Division of Obstetrics and Gynecology/Örnsköldsvik Hospital, Örnsköldsvik, Sweden.
Department of Clinical Microbiology/Infection and Immunology, Umeå University, Umeå, Sweden.
J Immunol. 2024 Sep 1;213(5):567-576. doi: 10.4049/jimmunol.2300781.
Endometriosis, affecting 10% of women, is defined as implantation, survival, and growth of endometrium-like/endometriotic tissue outside the uterine cavity, causing inflammation, infertility, pain, and susceptibility to ovarian cancer. Despite extensive studies, its etiology and pathogenesis are poorly understood and largely unknown. The prevailing view is that the immune system of endometriosis patients fails to clear ectopically disseminated endometrium from retrograde menstruation. Exosomes are small extracellular vesicles that exhibit immunomodulatory properties. We studied the role of endometriotic tissue-secreted exosomes in the pathophysiology of endometriosis. Two exosome-mediated mechanisms known to impair the immune response were investigated: 1) downregulation of NKG2D-mediated cytotoxicity and 2) FasL- and TRAIL-induced apoptosis of activated immune cells. We showed that secreted endometriotic exosomes isolated from supernatants of short-term explant cultures carry the NKG2D ligands MICA/B and ULBP1-3 and the proapoptotic molecules FasL and TRAIL on their surface, i.e., signature molecules of exosome-mediated immune suppression. Acting as decoys, these exosomes downregulate the NKG2D receptor, impair NKG2D-mediated cytotoxicity, and induce apoptosis of activated PBMCs and Jurkat cells through the FasL- and TRAIL pathway. The secreted endometriotic exosomes create an immunosuppressive gradient at the ectopic site, forming a "protective shield" around the endometriotic lesions. This gradient guards the endometriotic lesions against clearance by a cytotoxic attack and creates immunologic privilege by induction of apoptosis in activated immune cells. Taken together, our results provide a plausible, exosome-based mechanistic explanation for the immune dysfunction and the compromised immune surveillance in endometriosis and contribute novel insights into the pathogenesis of this enigmatic disease.
子宫内膜异位症影响了 10%的女性，其定义为子宫内膜样/子宫内膜组织在子宫腔外的植入、存活和生长，导致炎症、不孕、疼痛和易患卵巢癌。尽管进行了广泛的研究，但它的病因和发病机制仍不清楚。目前的观点是，子宫内膜异位症患者的免疫系统无法从逆行性月经中清除异位播散的子宫内膜。外泌体是具有免疫调节特性的小型细胞外囊泡。我们研究了子宫内膜异位组织分泌的外泌体在子宫内膜异位症病理生理学中的作用。研究了两种已知会损害免疫反应的外泌体介导机制：1）下调 NKG2D 介导的细胞毒性；2）FasL 和 TRAIL 诱导激活免疫细胞的凋亡。我们表明，从短期植入培养物上清液中分离的分泌性子宫内膜异位外泌体表面携带 NKG2D 配体 MICA/B 和 ULBP1-3 以及促凋亡分子 FasL 和 TRAIL，即外泌体介导免疫抑制的特征分子。这些外泌体作为诱饵，下调 NKG2D 受体，损害 NKG2D 介导的细胞毒性，并通过 FasL 和 TRAIL 途径诱导激活的 PBMC 和 Jurkat 细胞凋亡。分泌的子宫内膜异位外泌体在异位部位形成免疫抑制梯度，在子宫内膜异位病变周围形成“保护屏蔽”。这种梯度通过诱导激活免疫细胞凋亡来保护子宫内膜异位病变免受细胞毒性攻击，并产生免疫特权。总之，我们的研究结果为子宫内膜异位症中免疫功能障碍和免疫监视受损提供了一种基于外泌体的合理机制解释，并为这种神秘疾病的发病机制提供了新的见解。
