Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target

Agostinis, Chiara; Balduit, Andrea; Mangogna, Alessandro; Zito, Gabriella; Romano, Federico; Ricci, Giuseppe; Kishore, Uday; Bulla, Roberta

doi:10.3389/fimmu.2020.599117

Cited by 66 publications

(59 citation statements)

References 188 publications

(197 reference statements)

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“…Indeed, red lesions are very active lesions with a high angiogenesis, whereas Wright stain–positive lesions are mainly composed of fibrosis, and black lesions correspond to intermediate state, but also by chronic inflammatory and/or fibrotic character of the pathology. 3 , 23 In the present series, the SUVmax values of endometriosis lesions fell into the same range. The lesions of endometriosis with the highest 18 F-FDG uptake were located in pelvic peritoneum and adnexal area (SUVmax 2.3–5.3).…”

Section: Discussionsupporting

confidence: 70%

Interference of Known or Suspected Endometriosis in Reporting FDG PET/CT Performed in Another Indication

et al. 2022

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Introduction: Endometriosis is a common gynecologic condition that may be visualized on 18 F-FDG PET/CT and mimic lesions of malignancy. We analyzed the interference of known or suspected endometriosis in reporting 18 F-FDG PET/CT performed in another indication. Results: The PET/CT images of 18 women with known (n = 15) or suspected (n = 3) endometriosis were analyzed. Based on clinical follow-up and results of other imaging, biopsy, and/or postsurgical histology, the presence of lesions of endometriosis at the time of 18 F-FDG PET/CT was confirmed in 13 of 18 patients (72%). The per-patient positivity rate of 18 F-FDG PET/CT was 8/18 (44%; 95% confidence interval, 22%-69%). The patient-based detection rate of 18 F-FDG PET/CT in patients with confirmed lesions of endometriosis was 8/13 (62%; confidence interval, 32%-86%). On per-lesion/site basis, 18 F-FDG PET/CT detected 11 of 20 sites (55%) of endometriosis. The SUVmax of these lesions/sites ranged between 1.8 and 5.3 (median, 3.8). In 9 of 18 patients (50%), a total of 13 non-endometriosis-related lesions/sites were detected by 18 F-FDG PET/CT; their SUVmax ranged between 2.7 and 23 (median, 9.4). Conclusion:The interference of known or suspected endometriosis in reporting 18 F-FDG PET/CT performed in another indication was limited but possible and should be kept in mind, even in postmenopausal women, as the oldest patient with 18 F-FDG-positive endometriosis was aged 63 years. The lesions of endometriosis showed inconstant 18 F-FDG uptake with overlap of SUVmax with low-grade malignancies. In our series, the greatest SUVmax value of lesion of endometriosis was 5.3, somewhat higher than the threshold of 4 previously proposed for identification of malignant transformation of endometriosis.

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Section: Discussionsupporting

confidence: 70%

Interference of Known or Suspected Endometriosis in Reporting FDG PET/CT Performed in Another Indication

et al. 2022

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“…It is largely considered that macrophages, among various immune cells, exert a pivotal role in the pathogenesis of EM ( 22 , 43 , 44 ). These cells could be responsible for the local synthesis of C3 in EM lesions as well ( 45 ), but, since we did not notice differences in mouse peritoneal washings and in co-culture experiments ( Supplementary Figure 9 ), we decided to focus only on MCs.…”

Section: Discussionmentioning

confidence: 99%

“…Immunotherapy is beginning to be considered as an option for EM. In the light of the possibility to use complement immunotherapy with blocking antibodies in EM ( 22 ), we examined the underlying mechanisms of C3 expression and its cellular cross-talk, making it a novel potential therapeutic target for EM.…”

Section: Introductionmentioning

confidence: 99%

The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis

et al. 2021

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The complement system is a major component of humoral innate immunity, acting as a first line of defense against microbes via opsonization and lysis of pathogens. However, novel roles of the complement system in inflammatory and immunological processes, including in cancer, are emerging. Endometriosis (EM), a benign disease characterized by ectopic endometrial implants, shows certain unique features of cancer, such as the capacity to invade surrounding tissues, and in severe cases, metastatic properties. A defective immune surveillance against autologous tissue deposited in the peritoneal cavity allows immune escape for endometriotic lesions. There is evidence that the glandular epithelial cells found in endometriotic implants produce and secrete the complement component C3. Here, we show, using immunofluorescence and RT-qPCR, the presence of locally synthesized C3 in the ectopic endometriotic tissue, but not in the eutopic tissue. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse into the peritoneum of recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. Peritoneal washings from the wild type mice with EM showed more degranulated mast cells compared to C3 knock-out mice, consistent with higher C3a levels in the peritoneal fluid of EM patients. We provide evidence that C3a participates in an auto-amplifying loop leading to mast cell infiltration and activation, which is pathogenic in EM. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts.

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“…Indeed, genome-wide association methodology has allowed the identification of causative variants in/near genes that can be assigned to biological pathways important in chronic inflammation [13]. Immune dysregulation has been reported as a significant contributor to the onset and worsening of the disease, constituting a therapeutic target in endometriosis [14]. Over the years, several studies have been conducted, both in humans and in mice, to evaluate the possible use of immunomodulatory agents in the treatment of endometriosis [15].…”

Section: Endometriosis As a Chronic Inflammatory Diseasementioning

confidence: 99%

Genetics and Inflammation in Endometriosis: Improving Knowledge for Development of New Pharmacological Strategies

Giacomini

Minetto

Piani

et al. 2021

IJMS

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According to a rich body of literature, immune cell dysfunctions, both locally and systemically, and an inflammatory environment characterize all forms of endometriosis. Alterations in transcripts and proteins involved in the recruitment of immune cells, in the interaction between cytokines and their receptors, cellular adhesion and apoptosis have been demonstrated in endometriotic lesions. The objective of this narrative review is to provide an overview of the components and mechanisms at the intersection between inflammation and genetics that may constitute vanguard therapeutic approaches in endometriosis. The GWAS technology and pathway-based analysis highlighted the role of the MAPK and the WNT/β-catenin cascades in the pathogenesis of endometriosis. These signaling pathways have been suggested to interfere with the disease establishment via several mechanisms, including apoptosis, migration and angiogenesis. Extracellular vesicle-associated molecules may be not only interesting to explain some aspects of endometriosis progression, but they may also serve as therapeutic regimens per se. Immune/inflammatory dysfunctions have always represented attractive therapeutic targets in endometriosis. These would be even more interesting if genetic evidence supported the involvement of functional pathways at the basis of these alterations. Targeting these dysfunctions through next-generation inhibitors can constitute a therapeutic alternative for endometriosis.

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Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target

Cited by 66 publications

References 188 publications

Interference of Known or Suspected Endometriosis in Reporting FDG PET/CT Performed in Another Indication

Interference of Known or Suspected Endometriosis in Reporting FDG PET/CT Performed in Another Indication

The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis

Genetics and Inflammation in Endometriosis: Improving Knowledge for Development of New Pharmacological Strategies

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