Endometriosis as an immune-mediated disease: pathogenetic mechanisms and therapeutic strategies

Sofia Shifon, Tamara Tyrinova, Т. В. Тыринова, Tatyana Veretelnikova, Н. М. Пасман, Natalia Pasman, Elena Chernykh, Е. Р. Черных
Frontiers in immunology · 2025 · vol. 16 , pp. 1727183 · doi:10.3389/fimmu.2025.1727183 · PMID:41488658 · PMC12756115 · W4417449150
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This review analyzes 198 publications to establish that endometriosis involves significant innate and adaptive immune dysfunctions, including macrophage and NK cell alterations, complement activation, and specific cytokine profiles, with distinct immunological features across different endometriosis forms.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This review synthesizes evidence from 198 publications (selected from 1,209 records) to analyze immunopathogenetic mechanisms in endometriosis across innate and adaptive immunity and to outline potential immune-targeted therapeutic strategies. It reports that endometriosis involves macrophage dysfunction with a shift toward an M2 phenotype, reduced NK-cell cytotoxicity, complement activation with proinflammatory/proangiogenic effects, a Th2-skewed and Treg-enriched response alongside B-cell activation and autoantibody production, and a cytokine pattern showing both pro-inflammatory (IL-1β, IL-6, TNF-α) and immunosuppressive (IL-10, TGF-β) mediators; it further highlights immune differences by clinical form, including Treg deficiency in adenomyosis and a deep infiltrating endometriosis role for IDO1/COX-2/MMP-9 and complement-mediated tissue destruction. A key caveat explicitly discussed is heterogeneity across disease forms and stages, unclear local–systemic relationships, possible effects of prior therapy, and variability in methods (e.g., flow cytometry, ELISA, PCR) that may contribute to inconsistent findings. This paper is centrally about endometriosis — it provides a comprehensive review of immune-mediated pathogenetic mechanisms and therapeutic strategies, including distinct immunological features relevant to adenomyosis as an internal endometriosis form.

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Abstract

Endometriosis, which affects approximately 10% of women of reproductive age, is a complex inflammatory disease with significant immune system disturbances caused by an inadequate immune response to retrograde menstruation and leading to the establishment of immune evasion mechanisms by ectopic tissue. This review provides an analysis of the immunopathogenetic mechanisms of endometriosis based on 198 high-quality publications selected from 1,209 potentially relevant articles in the PubMed, Scopus, Web of Science, and Google Scholar databases for the period 1927-2025. The study revealed that endometriosis is associated with profound alterations in both innate and adaptive immunity. Key pathogenetic mechanisms include macrophage dysfunction with a shift to the M2 phenotype, reduced cytotoxic activity of NK cells, complement system activation with proinflammatory and proangiogenic effects, a predominant Th2 response with an increase in Treg cells, and B-lymphocyte activation with autoantibody production. The cytokine profile is characterized by a concurrent increase in both pro-inflammatory mediators (IL-1β, IL-6, TNF-α) and immunosuppressive factors (IL-10, TGF-β). The complement system contributes to pathogenesis through C3a/C5a-mediated inflammation, angiogenesis promotion, and interactions with dysbiotic endometrial microbiota. Different forms of endometriosis have specific immunological features: ovarian endometriosis combines local immunosuppression with systemic inflammation, adenomyosis is characterized by pro-inflammatory changes with a Treg cell deficiency, and deep infiltrating endometriosis is distinguished by the activation of the IDO1/COX-2/MMP-9 signaling pathway and complement-mediated tissue destruction. Understanding the specifics of immunopathogenesis opens new avenues for developing targeted immunotherapy, which may include modulating immune cell functions, using cytokine inhibitors, blocking immune checkpoints, and employing nanotechnological approaches.

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Condition tags

endometriosisadenomyosisdie_deep_infiltrating

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Adaptive Immunity Adaptive Immunity Adaptive Immunity

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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