Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
Department of Medical Sciences, Section of Dermathology and Infective Medicine, University of Ferrara, Ferrara, Italy.
Am J Reprod Immunol. 2019 Oct;82(4):e13174. doi: 10.1111/aji.13174. Epub 2019 Aug 17.
We first reported human herpesvirus (HHV)-6A DNA presence in 43% of endometrial cells from women with idiopathic infertility, whereas no fertile control women harbored the virus. We investigated the effect of HHV-6A infection on the immunological status of the endometrium.
Endometrial biopsies, uterine flushing, and whole blood samples were collected from 67 idiopathic infertile women (mid-secretory phase). We analyzed the endometrial immunological status evaluating: (a) the effect of HHV-6A infection on endometrial immune profile analyzing the ratio of interleukin (IL)-15/ fibroblast growth factor-inducible 14 (Fn-14) and IL-18/ TNF-related weak inducer of apoptosis (TWEAK) mRNA as a biomarker of endometrial (e)natural killer activation/maturation, angiogenesis, and Th1/Th2 balance; (b) endometrial receptivity to trophoblasts in endometrial 3D in vitro model; (c) natural killer (NK) cells and T cells percentage and subpopulations by flow cytometry.
We confirmed the presence of HHV-6A infection in a 40% of idiopathic infertile women, characterized by an immune profile reflecting eNK cell cytotoxic activation and a decrease in CD4+ CD25+ CD127dim/ regulatory T cells. The co-culture of endometrial epithelial cells with spheroids generated from the extravillous trophoblast-derived cell line JEG3 showed a twofold expansion of spheroids on endometrial epithelial-stromal cells (ESC) culture surface from HHV-6A negative women while no expansion was observed on the surface of ESC from HHV-6A positive women.
The identification of an effect of HHV-6A infection on endometrial immune status opens new perspectives in idiopathic infertile women care management. In addition, it would be possible to select antiviral therapies as novel, non-hormonal therapeutic approaches to those idiopathic infertile women characterized by the presence of endometrial HHV-6A infection, to increase their pregnancy rate.
我们首次报道，在 43%的特发性不孕女性的子宫内膜细胞中存在人类疱疹病毒 6A（HHV-6A）DNA，而没有生育能力的对照组女性没有携带该病毒。我们研究了 HHV-6A 感染对子宫内膜免疫状态的影响。
从 67 名特发性不孕女性（中分泌期）中采集子宫内膜活检、子宫冲洗和全血样本。我们通过分析子宫内膜免疫状态来评估：（a）HHV-6A 感染对子宫内膜免疫谱的影响，分析白细胞介素 15（IL-15）/成纤维细胞生长因子诱导 14（Fn-14）和白细胞介素 18（IL-18）/肿瘤坏死因子相关弱凋亡诱导因子（TWEAK）mRNA 的比值，作为子宫内膜（e）自然杀伤细胞激活/成熟、血管生成和 Th1/Th2 平衡的生物标志物；（b）在子宫内膜 3D 体外模型中子宫内膜对滋养层的接受能力；（c）通过流式细胞术检测自然杀伤（NK）细胞和 T 细胞的百分比和亚群。
我们证实了 40%的特发性不孕女性存在 HHV-6A 感染，其免疫谱特征是 eNK 细胞的细胞毒性激活和 CD4+CD25+CD127dim/调节性 T 细胞的减少。将子宫内膜上皮细胞与源自绒毛外滋养层衍生细胞系 JEG3 的球体共培养，发现来自 HHV-6A 阴性女性的球体在子宫内膜上皮-间质细胞（ESC）培养表面上扩大了两倍，而在 HHV-6A 阳性女性的 ESC 表面上没有观察到扩大。
HHV-6A 感染对子宫内膜免疫状态的影响的鉴定为特发性不孕女性的护理管理开辟了新的视角。此外，对于那些存在子宫内膜 HHV-6A 感染的特发性不孕女性，可以选择抗病毒治疗作为新的非激素治疗方法，以提高她们的妊娠率。
