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- Björk, Emma, 1977-, et al.
(författare)
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Endometriotic tissue-derived exosomes downregulate NKG2D-mediated cytotoxicity and promote apoptosis : mechanisms for survival of endometriotic tissue at ectopic sites
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Endometriosis, affecting 10% of women, is defined as implantation, survival, and growth of endometriumlike/endometriotic tissue outside the uterine cavity, causing inflammation, infertility, pain andsusceptibility to ovarian cancer. Despite extensive studies, its etiology and pathogenesis are poorlyunderstood and largely unknown. The prevailing view is that the immune system of endometriosispatients fails to clear ectopically disseminated endometrium from retrograde menstruation. Exosomes aresmall extracellular vesicles that exhibit immunomodulatory properties. We studied the role ofendometriotic tissue-secreted exosomes in the pathophysiology of endometriosis. Two exosome-mediatedmechanisms known to impair the immune response were investigated: 1) downregulation of NKG2Dmediatedcytotoxicity and 2) FasL- and TRAIL-induced apoptosis of activated immune cells. We showedthat secreted endometriotic exosomes isolated from supernatants of short-term explant cultures carry theNKG2D ligands MICA/B and ULBP1-3; and the proapoptotic molecules FasL and TRAIL on theirsurface, i.e. signature molecules of exosome-mediated immune suppression. Acting as decoys, theseexosomes downregulate the NKG2D receptor, impair NKG2D-mediated cytotoxicity and induce apoptosisof activated PBMC and Jurkat cells through the FasL- and TRAIL pathway. The secreted endometrioticexosomes create an immunosuppressive gradient at the ectopic site, forming a “protective shield” aroundthe endometriotic lesions. This gradient guards the endometriotic lesions against clearance by a cytotoxicattack and creates immunologic privilege by induction of apoptosis in activated immune cells. Takentogether, our results provide a plausible, exosome-based mechanistic explanation for the immunedysfunction and the compromised immune surveillance in endometriosis and contribute with novelinsights into the pathogenesis of this enigmatic disease.
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| 2. |
- Björk, Emma, et al.
(författare)
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Enhanced CD56 expression and increased numbers of CD56+bright cells in the peripheral blood of untreated endometriosis patients
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Problem: Endometriosis is characterized by ectopic implantation of endometrial-like tissue and impaired immuneresponses such as the cytotoxic function of NK cells. NK cells can be divided into two subpopulations where theCD56+bright cells produce more cytokines and have low natural cytotoxicity compared to CD56+dim cells. Themajority (>90%) of circulating NK cells are CD56+dim whereas very few (0-10 %) are CD56+bright.Method of Study: Using flow cytometry, NK cell subpopulations were analyzed in peripheral blood from 21individuals with endometriosis and 12 healthy controls. Furthermore, the NKG2D receptor expression on PBMCswas analyzed in untreated and treated endometriosis patients and controls.Results: We found an increased level of CD56+bright cells in 8 of 21 endometriosis patients. After surgery andhormonal treatment, the levels were normalized to that of controls. In a new cohort, the NKG2D receptorexpression on PBMCs was analyzed, with a lower expression in untreated patients compared to controls andpatients treated by surgery and hormones.Conclusions: Our findings of a dominant CD56+bright NK cell subpopulation in peripheral blood, anddownregulated levels of the NKG2D receptor on PBMCs, may explain the impaired cytotoxic immune functioncausing the persistence of ectopic endometrium in untreated endometriosis patients.
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