{"paper_id":"bf7770a3-cac5-4599-8f1a-b4de9b8044c6","body_text":"Explor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 454\nEndometriosis through an immunological lens: a pathophysiology \nbased in immune dysregulation\nAlison McCallion    , Danielle J. Sisnett    , Katherine B. Zutautas    , Donya Hayati    , Katherine G. Spiess    , \nStanimira Aleksieva    , Harshavardhan Lingegowda    , Madhuri Koti    , Chandrakant Tayade*\nDepartment of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada\n*Correspondence: Chandrakant Tayade, Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON \nK7L 3N6, Canada. tayadec@queensu.ca\nAcademic Editor: Satish Kumar Gupta, Indian Council of Medical Research, India\nReceived: November 8, 2021  Accepted: March 8, 2022  Published: July 26, 2022\nCite this article:  McCallion A, Sisnett DJ, Zutautas KB, Hayati D, Spiess KG, Aleksieva S, et al. Endometriosis through an \nimmunological lens: a pathophysiology based in immune dysregulation. Explor Immunol. 2022;2:454–83. https://doi.\norg/10.37349/ei.2022.00062\nAbstract\nEndometriosis (EMS) is an inflammatory, gynaecologic disease characterized by the growth of endometrial \ntissues outside the uterus. With no satisfactory therapies or non-invasive diagnostics available, a shift \nin perspectives on EMS pathophysiology is overdue. The implication of immune dysregulation in EMS \npathogenesis and disease progression has been an evolving area of research, with numerous immune \nand inflammatory pathways identified. Traditional theories regarding the establishment of endometriotic \nlesions have lacked mechanistic explanations for their proliferation and survival until recent research \nunearthed the involvement of mesenchymal stem cell (MSC) and myeloid-derived suppressor cells \n(MDSCs) in a complex network of immune-endocrine signaling. The unique immunology of EMS is likely \nowing to estrogen dominance, as endocrine imbalance reliably cultivates immune dysregulation. Many of \nthe phenomena observed in EMS parallel immune biology seen in various cancers, including accelerated \nsomatic mutations in endometrial epithelial cells. Here, the high mutational load leads to EMS neoantigen \ndevelopment which potentially contributes to the lesion immune microenvironment. As well, EMS \nmanifests comorbidity with several chronic inflammatory diseases that share common dysregulation \nof the interleukin-23 (IL-23)/IL-17 pathway (as seen in inflammatory bowel disease, psoriasis, and \nrheumatoid arthritis). EMS is especially relevant to the study of chronic pelvic pain (CPP) as 60% of EMS \npatients experience this symptom and chronic inflammation is believed to be central to the process of pain \nsensitization. Since the onset of the disease usually occurs in adolescence, and diagnosis only occurs years \nlater once moderate to severe symptoms have developed, it is vital to innovate non-invasive diagnostic \ntools for earlier detection. Several potential biomarkers are being studied, including some cytokines, gene \nsignatures, and extracellular vesicle (EV) signatures. By incorporating the immune perspectives of EMS \ninto our research, approaches to diagnosis, and treatment solutions, the field has more promising avenues \nto clearly define EMS and offer patients relief.\nOpen Access   Review\n© The Author(s) 2022. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International \nLicense (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution \nand reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nExploration of Immunology\n\n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 455\nKeywords\nEndometriosis, immune dysregulation, mesenchymal stem cells, somatic mutation, estrogen dominance, \nchronic inflammation, cytokine pathways, extracellular vesicles\nIntroduction\nEndometriosis (EMS) is an inflammatory gynaecologic disease that affects about 10% of menstruating \nindividuals worldwide. It is characterized by the growth of endometrial-like tissue at ectopic sites outside of the \nuterus; lesions most commonly being found on the peritoneal wall, exterior of uterus, ovary, bladder, or colon. \nIn Canada alone, EMS is estimated to cost the healthcare system $1.8 billion annually [1]. The disease causes \nsevere pelvic pain and infertility, and we do not have reliable non-invasive diagnostics or curative therapeutic \noptions. To compound this difficulty, the average time between the onset of symptoms and diagnosis is \napproximately seven years. This is partially owing to the fact that the pathogenesis and pathophysiology of \nEMS are poorly understood. Aside from being under-studied, EMS is a multifaceted disease with etiologies \nrooted in genetics, hormonal imbalance, immune dysregulation, and phenotypic heterogeneity. Though years \nof research have unraveled individual contributions of these aspects, the mechanisms of their interplay \nremain largely elusive.\nBecause EMS is an estrogen-dominant disease, most first-line treatments attempt to address this \nimbalance through hormonal contraceptive therapies. These options do not cause regression of existing \nlesions, and contraception is not a satisfactory option for those who wish to conceive children. In recent years \nthe field has acknowledged several immune cells and pathways that are dysregulated in EMS, contributing to \nsevere inflammation, fibrosis, and angiogenesis in lesions. For this reason, immune-focused therapies with \nproven success in other chronic inflammatory diseases and several cancers are being explored in EMS. However, \nprecise understanding of the complex immune-regulatory pathways is integral to the future application of \nimmune-based therapeutics. Additionally, with high incidence of comorbidities and individual mutational \nvariations, personalized medicine for EMS is an area needing significant research and development.\nDespite these challenges, the field continually makes new discoveries in an immunological scope \nto understand EMS pathophysiology. The complexity of immune dysregulation in EMS is an active area \nof ongoing research, driving a forward deeper understanding of EMS pathophysiology and allowing us to \nattempt new approaches to diagnosis and treatment. In this article, we summarize current knowledge within \na broader immune context and discuss areas of promising investigations with perspectives on diagnostics \nand treatments.\nTheories of endometriosis lesion establishment\nSeveral theories exist to explain the presence of EMS lesions, and while their applicability varies across disease \nphenotypes, each has its own merit. Familial associations have been documented for EMS [2–4] and have \nbeen reviewed elsewhere [5–8]. A pioneer of EMS pathogenesis research was John Sampson, and his works \nhave been discussed extensively by Yovich et al. [9]. The widely accepted Sampson’s theory of retrograde \nmenstruation, in our opinion, is most feasible as a part of a larger story which includes immune dysregulation \nand aberrant stem cell activity as discussed below.\nCoelomic metaplasia\nThis theory postulates that metaplasia and transdifferentiation occur in the mesothelium of the peritoneum \nand within the ovarian germinal epithelium, thereby transforming these cells into endometrial tissue that \ncan cause lesion development [10 ]. This hypothesis may explain rare cases of EMS seen in males [11 , 12]. \nMetaplasia could also explain rare distal EMS lesion sites such as lymph nodes [10] and lungs [13]. Some have \ntheorized that the presence of deep infiltrating EMS (DIE) is caused by metaplasia of the coelomic epithelium, \nhowever, there is a high prevalence of rectovaginal DIE that co-occurs with other forms of EMS, where \ncoelomic metaplasia cannot explain lesion presence [14]. Metaplasia can also arise from events unrelated to \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 456\nthe coelomic epithelium, or from ectopic tissue implanting into peritoneal sites [15 ]. These theories can be \napplied to certain phenotypes of EMS, however, they do not account for the prevalent immune dysregulation \nseen in the disease pathophysiology.\nMullerian remnant theory\nThe Mullerian ducts, which normally differentiate to form the female reproductive tract, are said to be involved \nin this etiological hypothesis of EMS. The ectopic endometrial tissue that is characteristic of EMS is theorized \nto originate from primitive embryonic Mullerian tissue that was misplaced during fetal development [16, 17].\nMayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, caused by an anomaly in the Mullerian tract, is \ncharacterized by abnormalities or absence of the uterus and vagina, despite the normal function of ovaries \nand (46,XX) karyotype. MRKH patients have been shown to have a significant incidence of EMS, bolstering this \nhypothesis [18]. There has also been EMS documented in individuals with Mullerian anomalies, despite no \nobstruction in menstrual flow [19]. Additionally, cases of EMS in girls before menarche [20], as well as males \nwith lesions along the route of the Mullerian duct, align with this hypothesis [11]. However, this theory is not \nsufficient for explaining the placement of lesions seen outside of Mullerian rests [12 ], or the immunological \naspects of EMS.\nIatrogenic scar endometriosis\nIatrogenic endometriotic growths typical of EMS can develop within incision scars from gynecologic \nsurgery [21]. Specifically, iatrogenic scar EMS is suggested to arise from accidental auto-transplantation of \nendometrial cells [22–24]. Lesions may be found in incisions from cesarian, appendectomy [22], hysterotomy, \ntubal, trocar-site, amniocentesis, and episiotomy surgeries [25, 26]. This hypothesis explains rare cases of EMS \ndevelopment in those who have recently undergone pelvic surgery. Endometrial cells being transplanted into \nincision sites is a reality of the cesarian section, yet the occurrence of EMS in the scar is quite low, indicating \nother unidentified factors lead to disease development in these cases [22 ]. Immune tolerance during \npregnancy in combination with the displacement of endometrial cells is a reasonable speculation for the \netiology of lesion establishment in cases of cesarian section surgery [26]. This is evidenced by the increased \nrisk of scar EMS for those who deliver prior to labor onset before immune tolerance has subsided [27].\nRetrograde menstruation\nRetrograde menstruation, originally proposed by Sampson [28 ], is currently the most widely-accepted \nhypothesis for the etiology of EMS. This hypothesis postulates that endometrial fragments shed during \nmenstruation travel backward through the fallopian tubes into the peritoneal cavity, where cells can adhere \nand develop into endometriotic lesions.\nRetrograde menstruation has been well established as a normal physiological process, occurring in \n90% of menstruating individuals [29 ]. Some non-human primates like baboons, who also menstruate, have \nexhibited cases of spontaneous EMS associated with a higher prevalence of retrograde menstruation [30 ]. \nAlso in baboon models, forced menstrual reflux by cervical occlusion has been shown to induce EMS [31 ]. \nSimilarly, EMS and retrograde menstruation have been shown to be increased in individuals with outflow \nobstruction, such as those with malformation of Mullerian ducts [19 ]. There is also a positive association \nbetween EMS and high menstrual volume (typical of heavy periods or greater numbers of menstrual \ncycles) [32 ]. Additionally, differences in endometrial tissue adhesion capability have been identified in \npatients with EMS; adhesion molecules such as integrins, syndecans, cluster of differentiation 44 (CD44), \nintercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and epithelial \ncadherin (E-cadherin) can be dysregulated in EMS patients, explaining the increased capacity to adhere to \ndamaged peritoneum [12, 33].\nWhile 90% of females exhibit retrograde menstruation, only 7–10% are estimated to have EMS [34 ], \nmeaning that other factors must contribute to disease establishment. For lesion establishment to occur \nfrom displaced endometrial cells, there must be immune evasion, attachment, invasion, vascularization, and \ngrowth. Although endometrial fragments are misplaced at ectopic sites, the adaptive immune system may \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 457\nnot mount an effective response to clear debris due to the recognition of endometrial cells as self-versus \nforeign antigens. Several pathways of immune dysfunction have been identified in EMS that could contribute \nto lesion establishment. For instance, macrophages (normally recruited for tissue repair and debris \nclearance) have been shown to produce increased amounts of vascular endothelial growth factor (VEGF) \nin EMS patients compared to controls [35 ]. This increase in VEGF, an angiogenic factor, could be supporting \nthe vascularization of the lesion. Another mechanism previously described is estrogen receptor β (ERβ) \ninteracting with apoptotic machinery to decrease tumor necrosis factor-alpha (TNF-α)-mediated apoptosis, \nproposed as a mechanism by which displaced cells evade immune clearance [36 ]. Many other mechanisms \nin addition to immune dysfunction can complicate the pathophysiology of the disease, such as genetic, \nenvironmental, and endocrine factors. While retrograde menstruation is a plausible theory explaining the \npresence of endometrial cells in the peritoneal cavity, more recent discoveries relating to stem cells and \nimmune pathways have allowed us to theorize how immunological factors lead to EMS after endometrial cells \nenter the peritoneal cavity.\nStem cell theory\nSomatic stem cells, also known as adult or tissue-specific stem cells, play a critical role in the regulation of \nadult tissue regeneration and restoration of the local microenvironment following injury [37 ]. The human \nendometrium is a dynamic tissue that undergoes cyclic regeneration through the replacement of epithelial \nand mesenchymal tissue following menses. A growing body of evidence suggests endometrial epithelial \nstem/progenitor cells are involved in the repair process, along with CD140b +CD146+ or sushi domain \ncontaining-2+ (SUSD2+) endometrial mesenchymal stem cells (MSCs), and endometrial stem cells that may \nbe of Mullerian origin [38 ]. Additionally, non-resident bone marrow-derived stem cells (BMDSCs), which \ndifferentiate into populations of hematopoietic stem cells, MSCs, and progenitor cells may be involved. It \nis possible that these cells restore endometrial tissue. Du et al. [39 ] found murine uteri with reperfusion \ninjury harbored nearly twice as many BMDSC-derived MSCs compared to uninjured uteri (42 versus 22 MSCs \nper 105 stromal cells). As well, BMDSCs have been shown to differentiate into non-hematopoietic lineages \nincluding kidney, intestine, lung, and muscle cells [40]. Pathogenic alteration of stem cell regulation, function, \nnumber, and location provides a basis for lesion establishment in EMS.\nThe MSC theory of EMS purports that endogenous endometrial stem/progenitor cells, predominantly \nlocated in the endometrium basalis, travel in the menstrual fluid to reach the peritoneum and incorporate \nwithin lesions. Several researchers have noted the presence of basalis-like tissue in the menstrual effluent and \nendometrium functionalis of endometriosis patients [41, 42]. As well, some have theorized a deeper plane of \nseparation between functionalis and basalis at menstruation, theoretically including more basalis-associated \nprogenitor cells within the menstrual effluent of endometriosis patients [43 ]. In the context of retrograde \nmenstruation, this would effectively boost the progenitive capacity of menstrual effluent in endometriosis \npatients as proportionally more progenitor/stem cells are transported to the peritoneal cavity. One school \nof thought hinges on the concept that decidualization primes endometrial stromal cells to recruit MSCs and \nprioritize tissue remodeling as part of normal endometrium restoration after menstrual shedding [44 ]. It \nis possible that with increased or dysregulated MSCs, endometrial stromal cells herd MSCs to ectopic sites \nwhere lesion establishment occurs. In the presence of an existing lesion, local dysregulation of cytokines, \nsuch as elevated C-C motif chemokine ligand 2 (CCL2), CCL5, C-X-C motif chemokine ligand 8 (CXCL8), VEGF, \nand placental growth factor [45–48], contribute to an inflammatory microenvironment that may recruit stem \ncells to the lesion site.\nThe involvement of MSCs is not limited to scaffolding lesion establishment. The cells exhibit \nimmunomodulatory properties that inhibit proliferation, activation, and differentiation of CD4 + T cells \nto pro-inflammatory T helper (Th) Th1 and Th17 subtypes and promote the generation of tolerogenic \nregulatory T (Treg) cells [49 ]. In addition, tissue-resident MSCs have shown the capacity to modulate the \nactivity of natural killer (NK) cells in a manner that reduces cytotoxicity and provides feedback that positively \ninfluences the proliferative and pro-angiogenic properties of MSCs. Reduced cytotoxicity of NK cells is also \nwell documented in EMS [50]. MSCs have been shown to polarize macrophages to the M2 phenotype through \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 458\nthe release of prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase 1 (IDO1), CCL2, and CXCL12 [51 –54]. \nIn fact, MSCs have been found to exhibit more immunosuppressive and M2-polarizing signals in vitro when \nderived from EMS lesions compared to eutopic endometrium derived MSCs, which Abomaray et al. [55 ] \ntheorized aids immune evasion to support lesion establishment. The secretory profile of MSCs includes \nchemoattractant cytokines that further MSC recruitment (CXCL12, CCL2, CXCL8) as well as antiapoptotic \n[insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGF-β), basic fibroblast growth \nfactor (bFGF), hepatocyte growth factor (HGF)], proliferative [interleukin-6 (IL-6), stromal cell-derived \nfactor-1 (SDF-1), macrophage colony-stimulating factor (M-CSF)], and angiogenic [VEGF, placental growth \nfactor (PIGF), monocyte chemoattractant protein-1 (MCP-1), bFGF] chemokines [56]. Overall, the breadth of \ninteractions induced by MSCs appears to promote an immunosuppressive environment, permissive to the \nestablishment and sustainment of ectopic tissue/lesions within the peritoneal cavity.\nThe presence of stem/progenitor cells of BMDSC origin may be associated with disease pathogenesis, \nas these cells have been shown to migrate to areas of tissue damage and inflammation. A study by Sakr \net al. [57] showed that CD45 − donor BMDSCs favored engrafting endometriotic lesions over eutopic \nendometrium in EMS-induced mice following bone marrow transplantation. This evidence supports \nthe involvement of circulating BMDSCs in endometriotic lesion establishment. Furthermore, BMDSCs \ncould regulate the formation and maintenance of blood vessels through their supply of myeloid cells, \nsuch as macrophages and mast cells, which release angiogenic factors including VEGF, TNF-α, and \nangiopoietin [38, 58]. Neoangiogenesis is a key feature in EMS lesion establishment and survival.\nChen et al. [59 ] found endometrial stromal cells interact with BMDCs to induce them to differentiate \ninto stromal, epithelial, or leukocyte cell types via paracrine activity. BMDCs inhibit lymphocyte immune \nresponses through increased expression of programmed cell death 1 (PD-1) and its ligand PD-L1 expression \non T cells. Indeed, elevated serum PD-1/PD-L1 expression was observed in eutopic and ectopic endometria, \nas well as serum-derived CD4 +/CD8+ T cells in patients with versus without EMS, the occurrence of which \nis reported to be exacerbated by elevated estradiol [60 ]. The chemotactic capacity of BMDSCs is specially \nenhanced with elevated CXCL12 levels, as is seen in EMS lesions [61 ]. In a mouse model of EMS, elevated \nCXCL12 has been shown to support the recruitment of bone marrow cells, a source of endothelial progenitor \ncells, to allow for neovascularization of EMS lesions [61, 62].\nMyeloid-derived suppressor cells\nMyeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells with \npotent immunosuppressive and angiogenic activity. Several studies have noted an association between MDSC \naccumulation and the progression of inflammatory diseases, including EMS [63 –66]. MDSCs are present \nin small numbers in healthy tissue, although they rapidly expand in response to inflammatory disease \nthrough interactions with molecules such as IL-1β, IL-6, IL-10, and TNF-α [65 , 67]. Elevated concentrations \nof these inflammatory cytokines in the peritoneal fluid (PF) of EMS patients may also be implicated in \nthe transformation of monocytes into MDSCs [68 –70]. The presence of chemokines CXCL1, CXCL2, and \nCXCL5 at the site of the lesion promotes MDSC migration to the ectopic environment [63 ]. Furthermore, \nGuo et al. [71 ] observed significantly elevated concentrations of CCL3 and CCL5 in EMS patients, cytokines \nassociated with recruitment of MDSCs. Alongside this effect, recruited MDSCs may further secrete C-X-C motif \nchemokine receptor 2 (CXCR2), which has been associated with interferon-γ (IFN-γ)-induced upregulation \nof immunosuppressive molecules (e.g., PD-1, PD-L1, CD152) that promote exhaustion of CD4 + and CD8 + T \ncells [66]. The presence of CXCR2 + MDSCs may further enhance the production of IL-6, which is implicated \nin lesion establishment through the promotion of epithelial-mesenchymal transition, a pathogenetic \nmechanism whereby endometrial cells transition from an epithelial phenotype to a more motive and invasive \nmesenchymal phenotype [72]. Chen et al. [64] associated the presence of elevated levels of monocytic-MDSCs \n(M-MDSCs) in peripheral blood and PF of EMS patients with suppressed pro-inflammatory Th and cytotoxic T \ncells in peripheral blood and enhanced anti-inflammatory Treg cells in the PF compared to healthy controls. \nThus, the recruitment and accumulation of excess MDSCs in the ectopic environment may be responsible for \nthe protection and promotion of endometriotic implants in the peritoneal cavity. In addition, Chen et al. [64] \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 459\ndetected the presence of elevated M-MDSCs was further associated with an increase in the production of \nreactive oxygen species (ROS), possibly via the Notch signaling pathway [64, 73]. Findings by Ngô et al. [74] \npropose the involvement of ROS in increasing the proliferative rate of stromal and epithelial cells, both of \nwhich contribute a large proportion of the lesion’s composition.\nMDSCs further contribute to the development of EMS through cell-to-cell interactions. Morales et al. [75] \nhave described the capacity of MDSCs to enhance the inflammatory responses of mast cells. As well, mast \ncells release chemoattractants to increase MDSC recruitment and expansion, predominantly through the \npromotion of CCL2 secretion and elevated IL-17 production [76 –78]. Within lesions, mast cells may further \ninteract with endometrial cells to secrete CCL8, which promotes endometrial cell migration and angiogenesis \nat the site of release, and may further upregulate pro-inflammatory factors such as IL-6, IL-10, IL-13, TNF-α, \nand VEGF [79, 80].\nThe involvement of MSCs and MDSCs in EMS lesion establishment is a promising hypothesis with \nstrong evidence. The findings to date are congruent with a story of EMS pathogenesis where dysregulated \nimmune signaling bridges the gap between retrograde menstruation and lesion establishment.\nPrevalent relationships of endocrine and immune systems in endometriosis \npathophysiology\nEMS has long been considered an endocrinological disease. With recent research identifying significant \nimmune dysregulation in the disease pathophysiology, we must consider the relationships between \nendocrine and immune systems. As EMS is an estrogen-dependent disease, hormonal therapies are the \nfirst-line treatments offered to patients, including combined estrogen and progesterone contraceptives, \nsynthetic androgens, and gonadotrophin-releasing hormone (GnRH) agonists [81 –83]. These therapies do \nnot stop the progression of lesion growth and in many cases fail to provide patients with pain relief [84 ]. \nEstrogen has a complex role in immune functions as it can activate pro- and anti-inflammatory pathways \nin different cell types at different cycle points [85 –87]. All immune cells express receptors for estrogen \n(ERα, ERβ) [86] while several express progesterone receptors (PRs), and respond to hormonal stimulation \nby altering inflammatory behavior, differentiating, or activating, depending on the cell and signal [88 –94]. \nSeveral immune cell populations are pertinent in EMS immunopathophysiology; including but not limited to \nmast cells, macrophages, and various types of T cells, which are all affected by estrogen dominance.\nEstrogen and progesterone can activate ERs and PRs as transcriptional factors, but also as non-genomic \nmembrane receptors to rapidly activate cellular responses in leukocytes [95–97]. Hormonal stimulation also \nalters the immune signaling of the endometrium. High estrogen induces endometriotic epithelial and stromal \ncells to secrete more inflammatory and chemokinetic factors, including CCL5, granulocyte-macrophage \ncolony-stimulating factor (GM-CSF), IL-6, IL-8, and CXCL12 [98 –100]. Since endometriotic lesion tissue \noverexpresses aromatase (CYP19 ), estradiol is biosynthesized in high amounts [101 ]. Combining this \nwith impaired local metabolic enzyme activity, including poor conversion of 17β-estradiol to estrone by \n17β-hydroxysteroid dehydrogenases (17β-HSD) [102 ], the lesion hormonally contributes to its own local \ninflammatory microenvironment.\nEndocrine and immune systems work closely together in the menstrual cycle, and menstruation is a \nhighly immunologically active process. It is known that most immune cells are hormonally regulated and their \npresence in endometrial tissue follows a cyclic fluctuation according to the menstrual cycle, with an increase \nin abundance of macrophages, mast cells, neutrophils, NK cells, and Th1 cells at day 26–28 [90 , 103–105]. \nThe systemic hormonal imbalance in EMS manifests as both abnormally high estrogen and also the \ndevelopment of progesterone resistance; a lack of response to progesterone by endometriotic tissue. In the \nnormal endometrium, progesterone regulates appropriate apoptosis and counteracts epithelial proliferation \ninduced by estrogen. Receptors for estrogen (ERα, ERβ) and progesterone (PR-A, PR-B) are expressed \nabnormally in endometriotic tissue; lesions express more ERβ and less ERα than healthy endometrium, \nand generally low transcript levels of PR mRNA [106 , 107]. With the absence of PRs in endometrial stromal \ncells, normal progesterone-stimulated production of the enzyme 17β-HSD-2 is disabled, hindering estradiol \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 460\nmetabolism and further maintaining a high estrogen level [108]. This is compounded by estradiol production \nresulting from aromatase activity in endometriotic tissue, as CYP19 expression is significantly increased in \nendometriosis lesions compared to healthy endometrium [109, 110].\nSeveral immunological alterations are associated with supraphysiological estrogen. For example, high \nestrogen is associated with a systemic increase in G-CSF as granulocytes are important in the process of \novulation [111]. Normally progesterone rescues this effect, but in the progesterone-resistant state of EMS, \nestrogen may contribute to chronic leukocyte colony stimulation (Figure 1A). Likewise, other immune \nimpacts of progesterone are relevant in EMS, where inflammatory events normally rescued by progesterone \nare left unregulated. Progesterone inhibits chemokine secretion by stromal cells [100 ], opposing estrogen’s \nagonistic effect on chemokine secretion in stromal cells (Figure 1B). Progesterone also inhibits mast cell \nmigration [112 ], secretion and histamine release [113 ]. Mast cells fluctuate cyclically and are actively \ninvolved in the menstruation process [114, 115], and it is known that mast cells can mature and activate upon \nestrogenic stimulation [95 ]. Mast cells have been found in higher quantities in the tissue of endometriotic \nlesions compared to eutopic endometrium and the endometrium of healthy women [116 , 117]. In addition, \nthe vital mast SCF has been observed in higher concentrations in women with EMS [118].\nFigure 1. The immune-endocrine relationships of the endometriotic lesion. (A) Estradiol is sourced from systemic circulation \nand, to a small extent, the lesion tissue itself. Estradiol acts on immune cells to secrete inflammatory, angiogenic, chemokinetic \nmolecules which contribute to lesion growth and disease progression; (B) estradiol causes the endometriotic lesion to produce \nimmune signaling molecules [CCL5, GM-CSF, IL-6, IL-8, CXCL12, VEGF, stem cell factor (SCF)], subsequently acting on local \nimmune cells to further increase inflammation, angiogenesis, and proliferation of the lesion\nEMS patients have a significantly higher number of endometrial and peritoneal macrophages as \ncompared to healthy women during the proliferative phase, and other reports found significantly higher \nmacrophages in EMS patients regardless of menstrual phase [119 , 120]. Macrophages polarize into either \nM1 or M2 phenotype, which have distinguished cytokine profiles and downstream actions. Generally, the \nM1 phenotype is pro-inflammatory, it is the classically activated macrophage that scavenges and launches \nimmune responses to infections [121 ]. Meanwhile, M2 macrophages are alternatively activated and have \ngenerally anti-inflammatory downstream effects [121 , 122]. Studies of macrophages under estrogenic \nstimulation have observed polarization to the M2 phenotype, which is considered more permissive, and \nthis may support ectopic endometriotic lesion proliferation by allowing decidualized endometrial cells to \nescape clearance and survive/proliferate at ectopic sites [123 –126]. Macrophages from EMS patients were \nfound to express much more ERβ, which induces more inflammatory secretions from macrophages such \n\n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 461\nas TNF, IL-1⍺, and IL-1β (Figure 1A) [119 , 127, 128]. Since the immunomodulatory actions of estrogen are \ncomplex, other studies have found estradiol-induced polarization of macrophages to the M1 phenotype \nwhich performs inflammatory roles secreting cytokines like IL-6 and TNF-α, which may contribute to the \nincreased inflammation of the EMS immune microenvironment [129 ]. Macrophages also contribute to pain \nsymptoms in concert with estrogenic activation in EMS [87 , 130]. These endocrine relationships require \nfurther investigation to improve our understanding of the roles of macrophages in EMS pathophysiology.\nT cells have been identified for their role in various immunological pathways of EMS pathophysiology, \nand most T cell populations are influenced by estrogen [104 ]. Th cells exhibit an interesting relationship to \nestrogen and progesterone balance, where the pro-inflammatory Th1 population rises in the estrogen-dominant \nfollicular phase while a Th2 population takes over in the luteal phase to contribute their immunoregulatory \nrole, as observed by Faas et al. [91 ]. As well, estradiol has PD-1-dependent and -independent suppressive \nactions in the function of Treg cells (Figure 1A) [131 ]. Importantly, Mohammad et al. [132 ] elucidated the \nsignificance of ERα activation in the function, regulation, and survival of T cells by observing poor activation \nand survival of ER⍺-knockout T cells in a mouse model of colitis. A particularly interesting inflammatory \npathway involving Th17 cells has been noted in EMS, and increased Th17 level in the PF of patients has \nbeen identified in association with disease severity [133]. Fuseini et al. [134] showed that ERα in Th17 cells \nincreases the IL-23/IL-17 inflammatory pathway by upregulating IL-17A production. This inflammatory \npathway has become increasingly relevant to our understanding of EMS pathophysiology, specifically relating \nto the recruitment of macrophages [135 ]. The involvement of estradiol and other endocrine factors is a \nsignificant aspect of T cell function and should be considered in researching EMS pathophysiology.\nAn important question to consider is whether the immune-endocrine relationship in EMS pathophysiology \nis bi-directional. It is known that hormones influence immune cell actions and immune signaling. However, \na less observed relationship is the impact of immune events on sex hormone metabolism and receptor \nregulation. Some pathways in both normal and disease scenarios have been identified. In endometrial \ncarcinoma, estrogen-stimulated IL-6 has been found to upregulate stromal cells’ expression of aromatase, \ndriving forward metabolism of androgens to 17β-estradiol, resulting in a positive feedback loop of IL-6 and \nE2 production [136 ]. Both aromatase and IL-6 have roles identified in the pathophysiology of EMS [137 ], \nand given this feedback loop has been identified in other estrogen-dependent diseases, e.g., various breast \ncancers [138], this very feedback loop could exist in the disease. In several endocrine-dependent cancers, \nERα can be activated by IL-1β and TNF-α via the IkappaB kinase-beta (IKK-β) pathway [139 ]. These \ncytokinic ER activation pathways are not well studied in EMS, though given the existing parallels between \nEMS and cancer, the capacity of immune signaling to activate sex steroid hormone receptors may be worth a \ndeeper investigation.\nMutations and cancer parallels in endometriosis\nKnowledge of the endometriotic microenvironment is continuously expanding with new information \ncentered around angiogenesis, cytoarchitecture, etiology, and immune cell presence; the field is diversifying. \nThese seemingly independent fields are all relevant to novel establishing tissues. This framework allows for \nparallels to be made to malignant cancerous tissues. This is not to equate EMS to cancer, but to provide an \nalternative perspective in analyzing endometriotic lesions through the lens of cancer research. The breadth \nof cancer research has made discoveries that could prove beneficial to the field of EMS research. As this \nschool of thought has been gaining traction in the field, we hope to provide insight into the pathophysiology \nof EMS through this perspective. With a focus on somatic mutations and immune cell dysfunction, there may \nbe insights into potential biomarkers and novel therapeutics for EMS.\nSomatic mutations in endometriosis\nGenomic studies in EMS patients typically aim to comment on disease etiology and heritability [140, 141]. \nOne emerging topic is somatic mutations and their influence on EMS pathophysiology. Whole exome \nsequencing of EMS has revealed the presence of single nucleotide variations in ectopic and eutopic \nsites, with mutually exclusive mutations across these locations [142]. Alterations to genes supporting \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 462\ncell adhesion, apoptosis, and cell cycle pathways have all been identified and maintain a heterogeneous \npresentation across patients. These pathways have similarities with known cancer driver mutations, \nallowing for proliferation and metastasis of tissues. Cancer driver mutations such as AT-rich interaction \ndomain-containing protein 1A gene (ARID1A), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic \nsubunit alpha (PIK3CA), and Kirsten rat sarcoma virus proto-oncogene (KRAS) mutations have been found \nin the epithelium of EMS patients [143– 145]. There is still a large debate over the role that these mutations \nplay in the potential progression of EMS to endometrial cancers, however, even in non-cancerous lesions, \nsuch as those in DIE, these mutations are present [143]. The acquisition and interpretation of this data have \nbeen extensively reviewed elsewhere [140], however, one dimension of this discussion yet to be brought \nto EMS is the impact of somatic mutations on immune function. Cancer literature highlights the influence \nthat somatic mutations can have on immune cell infiltration as well as cytotoxic capacity [146– 149], thus \ncalling us to discuss the effect of mutations in pathways beyond just the cytoarchitecture of the lesion itself.\nMutational load, the amount of somatic mutations present within a tissue, has been correlated with tumor \nleukocyte infiltration [146, 148, 149]. This in part could be due to the over-activation of the mutated signaling \npathways having downstream targets that contribute to inflammation, such as IFN-γ and TGF-β [147, 150, 151], \nhowever, the formation of neoantigens is where the current focus lies. Neoantigens are proteins that have \nbeen modified due to mutations, and that present as novel targets for the immune system. With a higher \nmutational load, there is the potential for greater neoantigen formation and thus a greater capacity for \nmounting an immune response against these new targets (Figure 2) [146 ]. Across various cancers, there is \nan association with mutational load, neoantigen formation, tumor leukocyte infiltration, and the expansion \nof the T cell repertoire [148 , 149]. Comparing the ratio of gene expression within T cells infiltrating these \ngenetically different tissues, there is an increase in cytolytic capacity, as measured by granzyme A expression \nas well as an increase in Treg marker forkhead box p3 (Foxp3), potentially counterbalancing the immune cell \nclearance taking place [148]. Due to this heightened tumor leukocyte infiltration, the mutational load can be \nassociated with better patient outcomes, however, this is very microenvironment specific, as the functional \ncapacity of the infiltrating cells still needs to be considered. Additionally, the mutational landscape at each \ntumor or potentially lesion site has its own microenvironment. Within EMS, both intra- and inter-lesion \nheterogeneity of mutations has been identified, thus it is fair to assume that the neoantigens present will \ndiffer at all locations. This adds complexity, in that parallel immune interactions are taking place with \nspecificity to their microenvironment. EMS literature has identified the presence of CD8 + T cells as well as \nan abundant immune infiltrate at the lesion site [152, 153]. Further research is needed however to elucidate \nthese immune populations and to identify the functional status of these cells. This information would bring \nus one step closer to understanding the lesion’s complex network, of which somatic mutations are a part.\nAs previously mentioned, it is the epithelial cells within endometriotic lesions as well as tumors, that \nharbor the vast majority of somatic mutations [143 –145, 154]. Stromal cells have been reported to have \nvery few or no somatic mutations, however, they do carry epigenetic modifications [154–156]. This marked \ndifference in mutation presence is explained by the relationship between these tissues and their contribution \nto the lesion/tumor site; epithelial cells are under the influence of stromal cells [150 ]. The epigenetic \nmodifications of stromal cells cause alterations to their receptor expression and cytokine release [157 ]. \nBoth mechanisms are exploited to promote the proliferation of epithelial cells, increasing their mutation \nacquisition. Within EMS this can manifest as increased ERβ, supporting proliferation by heightening the \nsensitivity to estrogen, PR downregulation contributing to progesterone resistance, and increased paracrine \ncytokine production of growth factors (HGF and TGF-β) targeted to the epithelium [150, 157]. Once combined, \nthese signals increase the rate of epithelial proliferation and mutation. Advancing our understanding of \nthis complex relationship will allow for a greater understanding of these inherent cell properties and how \nmutations fit in their physiology.\nThe study of somatic mutations within EMS is in its infancy. New findings continue to highlight the dynamic \nnature of these tissues, guiding us to adjust our perception of normal tissues and the role of cancer driver \nmutations. Lac et al. [158] identified that 50% of healthy endometrium contains cancer driver mutations and \nthat acquisition will increase proportionally with age. Mutations are no longer relegated to the abnormal, \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 463\nrequiring us to adjust our perspective of “normal” tissues. We must seek to understand the pathways they \nexploit and the potential room for their influence at various stages of disease progression. Adding to this \ncomplexity is the presence of allelic variations in mutations, thus while the presence of one may influence \ntumor leukocyte infiltration and correlate with positive patient outcomes, another may not [147 , 159]. The \nimportance of individual microenvironments cannot be understated and will eventually be the focus in \ntherapeutics, as immune-centered therapies continue to rise. Anti-PD-1/PD-L1 therapies in various cancers \nhave looked to mutational load as an indicator of patient success with immunotherapies [146 , 147, 160]. \nThis underscores the need for understanding the status of immune cells present within the lesion and how \nthey interact with these mutations to capitalize on those networks. Finally, more work is needed considering \na place for neoantigens within EMS. The prevalence of these mutations in normal tissues may be preventing \nthe immune system from mounting a response to those within endometriotic lesions as it does not recognize \nthese as foreign. The selection process of T cells within the reproductive tract as well as the repertoire of \nthese cells needs further research to understand at what point these mutations can be recognized as foreign \nand then cleared.\nFigure 2. Lesion immune microenvironment and inflammatory cycle. (1) Inherent mutational predispositions differ across epithelial \nand stromal cells. Epi-genetic stromal cell alterations promote an environment that stimulates further replication and mutational \nacquisition within epithelial cells. (2) This increased presence of somatic mutations allows for the formation of neoantigens which \nare detected by antigen-presenting cells (APCs) and presented to adaptive immune cells. (3) The lymphocyte fate from these \ninteractions is yet to be determined, forming a novel target of the investigation to define immune phenotype and activation status \nof T cells in response to lesion-specific neoantigens. (4) Phenotypic fate is not yet determined, but higher immune cell infiltration \nhas been seen in lesions with increased somatic mutations. Elevated immune cell infiltration is a facet of another potentially \ndysregulated pathway within the lesion microenvironment. (5) IL-23, which is increased in EMS, is mainly secreted by APCs. \n(6) This cytokine is crucial for the expansion and stabilization of “pathogenic” Th17 cells resulting in high levels of IL-17, which has \npotent pro-inflammatory and pro-angiogenic actions in EMS. (7) IL-23 may also then promote the dysregulated ratio of Th17 and \nTreg cells seen in EMS derailing immune homeostasis. (8) As IL-17 receptor A (IL-17RA) is expressed on immune cells including \nT cells, IL-17 may promote Th17 cells to induce inflammation, recruit neutrophils, and further produce pro-inflammatory cytokines, \nsupporting the establishment and maintenance of endometriotic lesions\nThe immunological basis of chronic pelvic pain\nChronic pelvic pain (CPP) is defined as non-menstrual pain originating from the pelvic region which typically \npersists for more than 6 months [161, 162]. CPP is estimated to affect 26% of the world’s female population, \naccounting for 40% of laparoscopies and 12% of hysterectomies annually in the US [162]. In regards to EMS, \nwhich is commonly characterized by debilitating CPP , more than 60% of all EMS patients report CPP [163 ]. \nIn fact, of the 60% of laparoscopies performed for CPP of which an abnormality is identified, 85% of these \n\n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 464\npatients reveal early-stage EMS or adhesions [162 ]. Existing evidence indicates that CPP can frequently \npersist in EMS patients following successful lesion excision, despite a lack of lesion regeneration and/or \nthe usage of hormonal therapies [163 , 164]. Furthermore, it is well known that the number or spread of \nlesions, as classified by the American Society for Reproductive Medicine (ASRM) staging, is not indicative of \none’s degree of pain [161, 165–167]. This supports the idea that EMS-related CPP is not entirely reliant on \nthe presence or number of lesions and is likely driven by other factors. Moreover, due to the complexity of \nCPP symptomology, which is reviewed extensively elsewhere [162, 168], identifying the exact mechanism(s) \nof CPP is extremely challenging. However, several hypotheses have been proposed to be the cause of CPP , \nincluding immune dysfunction, neuropathies, and psychosocial modulators [162, 169].\nThe scope of CPP is broad, however, the aspect of immune dysfunction is a very understudied area. \nWhile the mechanistic link between CPP and EMS remains undefined, one of the avenues being explored is \nthe link between CPP , EMS, and inflammation. There are various evidence that CPP results from a localized \npro-inflammatory milieu containing upregulated Th cells, mast cells, and the secretion of inflammatory \nmediators [162, 169, 170]. EMS is characteristically known for its chronic inflammatory milieu [171 ]. This \nlink is particularly of interest due to the well-documented immune-centered comorbidities in EMS and their \nrole in CPP , as discussed elsewhere [169, 170, 172]. The dysregulated inflammation in CPP/EMS increases \nthe infiltration of immune cells, such as mast cells, macrophages, and lymphocytes [169 , 171, 173], which \nfurther amplifies inflammation in the microenvironment. Specifically, mast cells promote the infiltration \nof other inflammatory cells that further activate mast cells, creating a positive feedback loop of chronic \ninflammation [169]. Cytokines secreted by activated mast cells (IL-6, IL-21, IL-23, and TGF-β) are also known \nto regulate Th17/Treg cell differentiation and plasticity, suppressing Treg control of self-tolerance which is \ncrucial to avoid immune dysfunction [169, 170]. Mast cells may play a key role in chronic pain and hyperalgesia \nin EMS due to their expression of nerve growth factor (NGF) receptors, as the downstream results of binding \nof NGF may result in a feedback mechanism which promotes pain sensitization [169 ]. Furthermore, due to \nthe shared neural pathways innervating the bladder, colon, and female reproductive tract, this can lead to \ncross-organ sensitization and CPP [162, 163].\nIt is suggested that cross-talk between the nerves and immune cells/modulators within the chronic \ninflammatory milieu of EMS results in the activation of central and peripheral pain pathways, magnifies pain \nsignals, and leads to CPP [162, 169–171, 173, 174]. Particularly, PGE2, TNF-α, NGF, CCL5, IL-8, and IL-1β are \nkey inflammatory mediators increased within the endometriotic microenvironment which directly activate \nsensory nerve endings and create a positive feedback loop to further exacerbate inflammation [163]. In EMS, \nIL-1β specifically is known to stimulate NGF promoting local neurogenesis, and is associated with severe \ndeep dyspareunia [175, 176].\nIt is also crucial to consider psychosocial modulators, such as trauma, abuse, and poor mental health as \npossible contributing factors for CPP . Women with CPP are significantly more likely to report experiencing \nphysical/sexual/verbal/emotional abuse during childhood [162]. Although the cause-and-effect of this pain \nis difficult to decipher, it is speculated that these psychosocial modulators uniquely sensitize patients due \nto their experience of trauma, making them more vulnerable to developing CPP . As psychosocial health \nbreaches the scope of this article, we encourage readers to review the literature on this topic [162, 177, 178]. \nOverall, it is clear that CPP has an extremely complex etiology. However, as there are growing reports of these \nkey inflammatory mediators contributing to CPP , we must improve our understanding so as to utilize this \nnovel information that will aid in defining disease pathophysiology and the development of an effective and \nnon-invasive therapy avenue for EMS patients suffering from CPP .\nRole for Th17 pathway in EMS lesion microenvironment\nAs previously mentioned, there are a few key immunological factors known to be increased in the PF of \nEMS patients, including IL-1β, IL-6, TGF-β1, IL-17, and VEGF [174 , 179, 180]. These mediators greatly \ninfluence the microenvironment in EMS, driving neurogenesis and persistently bathing lesions in a \npro-inflammatory and pro-angiogenic environment that is engineered to support lesion establishment and \nsurvival [161, 165, 171, 181]. Interestingly, IL-1β, IL-6, and TGF-β1 have been well-documented to be directly \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 465\ninvolved in the differentiation of “pathogenic” Th17 cells, when in combination with IL-23 [182 –185]. \nSpecifically, TGF-β1, IL-1β, and IL-6 are known to promote Th17 cell differentiation from naive CD4+ T cells by \ninducing a signal transducer and activator of transcription 3 (STAT3)-dependent expression of IL-21, IL-23R, \nand retinoid-related orphan receptor γt (RORγt), a lineage-specific transcription factor required for Th17 \ncell generation which promotes expression of genes IL23R  and IL17A [182–184]. IL-17 and IL-21 produced \nby developing Th17 cells then mediate Th17 cell amplification, while IL-23 is particularly crucial for the \nexpansion and stabilization of Th17 cells, as well as their ability to induce tissue inflammation [182 –185]. \nExposure to IL-23 also reduces the concentration of anti-inflammatory IL-10 in developing Th17 cells, which \nmay further evoke a “pathogenic” profile in these cells  (Figure 2) [182 , 185]. In fact, IL-17-producing Th17 \ncells generated with TGF-β1 and IL-6 alone have been found to be incapable of inducing autoimmune disease \nor producing “pathogenic” Th17 cells without further exposure to IL-23 [182 , 185]. The key role of IL-23 is \nfurther underlined by evidence that loss or inhibition of the IL-23-specific p19 subunit results in protection \nfrom various autoimmune diseases, including experimental autoimmune encephalomyelitis and autoimmune \ncolitis, whereas loss of IL-17 or IL-17RA alone resulted in no protection or exacerbation of disease [184–186].\nIt is important to note that these Th17 cells are highly plastic and can be driven to become either \n“non-pathogenic” , producing IL-10 and protective against pathogens, or “pathogenic” , producing IL-17 and \ncontributing to chronic inflammation [182, 185, 187]. As EMS patients have elevated levels of IL-17 compared \nto healthy controls [180 , 188], Th17 cells are likely “pathogenic” in EMS and a potential source of IL-17. \nThis is of interest due to the well-known pro-inflammatory and pro-angiogenic actions of IL-17 in chronic \ninflammatory disorders and the pivotal role of this cytokine in the pathogenesis of EMS [135 , 188, 189]. \nFurthermore, as levels of IL-23 have been found to be elevated in EMS [179 , 190, 191], IL-23 is likely a key \ncontributor in driving Th17 cells to this pathogenic profile, producing IL-17 and exacerbating EMS [188 ]. \nHowever, the involvement of group 3 innate lymphoid cells (ILC3s) in this IL-23/IL-17 axis must also be \nexamined in the pathophysiology of EM, as IL-23 can similarly act on ILC3s to produce IL-17 [192, 193].\nThere is a critical balance between Th17 and Treg cells necessary to maintain immune homeostasis [194]. \nDisruptions in this ratio of Th17 and Treg cells have been well documented in EMS [133, 195–197]. Specifically, \npatients with EMS have been found to have lower Treg cells (tolerant) and greater Th17 cells (inflammatory), \nand this Th17 increase is associated with disease severity [133 , 197]. This is of interest, if IL-23 is a key \ncontributor in driving Th17 cells to a pathogenic profile, IL-23 may then control the balance between Th17 \nand Treg cells which is critical to preventing chronic inflammation and autoimmunity [194, 198–200].\nThis evidence may call into question whether endometriosis should be investigated as an autoimmune \ndisorder. Indeed, some studies have found an association of endometriosis with autoimmune diseases, and \nothers have identified autoantibodies within endometriosis [201]. However, according to a systematic review \nand meta-analysis by Shigesi et al. [202], out of 26 investigations, only 5 had good quality evidence, of which 4 \nreported an association of endometriosis with one or more autoimmune diseases.\nImmune-centered comorbities may share common pathological mechanisms\nAs we have discussed, the IL-23/Th17 axis is dysregulated in EMS, as well as various other chronic \ninflammatory diseases, including psoriasis, inflammatory bowel disease, rheumatoid arthritis, and multiple \nsclerosis [185 , 188, 200, 203, 204]. The clinical presentation of these diseases alongside EMS has been \nextensively discussed [165, 202, 205–208]. Here, we will focus on the current gaps in the literature, particularly \non the possible pathophysiological pathways shared between EMS and its comorbidities in order to aid in the \ndiscovery of novel therapeutic targets. The crucial role of the IL-23/Th17 axis in the pathogenesis of various \nchronic inflammatory diseases has been confirmed using IL-23-specific p19 subunit inhibitors [209 –211]. \nCurrently, a few p19-specific IL-23 inhibitors have been Food and Drug Administration (FDA)-approved for \nclinical use in the treatment of psoriasis and psoriatic arthritis, such as risankizumab, tildrakizumab, and \nguselkumab, which are also currently in trial for other diseases with dysregulated IL-23/Th17 axis, such as \nCrohn’s disease [209, 212–217].\n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 466\nSince the dysfunctionality of the IL-23/Th17 axis is a treatment target for the diseases comorbidly \nexhibited with EMS, it would also serve as a promising therapeutic target for EMS. Furthermore, as \nIL-23-driven Th17 cell differentiation is induced through Janus kinase (JAK)/STAT3 signaling, and this \npathway is upregulated in EMS [218], this could provide an additional therapeutic target for EMS or any \ncondition with dysregulated IL-23/Th17 axis. In fact, tofacitinib, a JAK inhibitor was tested on JAK/STAT \nsignaling in an EMS mouse model and was found to result in EMS lesion regression and reduced adhesion \nburden as compared to controls [218]. This dysfunctional signaling pathway may be a potential therapeutic \ntarget for EMS comorbidities, such as psoriasis, as STAT3 has recently been shown to be a key player in \nthe pathophysiology of psoriasis and psoriatic-like inflammatory conditions [219]. STAT3 has also been \nfound to be positively correlated with rheumatoid arthritis and STAT3 loss was found to block joint \ninflammation in mouse models of arthritis [220– 222]. This evidence suggests that both the IL-23/IL-17 \naxis and JAK/STAT3 signaling pathways may be viable therapeutic targets deserving further exploration in \nthe treatment of EMS and related comorbidities (Figure 3).\nFigure 3. Summarizing our perspectives on EMS therapeutic opportunities\nThe currently available options for EMS treatment are predominated by hormonal therapies, but many \nother opportunities exist to treat the immune dysregulation of EMS and target specific immune pathways. As \nEMS is a highly complex disease, treatment plans should move towards a personalized medicine approach, \nincorporating the individual’s hormonal and immunological profiles that can be captured through extracellular \nvesicle (EV) signatures.\nNew advances in EMS diagnosis\nThe current gold standard for diagnosis of EMS is diagnostic laparoscopy with inspection of the abdominal \ncavity and histological confirmation of suspected lesions. Considering the complex manifestations of \nEMS, obtaining the correct preoperative diagnosis is fundamental in defining the best treatment strategy. \nThe World Endometriosis Research Foundation has agreed that one of the key research priorities for EMS \nis the development of reliable non-invasive tests [223 ]. However, in a systematic review, May et al. [224 ] \nevaluated over 100 biomarkers for EMS in serum, plasma, and urine, and could not identify any biomarker or \ndiagnostic panel to recommend for clinical application. The heterogeneous nature of EMS poses a challenge \nin developing diagnostics capable of distinguishing different phenotypes and stages of EMS. Furthermore, the \nhigh incidence of comorbidities experienced by EMS patients create another challenge in finding diagnostic \nbiomarkers; overlapping inflammatory and endocrine mechanisms of comorbid diseases can confound EMS \n\n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 467\nsigns and symptoms. Since surgery is invasive and expensive, other tests including imaging and biomarkers \n[glycoproteins, growth factors, microRNAs (miRNAs), and long noncoding RNAs (lncRNAs)] have been \nevaluated for their non-invasive diagnostic potential [225, 226].\nImmunological and exosomal biomarkers in endometriosis\nImmunological markers and inflammatory cytokines have been extensively studied in EMS patients, and \ndespite an abundance of findings, no diagnostic value has been established. The most representative are \nIL-1, IL-6, IL-8, IFN-γ, MCP-1, and TNF-α [224 ]. Higher serum levels of IL-6 in EMS patients have been \nreported [227], though two systematic reviews could not verify a link between elevated serum levels of IL-6 \nand EMS due to testing parameters varying between studies [224 , 228]. Several studies have shown higher \nlevels of TNF-α in the serum of women with EMS [229–231], while others reported no difference [232, 233]. \nThe concentration of IL-8 is reported to be increased in the PF of women with EMS [234] in correlation with \ndisease stage severity [235 ]. As well, Carmona et al. [236 ] have reported that IL-8 is significantly higher in \nthe serum of patients with ovarian endometrioma compared to healthy controls, but not in the serum of DIE \npatients. Several cytokines have been reported with higher serum values in earlier stages [232]. If ranges can \nbe clearly defined, this could potentially help differentiate the EMS stage during diagnosis.\nAs discussed earlier, IL-17A and IL-23 are heavily involved in the pathogenesis of EMS and are found at \nsignificantly higher concentrations in the PF of EMS patients than in controls [188 , 237, 238]. Furthermore, \nIL-17 along with TNF-α are involved in increasing IL-8 secretion [239 ]. As these cytokines have all been \nobserved in higher levels in EMS patients’ serum or PF, and are all relevant to Th17-mediated inflammation, \nthis axis is worth investigating further in terms of diagnostic panel design.\nOther ILs have been studied in EMS, such as IL-4 which has been found to have higher serum values in \nadolescents with EMS [240]. As well, elevated serum IL-32 has been observed in EMS patients compared to \ncontrols [241]. Specifically, in cases of DIE, IL-33 has been found elevated in the serum and PF of patients \nversus healthy controls, with levels correlating to disease severity [242 ]. In peripheral blood, IL-8, MCP-1, \nand CCL5 showed potential as biomarkers, being significantly increased in EMS patients versus controls [48]. \nNK cells (CD57 + CD16) as potentially viable biomarkers have been reported to be lower in EMS and elevated \none month after surgery to resect EMS lesions [243 ]. Interestingly, the expression of a killer inhibitory \nreceptor known as killer inhibitory receptor 2 DL1 (KIR2DL1), on NK cells is reported to be higher in women \nwith EMS [244 ]. This may explain why NK cells are less active in the disease, but more importantly, this \ndiscrepancy may be useful in identifying EMS. Copeptin, a molecule increased in inflammatory conditions, \nhas been found significantly higher in EMS patient serum compared to controls and in correlation with \ndisease stage severity [245]. In a study by Tuten et al. [246] the inflammatory biomarker glycoprotein YKL-40 \nwas significantly elevated in patients with EMS compared to healthy controls, and positively correlated \nwith disease severity. While several immunological biomarkers have been studied in EMS, many have failed \nrepeatability tests. As well, most of these biomarkers are not EMS-specific enough to reliably diagnose EMS, \ngiven comorbid inflammatory diseases. For immunological biomarkers to be applicable in diagnostics, more \nresearch is required to define a unique panel of analytes.\nIn recent years, exosomes have emerged as a novel source of biomarkers in liquid biopsy has emerged with \nthe potential to be used for early diagnostics and drug delivery-based therapeutics. Exosomes are a unique \nsubset of EVs [247 ], at 30 nm to 150 nm in size they carry proteins, DNA, RNA, miRNA, and lncRNA [248 ]. \nThese vesicles play an important role in the exchange of biological information between different cells; the \nincorporated genetic molecules can be taken up by neighboring or distant cells, where their contents enact \ndownstream functions in recipient cells [248]. A study by Sun et al. [249] showed that exosomes isolated from \nthe eutopic endometrium of a mouse model of EMS polarized macrophages into an M2-like phenotype and \ncaused a reduction in their phagocytic ability, thereby enhancing the development of lesions. Furthermore, \nprimary human endometrial stromal cell cultures from EMS patients were found to secrete exosomes with a \nunique proangiogenic miRNA profile, and these exosomes conferred proangiogenic (tubulogenic) properties \nto human umbilical vein endothelial cells (HUVECs) in culture [250 ]. The link between exosomes, immune \n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 468\nfunction, and angiogenesis in EMS is what makes exosomes an exciting route to explore in noninvasive \nbiomarker research.\nIt has been reported that exosomes from ovarian endometrioma patients showed high levels of \necto-nucleotidases compared to simple ovarian cysts [251 ]. Ecto-nucleotidases regulate extracellular ATP \nand rising extracellular adenosine levels, contributing to the local immune suppression necessary for EMS \nprogression [251 ]. Detecting ecto-nucleotidases in more accessible biological fluids would make them \npromising non-invasive EMS biomarkers [251 ]. Our group has demonstrated that EVs from EMS patient \ntissues and plasma samples carry unique signatures of miRNAs and lncRNAs [252 ]. Endometrial (epithelial \nand endothelial) cell cultures treated with patient and control plasma-derived EVs exhibited signatures \nof inflammatory and angiogenic cytokines involved in EMS progression [252 ]. miRNA-lncRNA proteomic \nsignatures and networks inherent in EMS patient EVs have the potential to be used as biomarkers [252 ]. \nFurther, Zhang et al. [253 ] showed that two exosomal miRNAs, miR-22-3p and miR-320a are significantly \nupregulated in the serum of EMS patients. The two miRNAs may play an important role in EMS occurrence \nand development and have the potential to be biomarkers for the diagnosis of EMS [253 ]. Recently it was \nreported that exosomes isolated from PF samples of 28 women at different stages of the disease showed \nspecific proteins in the exosomes that were absent in the controls [254]. Five proteins were found exclusively \nin the EMS groups: peroxiredoxin 1 (PRDX1), histone H2A type 2-C, annexin A2 (ANXA2), inter-alpha-trypsin \ninhibitor heavy chain 4 (ITIH4), and the tubulin α-chain [254 ]. These proteins specifically found in EMS \npatient exosomes open up new avenues as biomarkers. It was illustrated in a study by Qiu et al. [255] that the \nexosomal antisense hypoxia-inducible factor (aHIF) is highly expressed in serum and endometriotic lesion \ntissue of EMS patients. This study also demonstrated that upon HUVECs internalizing exosomes from EMS \ncystic stromal cells, exosomal aHIF regulated angiogenesis-related genes, facilitating angiogenesis [255]. This \nhighlights the potential clinical value of circulating exosomal aHIF as a biomarker. Overall, despite extensive \nefforts to find EMS biomarkers, no previous candidate has achieved the sensitivity and specificity required for \na viable diagnostic tool. Exosomes show great promise as biomarkers and as novel drug delivery vehicles in \ncellular therapy (Figure 3). We must standardize the protocols and identification methods such that exosome \nbiomarkers can be used in clinical settings.\nVarious phenotypes of EMS have distinct mechanisms, and as a result, a single distinctive biomarker is \nnot feasible for all EMS cases. This is a central challenge to developing diagnostics, and further research is \nneeded to identify a panel of biomarkers that accounts for the heterogeneous manifestations of EMS.\nConclusions and future perspectives\nEMS is a highly complex, heterogeneous disorder that has multi-factorial etiology intertwined in genetic, \nhormonal, immune, and environmental predispositions. Recent evidences have uncovered the dynamic \nnature of the EMS lesion microenvironment with particular emphasis on immune-inflammatory changes \nand the evolving relationship between endocrine, immune, and pain aspects. While the general consensus \nin the literature is that EMS is a systemic disorder, further evidence is required to validate this notion. \nThe puzzling question yet to be answered is whether the lesion microenvironment contributes to the \ninflammatory changes or arises as a response to the growing lesion. Analysis of inflammatory markers in \nPF and within the lesion itself can only provide a snapshot of the disease captured at the time of sample \ncollection. However, we need to consider how long a patient has been harboring these lesions and associated \nchronic inflammation, hormonal imbalance, somatic mutations, or co-morbidities that might shape EMS \nlesion architecture. Another knowledge gap is the molecular/cellular underpinning of endometriotic lesion \ninitiation and subsequent progression. Does immune dysfunction in an EMS patient facilitate lesion initiation? \nStudies focused on single-cell RNA sequencing within the lesion microenvironment will provide new context \nassociated with the immune and non-immune basis of disease-specific pathways. It is important to keep in \nmind that the chronic nature of the disease combined with concurrent therapies to relieve lesion growth and \npain further complicates the precise understanding of the pathophysiology of the disease.\n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 469\nThere is growing consensus in the EMS research community that perhaps each EMS phenotype such as \nDIE, ovarian endometrioma, and peritoneal lesions have unique pathogenetic mechanisms, yet most studies \nlump EMS as one entity. Furthermore, associated comorbidities pose a significant challenge to understanding \nthe pathophysiology of EMS. Another major consideration is the lack of suitable animal models that would \nmimic the spontaneous human disease scenario. Despite these challenges, research for the last decade in \nthe EMS field has revealed new insights into disease pathogenesis via cell-cell communication through EVs, \nmiRNAs, genome-wide association studies, etc. Going forward, the integration of new advances in genomics, \nproteomics, and lipidomics, combined with the generation of new experimental animal models including \nhumanized mice will help pinpoint specific mechanisms contributing to EMS lesion growth and identify new \ndiagnostic and therapeutic targets.\nAbbreviations\naHIF: antisense hypoxia-inducible factor\nBMDSCs: bone marrow-derived stem cells\nCCL: C-C motif chemokine ligand\nCD44: cluster of differentiation 44\nCPP: chronic pelvic pain\nCXCL: C-X-C motif chemokine ligand\nDIE: deep infiltrating endometriosis\nEMS: endometriosis\nERβ: estrogen receptor β\nEV: extracellular vesicle\nGM-CSF: granulocyte-macrophage colony-stimulating factor\nIFN-γ: interferon-γ\nIL: interleukin\nJAK: Janus kinase\nlncRNAs: long noncoding RNAs\nMCP-1: monocyte chemoattractant protein-1\nMDSCs: myeloid-derived suppressor cells\nmiRNAs: microRNAs\nMSCs: mesenchymal stem cells\nNGF: nerve growth factor\nNK: natural killer\nPD-1: programmed cell death 1\nPD-L1: programmed cell death-ligand 1\nPF: peritoneal fluid\nPRs: progesterone receptors\nSTAT3: signal transducer and activator of transcription 3\nTGF-β: transforming growth factor beta\nTh: T helper\nTNF-α: tumor necrosis factor-alpha\nTreg: regulatory T\nVEGF: vascular endothelial growth factor\n\nExplor Immunol. 2022;2:454–83 | https://doi.org/10.37349/ei.2022.00062 Page 470\nDeclarations\nAuthor contributions\nAM conceived the main themes and subsections of the article. AM, DS, KZ, DH, KS, and SA reviewed and \ninterpreted literature and wrote body of paper. AM, DS, KZ devised schematic figures. DS created illustrations. \nHL reviewed literature, advised on article design, and revised body of text. CT and MK advised on article \ndesign and direction and offered expertise on the article subject matter. CT oversaw the writing process and \ncritically revised body of text.\nConflicts of interest\nThe authors declare that there are no conflicts of interest.\nEthical approval\nNot applicable.\nConsent to participate\nNot applicable.\nConsent to publication\nNot applicable.\nAvailability of data and materials\nNot applicable.\nFunding\nNot applicable.\nCopyright\n© The Author(s) 2022.\nReferences\n1. Levy AR, Osenenko KM, Lozano-Ortega G, Sambrook R, Jeddi M, Bélisle S, et al. Economic burden of \nsurgically confirmed endometriosis in Canada. J Obstet Gynaecol Can. 2011;33:830–7.\n2. 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