Eutopic Endometrium Immune Changes Involved in Development and Progression of Endometriosis: A Review

Endometriosis is a common chronic gynecological condition with endometrium-like tissue outside the uterine cavity. Based on the location of the lesions, several types of this disease, including superficial peritoneal endometriosis, ovarian endometriomas, and deep infiltrating endometriosis (DIE), can be distinguished [ 1 – 3 ]. The most common endometriosis symptoms are painful menstruation, severe dyspareunia, and chronic lower-abdominal pain, but endometriosis is also strongly linked to infertility, with a risk twice as high as that in healthy women [ 4 , 5 ]. Despite such a high prevalence of the disease and its bothersome symptoms, the precise pathogenesis of endometriosis has still not been fully elucidated, and several theories have attempted to explain its occurrence. Among them, great importance has been attached to the involvement of immune dysregulation in disease pathogenesis [ 6 ]. It involves the ectopic endometrial cells infiltration, which takes place because of retrograde menstruation, which is not the exclusive cause of endometriosis development, and immune alterations play an important role in the development of pathological lesions. Briefly, ectopic endometriotic cells, through the induction of inflammation, change the nature of the cellular infiltration, which further leads to the disease development [ 7 ]. The observed systemic immune-based abnormalities in endometriosis have been widely described as an important force participating in disease pathogenesis. An increase in the number of peritoneal neutrophils and macrophages, a decrease in the cytotoxic function of NK cells, and abnormalities in the number of T and B lymphocytes are characteristic of endometriosis patients [ 8 ]. Importantly, the immune profile is not homogenous for all tissues and fluids, as some immune cells display different tissue-specific properties [ 9 ]. Therefore, it can be hypothesized that the endometriosis eutopic endometrium is also a source of some immune alterations that are unique to this environment, determining the initiation and progression of the disease. Considering the heterogeneity of endometriosis, further exploration of the immune imbalance of the uterine cavity endometrium may shed new light on the disease development and progression. Knowledge about the nature of immune changes provides insight into the background of the disease and may help in the development of immunotherapy [ 10 ]. Thus, our aim was to discuss the impact of the immune environment of the normal endometrium on the formation and evolution of ectopic endometriotic implants.

The changes in the endometrium of patients with endometriosis described above indicate a shift in balance toward pro-inflammatory processes. Researchers have so far mainly focused on analyzing groups of specific immune cells, and this topic seems to have been covered quite extensively in the current literature. Our review of the literature suggests it is important to focus on the expression of receptors and other smaller molecules on the surface of particular immune cell types in the future. Such studies would provide an opportunity for a more in-depth analysis of the processes underlying disease progression. Specific receptors such as NKp46 and IL-1RII or molecules like FGL2 should be of particular interest. When analyzing the endometrial changes of patients with endometriosis, the collection of eutopic endometrial fragments is technically simple. Therefore, the analysis of immunologic abnormalities within the eutopic endometrium may be more clinically useful than the analysis of ectopic endometrial samples or peritoneal fluid, as eutopic endometrial samples can be collected during a simple biopsy, without the need for surgery. A close look at new reports of immune changes in the eutopic endometrium may provide a start in developing immunotherapies focused specifically on inhibiting disease progression. So far, anti-TNF therapy has been proven effective in reducing endometriosis lesions in animal models [ 175 ]. Similar effects were observed with anti-VEGF therapy [ 176 ]. The activation of NK cells, which aims to restore the cytotoxicity of this type of cell, also plays a promising role in endometriosis-targeted immunotherapy [ 177 ]. Although no large clinical trials have been conducted to evaluate the efficacy of immunotherapy in endometriosis, it seems that investigating the modulation of the above-mentioned molecules may be valuable. In the future, in addition to further observation of the changes that occur in the eutopic endometrium, it is important to determine the impact of the immunological changes that occur in the endometrium on fertility because the endometrium provides an environment for the developing embryo. The specific effect of IL-6 on endometrial receptivity or Tregs on implantation should be determined [ 69 , 178 ].

The initiation and progression of endometriosis depend on many biological factors and it is difficult to clearly identify factors that aggravate the disease. The endometriosis eutopic endometrium shows many differences at the immunological level that may play a role in the development of the disease. The predominant role in the process of disease progression is the shift towards a pro-inflammatory endometrium profile, which includes the increased presence of cells and cytokines, leading to such conditions. An in-depth understanding of immunological abnormalities of the endometrium could significantly improve the global management of patients with endometriosis through the diagnostic potential of certain immune cell receptors and novel therapeutic options.