.1 T-lymphocyte abnormalities
The development of EMs indicates that endometrial cells are successfully grown in ectopic sites, and the cellular immune function exercised by T lymphocytes is most closely related to cell growth and implantation. Under normal circumstances, the ratio of helper T cells (CD4) and suppressor T cells (CD8) in the T lymphocyte subpopulation is maintained, and the two are mutually induced and regulated, and the T cell network formed by them plays an important role in regulating immune responses and maintaining immune stability. If the CD4/CD8 ratio is out of balance, the immune response will be too low or too high, resulting in immunodeficiency due to poor clearance of foreign antigens, or autoimmune diseases due to damage to self tissue while clearing foreign antigens.
It was found that the proportion of activated T lymphocytes in the peritoneal fluid of EMs patients decreased and the CD4/CD8 ratio increased, suggesting that the immune regulation of EMs patients was disturbed and the function of helper T cells increased while that of suppressor T cells decreased, resulting in excessive activation of lymphocytes and release of active mediators, which was one of the factors leading to the formation of ectopic endothelium. However, Gallinelli et al [1] reported that patients with EMs have reduced T lymphocyte-mediated cellular activity and lower CD4/CD8 ratios, and that patients with EMs mainly exhibit low cellular immune function.
Auxiliary T cells are subdivided into Th1 and Th2 cells according to the cytokines they secrete, and the Th1 and Th2 subpopulations of T lymphocytes are associated with the pathological mechanisms of EMs. It has been found that the balance between Th1 and Th2 cells is altered in favor of Th2, probably because the immune defense mechanism of EMs is disrupted. Currently, the results of studies on changes in Th subpopulations in patients with EMs are inconsistent, and the relationship between Th1/Th2 cells and EMs remains to be further explored.
1.2 Abnormal natural killer cells (NK cells)
The ability of endometrial tissue to grow ectopically and spread widely like tumor cells may be related to the abnormal activity of NK cells in the body. It has been reported that the number of peripheral blood NK cells does not change significantly in patients with EMs, but their activity decreases significantly and is significantly negatively correlated with the severity of the lesion, and the decrease in NK cell activity causes the active endometrial cells in the peritoneal cavity to grow in the peritoneal cavity instead of being removed, which may be one of the important reasons for the development of EMs.
Recent studies have found that the decreased activity of NK cells is associated with interleukin (IL)-12, killer inhibitory receptors on NK cells, and intercellular adhesion molecule-1 (ICAM-1).
IL-12 is the most potent NK cell activator and has significant biological effects on NK cells and T cells, promoting the proliferation of NK cells and T cells and enhancing the killing activity of NK cells and cytotoxic T lymphocytes.IL-12 has a unique molecular structure, being a heterodimer consisting of two subunits, P35 and P40, linked by disulfide bonds.The heterodimeric structure is the basic molecular structure for IL-12 to perform its biological functions. Therefore, the free P40 subunit can bind to IL-12 receptor, but does not show biological activity after binding, so the overexpressed free P40 subunit can compete with IL-12 for IL-12 receptor, resulting in a decrease in the binding ability of IL-12 to NK cells and inhibition of NK cell function.
In addition, free P40 subunits can achieve this inhibitory effect by downregulating the expression of the IL-12 receptor β1 chain on NK cells. this was confirmed in a study by Gazvani et al [2] and the level of free P40 subunits in the peritoneal fluid of patients with EMs was found to be significantly higher than in controls, suggesting that dysregulation of the IL-12 system is associated with decreased NK cell activity.
Killing inhibitory receptors are a group of glycoprotein receptors expressed mainly on the surface of NK cells and some T cells, which specifically recognize and bind to major histocompatibility complex (MHC)-class I molecules on the cell surface and conduct negative response signals, thereby inhibiting the cytotoxic activity of killer cells. The expression of kill inhibitory receptors on NK cells is closely related to the activity of NK cells, and it was found that the expression of kill inhibitory receptors on NK cells was significantly higher in both peripheral blood and peritoneal fluid of patients with EMs than in controls, in agreement with the study of Maeda et al [3], which confirmed that increased expression of kill inhibitory receptors leads to a decrease in the function of NK cells in patients with EMs, which may lead to the development of EMs .
ICAM-1 is a natural ligand for lymphocyte function-associated antigen (LFA)-1, a member of the β2 integrin family that is expressed on all leukocytes.The binding of ICAM-1 to LFA-1 is the basis for the exercise of various immune functions by the body, including NK and lymphokine-activated NK cell-mediated cytotoxicity. It was found that ICAM-1 expression on secretory-phase endothelial cells was lower in patients with EMs compared to both proliferative-phase endothelium and controls [4], and this cyclic defect in ICAM-1 expression may lead to a reduced ability of NK cells to bind to secretory-phase endothelium that is refluxing into the peritoneal cavity, and then a corresponding reduction in its recognition and clearance by NK cells, which may lead to the development of EMs.
The shedding of ICAM-1 from the cell surface results in a soluble form, soluble ICAM-1 (sICAM-1), which can compete with ICAM-1 for binding ligands because it has the same extracellular structure as ICAM-1 but does not produce biological activity, and therefore inhibits ICAM-1/LFA-1-mediated intercellular adhesion and interferes with the recognition of target cells by immune cells. The levels of sICAM-1 were found to be higher in the peripheral blood and peritoneal fluid of patients with EMs than in normal controls, thus sICAM-1 plays an important role in the evasion of immune surveillance by ectopic endothelial cells, leading to the development of EMs [5.6].
1.3 Macrophage (MФ) abnormalities
As the main component of abdominal non-specific immunity, MФ constitutes the first line of defense in removing antigens from the abdominal cavity and has an important role in maintaining the stability of the abdominal environment. Studies have shown an increase in the number and activity of MФ in the peritoneal fluid of patients with EMs, as well as an increase in their production of growth factors and cytokines [7]. The role of growth factors and cytokines produced by MФ in the occurrence and development of EMs has also been reported in a large number of studies over the past 20 years, suggesting that they stimulate the growth of endometrial cells or tissues, increase the anchoring function of ectopic endometrium by regulating matrix metalloproteinases, and increase the angiogenesis of ectopic endometrium. The same activated MФ plays an important role in the occurrence and development of EMs by releasing cytokines and growth factors.
2.EMs and humoral immunity
Studies of autoantibody production in EMs patients have shown that the immunoglobulins (IgG, IgA, IgM) in the peripheral blood of EMs patients are elevated, polyclonal B cells are activated, and a variety of autoantibodies are present, such as anti-endometrial antibodies, anti-ovarian tissue autoantibodies and other titers are significantly increased. The causal relationship between these autoantibodies and the development of EMs is still controversial. The relationship between anti-endometrial antibodies and EMs has been reported extensively, and anti-endometrial antibody IgM was significantly higher in patients with EMs than in controls. In conclusion, anti-endometrial antibodies are highly expressed in patients with EMs, but their etiological and pathophysiological roles in the development of EMs need to be further investigated.
3, EMs and cytokines
3.1 IL
The increase in the number and activation of MФ, so that it produces a series of inflammatory cytokines released into the peritoneal cavity, these factors can activate leukocytes and stimulate MФ secretion IL-1, IL-6, IL-8, etc. The biological function of IL-1 is mediated by binding to the corresponding high-affinity receptors, and a large number of reports have confirmed that the level of IL-1 is elevated in patients with EMs, especially in stages I and II. In addition, EMs are associated with an inflammatory response and intraperitoneal MФ stimulates the production of IL-1β, which plays an important role in the formation of neovascularization in ectopic lesions of EMs [8]. IL-8 is an important MФ-secreted vascular growth factor that is involved in the pathological process of EMs by contributing to the formation of neovascularization.
Mulayim et al [9] found that IL-8 increased the adhesion between endometrial stromal cells and extracellular matrix (ECM), suggesting that IL-8 plays an important role in the implantation of ectopic endometrium.Iwabe and Selam et al [10.11] reported that IL-8 in peritoneal fluid as a potential autocrine factor could promote the growth of stromal cells in ectopic endometrium.Song Szyllo et al [12] reported that serum and peritoneal fluid IL-6 levels in patients with EMs were positively correlated with disease stage and decreased significantly with the clearance of endotopic foci after laparoscopic surgery, suggesting that the measurement of blood and peritoneal fluid IL-6 levels can be used as an indicator for monitoring, follow-up, and evaluation of treatment effects in EMs. Szyllo et al [13] showed that IL-4 levels were significantly increased in peripheral blood and peritoneal fluid of patients with EMs and were related to the severity of the disease, with higher levels in the late stages of the disease and normalization of serum IL-4 levels after drug treatment.
In addition, Gallinelli et al [1] showed that IL-13 has the ability to regulate the activation of mononuclear MФ in the peritoneal fluid, and that IL-13 in the peritoneal fluid of patients with EMs is significantly lower than that of non-EMs patients, suggesting that the effect of IL-13 on peritoneal MФ is diminished in EMs patients, and the lack of inhibition of MФ activation leads to an increase in the number of peritoneal MФ, activation and secretion of pro-inflammatory The ability to increase the activation and secretion of pro-inflammatory cytokines, thus contributing to the occurrence and development of EMs.
3.2 Tumor necrosis factor (TNF)
TNF-α, which is produced by mononuclear macrophages, has been studied more frequently, and its relationship with reproductive immunity is more important. Many studies have found that peritoneal fluid TNF-α is significantly higher in patients with EMs and unexplained infertility than in controls, and increases with the degree of lesions [14].Increased TNF concentration stimulates increased synthesis of IL-1, IL-6 and IL-8 by endometrial mesenchymal cells, which is consistent with the development of EMs. 8 gene and protein expression can promote the proliferation of endometrial mesenchymal cells.
3.3 Interferon (interferen.IFN)
IFN-α, IFN-β, IFN-γ and IFN-ω are produced by T cells and NK cells in vivo and have anti-tumor and immunomodulatory effects. decreased IFN-γ in the peritoneal fluid of EMs patients reduces their ability to clear ectopic endometrial cells and contributes to the formation of ectopic endometrial lesions. It was found that IFN-γ-2b inhibited cell proliferation in vitro and strengthened with increasing dose (50-2000u/ml), which may be related to the activation of NK cells by IFN to promote their killing function and induce the expression of MHC-II class molecules to improve the level of humoral and cellular immunity, a finding that provides a basis for the treatment of EMs.
3.4 Monocyte chemotactic protein-1 (MCP-1)
The expression of MCP-1 in the in situ endothelium of patients with EMs is enhanced and varies with the severity of the disease, and the expression in the secretory phase is higher than that in the proliferative phase at both protein and mRNA levels. song et al [12] found that the peritoneal fluid MCP-1 protein level is elevated in patients with EMs, which chemotactic and activates peritoneal fluid MФ, which can secrete a variety of cytokines involved in the adhesion, invasion and angiogenesis, thus contributing to the formation and development of EMs.
3.5 Vascular endothelial growth factor (VEGF)
VEGF is a newly discovered peptide growth factor, also known as vascular permeability factor, in recent years.Mahnke et al [16] found that VEGF concentrations in peritoneal fluid and serum were significantly higher in patients with EMs compared to controls, correlated with the severity of the disease, and changed cyclically, with a significant increase in the proliferative phase compared to the secretory phase, whereas no such change was observed in controls. However, Gagne et al [17] found no increase in serum VEGF levels in patients, suggesting that VEGF may play a more important role locally in EMs lesions. It is now believed that VEGF is mainly derived from activated MФ in the peritoneal fluid and that its expression is directly regulated by ovarian hormones. Japanese scholars also found that both in situ and ectopic endothelial VEGF expression was elevated in patients with EMs, and red non-transparent lesions showed higher VEGF activity than red transparent and black lesions, and suggested that there may be differences in the histogenesis of different lesions [18].
3.6 Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs)
MMPs are the most important group of proteases in the degradation of ECM, degrading almost all components of ECM, and are involved in numerous physiological and pathological processes.The TIMPs family, a multigene family of encoded proteins, are natural inhibitors of MMPs that have been identified in recent years.
TIMPs bind to the corresponding MMPs zymogens and their activated forms to inhibit the activity and production of MMPs [19].The homeostatic relationship between TIMPs and MMPs plays an important role in regulating the homeostasis of the ECM, and the MMPs/TIMPs ratio is a key factor in maintaining the stability of the body’s internal environment and the integrity of the ECM. Recent studies have shown that MMPs and TIMPs are involved in the pathological process of EMs, and that the lack of a normal response to progesterone in the in situ endometrium of women with EMs leads to altered expression of multiple MMPs, resulting in the ability of these tissues to establish ectopic lesions in vivo [20].
3.7 Other cytokines
It has been demonstrated that the increased amount of MФ in the peritoneal fluid of patients with EMs and the increased ability to secrete transforming growth factor, epidermal growth factor, hepatocyte growth factor, and fibroblast growth factor lead to an increase in vasoactive substances in the peritoneal cavity, which increases the formation of microvessels in the abdominal wall and creates conditions for ectopic implantation of the endometrium.
In conclusion, the immunological study of this disease has opened a new field to explore the pathogenesis, occurrence and development of EMs. With the further development of molecular biology and the joint efforts of modern medicine and its related laboratories, it is expected that the study of immunology will lead to a breakthrough in the therapeutic approach of EMs and open avenues for future treatment.