platform-for-quantitative-detection-endometrial-immune-cells-based-on

Platform for Quantitative Detection of Endometrial Immune Cells Based on Immunohistochemistry and Digital Image Analysis

To evaluate the endometrial immune microenvironment of patients with recurrent miscarriage (RM), a digital immunohistochemistry image analysis platform ...

Shenzhen Zhongshan Urology Hospital

CD8 T cells are the main candidates to recognize and respond to fetal HLA-C at the fetal-maternal interface, but data on the amount of peripheral CD8 T cells and their functions during the window of implantation in recurrent implantation failure (RIF) patients are limited. Peripheral blood was obtained from 56 women with RIF and 16 fertile women in the mid-luteal phase of the menstrual cycle, and the CD8 T cells were determined by FACS analysis. No statistical differences in the proportion of peripheral CD8 T cells were observed among the women with RIF and the control group. However, the levels of IFN-γ and TNF-α CD8 T cells in the RIF group were significantly higher than those in the control group. The cytolytic activity and regulatory proportion of CD8 T cells in RIF were similar to that in the control group. Our data indicated that the elevated expression levels of IFN-γ and TNF-α in peripheral CD8 T cells may contribute to an impaired immune tolerance in women with RIF.

Functional properties of peripheral CD8  T cells in patients with repeated implantation failure.

To investigate whether chronic endometritis (CE) affects the immune status of peripheral blood and endometrium in patients with recurrent reproductive failure (RRF).

Evaluation of peripheral and uterine immune status of chronic endometritis in patients with recurrent reproductive failure.

This study aims to evaluate the modulatory effects of vitamin D on peripheral blood and endometrial cellular immunity in women with recurrent implantation failure (RIF).

Potential impact of maternal vitamin D status on peripheral blood and endometrium cellular immunity in women with recurrent implantation failure.

Limited evidence revealed whether endometrial immunological factors contribute to implantation success in the first-attempted in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) patients.

New endometrial immune cell-based score (EI-score) for the prediction of implantation success for patients undergoing IVF/ICSI.

The definition of chronic endometritis (CE) differs among studies, and currently, there is no accepted consensus. This study aimed to establish the minimum number of immunohistochemical analysis of CD138 plasma cells to identify a clinically relevant CE.

Diagnosis of chronic endometritis: How many CD138 cells/HPF in endometrial stroma affect pregnancy outcome of infertile women?

Recurrent reproductive failure (RRF), such as recurrent pregnancy loss and repeated implantation failure, is characterized by complex etiologies and particularly associated with diverse maternal factors. It is currently believed that RRF is closely associated with the maternal environment, which is, in turn, affected by complex immune factors. Without the use of automated tools, it is often difficult to assess the interaction and synergistic effects of the various immune factors on the pregnancy outcome. As a result, the application of Artificial Intelligence (A.I.) has been explored in the field of assisted reproductive technology (ART). In this study, we reviewed studies on the use of A.I. to develop prediction models for pregnancy outcomes of patients who underwent ART treatment. A limited amount of models based on genetic markers or common indices have been established for prediction of pregnancy outcome of patients with RRF. In this study, we applied A.I. to analyze the medical information of patients with RRF, including immune indicators. The entire clinical samples set (561 samples) was divided into two sets: 90% of the set was used for training and 10% for testing. Different data panels were established to predict pregnancy outcomes at four different gestational nodes, including biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth, respectively. The prediction models of pregnancy outcomes were established using sparse coding, based on six data panels: basic patient characteristics, hormone levels, autoantibodies, peripheral immunology, endometrial immunology, and embryo parameters. The six data panels covered 64 variables. In terms of biochemical pregnancy prediction, the area under curve (AUC) using the endometrial immunology panel was the largest (AUC = 0.766, accuracy: 73.0%). The AUC using the autoantibodies panel was the largest in predicting clinical pregnancy (AUC = 0.688, accuracy: 78.4%), ongoing pregnancy (AUC = 0.802, accuracy: 75.0%), and live birth (AUC = 0.909, accuracy: 89.7%). Combining the data panels did not significantly enhance the effect on prediction of all the four pregnancy outcomes. These results give us a new insight on reproductive immunology and establish the basis for assisting clinicians to plan more precise and personalized diagnosis and treatment for patients with RRF.

Using Deep Learning in a Monocentric Study to Characterize Maternal Immune Environment for Predicting Pregnancy Outcomes in the Recurrent Reproductive Failure Patients.

Decidual natural killer cells (dNK), the predominant decidual lymphocytes in early pregnancy, are primarily identified based on their CD56 CD16 phenotype and play an important role in maintaining immune tolerance at the maternal-fetal interface. dNK dysfunction reportedly leads to pathological pregnancy. Indeed, various dNK-derived soluble factors are involved in a series of key processes related to pregnancy outcomes. In this review, we summarize the roles of these dNK-derived factors in immune tolerance and embryonic development to improve the current understanding regarding the physiological and pathological mechanisms that occur during pregnancy, while potentially informing the development of effective therapeutics.

The role of decidual natural killer cell-derived soluble factors in early pregnancy.

To investigate whether endometrial T-bet (Th1 lineage-committed transcription factor)/GATA3 (Th2 lineage-committed transcription factor) ratio has predictive potential for embryo implantation in infertile women undergoing in vitro fertilization-embryo transfer (IVF-ET).

Predictive role of endometrial T-bet/GATA3 ratio during mid-luteal phase for live birth in patients undergoing in vitro fertilization: A retrospective observational study.

To assess whether chronic endometritis (CE) affects embryo implantation in patients with repeated implantation failure (RIF).

Chronic endometritis impairs embryo implantation in patients with repeated implantation failure: A retrospective study.

This study aimed to develop reference intervals (RIs) of endometrial immune cells in control infertile women during the mid-luteal phase, and compare with the proportion of endometrial immune cells in recurrent reproductive failure (RRF) patients. Endometrial tissue sections were obtained from 113 fertile women and 79 patients with RRF, including 40 patients who had suffered recurrent miscarriage (RM) and 39 patients with repeated implantation failure (RIF) during the mid-luteal phase of the menstrual cycle. Immunohistochemical staining and quantitative analysis of CD56, Foxp3, CD163, CD1a and CD8 cells were performed in endometriums. RIs of endometrial immune cells in control infertile women were as follows: CD56 uterine natural killer cells (uNK) cells, 1.785-8.712%, forkhead box P3 (Foxp3) Tregs, 0.041-0.154%, CD163 M2 macrophages, 0.298-1.492%, CD1a dendritic cells (DCs), 0.006-0.081% and CD8 T cells, 0.674-2.504%. Compared with control infertile women, the percentage of endometrial CD56 uNK cells, CD163 M2 macrophages, CD1a DCs and CD8 T cells were significantly increased in patients with RRF. Moreover, Foxp3 Tregs levels were decreased in patients with RRF, and were statistically significant only in patients with RM. In conclusion, the RIs of endometrial immune cells were established in control infertile women during the mid-luteal phase, and a disordered endometrial immune microenvironment was observed in patients with RRF. The RIs of endometrial immune cells may be of important clinical significance for the treatment of RRF.

Establishment of reference intervals of endometrial immune cells during the mid-luteal phase.

This study aimed to investigate whether maternal obesity affects the immune status of peripheral blood and endometrium in patients with recurrent reproductive failure classified according to their body mass index (BMI). A total of 228 repeated implantation failure (RIF) and 266 recurrent miscarriage (RM) patients were enrolled in the study and further subdivided into three groups according to their BMI: (i) normal weight (18.5≤ BMI <23); (ii) overweight (23≤ BMI <25); and (iii) obese (BMI ≥25). Peripheral blood and endometrium samples were collected in the mid-luteal phase before IVF treatment or natural pregnancy. Peripheral immunocytes were analyzed by flow cytometry, while uterine immune cells were subjected to immunohistochemistry. In RM patients, significantly increased peripheral helper T cells and decreased cytotoxic T cells, NK cells were observed in the obese group compared with the normal-weight group. Meanwhile, in the endometrium, the percentage of NK cell, macrophage cell, M2 macrophage cell, and Treg cell significantly reduced with increased BMI in RIF patients, and the percentage of NK cell and M2 macrophage cell significantly decreased with increased BMI in RM patients. In conclusion, obesity may cause endometrial immune disorder in recurrent reproductive failure women, but was only associated with the peripheral immune change in RM patients.

Impact of body mass index on peripheral and uterine immune status in the window of implantation in patients with recurrent reproductive failure.

Is the ratio of endometrial T-box expressed in T cell (T-bet) and GATA-binding protein 3 (GATA3) changed in patients with recurrent miscarriage (RM) compared to fertile controls?

Comparing the peri-implantation endometrial T-bet/GATA3 ratio between control fertile women and patients with recurrent miscarriage: establishment and application of a reference range.

Article	Year
Functional properties of peripheral CD8 T cells in patients with repeated implantation failure. American journal of reproductive immunology (New York, N.Y. : 1989)\| PubMed ID: 28508475	2017
Evaluation of peripheral and uterine immune status of chronic endometritis in patients with recurrent reproductive failure. Fertility and sterility\| PubMed ID: 31718829	2020
Potential impact of maternal vitamin D status on peripheral blood and endometrium cellular immunity in women with recurrent implantation failure. American journal of reproductive immunology (New York, N.Y. : 1989)\| PubMed ID: 32277536	2020
New endometrial immune cell-based score (EI-score) for the prediction of implantation success for patients undergoing IVF/ICSI. Placenta\| PubMed ID: 32829188	2020
Diagnosis of chronic endometritis: How many CD138 cells/HPF in endometrial stroma affect pregnancy outcome of infertile women? American journal of reproductive immunology (New York, N.Y. : 1989)\| PubMed ID: 33152123	2021
Using Deep Learning in a Monocentric Study to Characterize Maternal Immune Environment for Predicting Pregnancy Outcomes in the Recurrent Reproductive Failure Patients. Frontiers in immunology\| PubMed ID: 33868275	2021
The role of decidual natural killer cell-derived soluble factors in early pregnancy. American journal of reproductive immunology (New York, N.Y. : 1989)\| PubMed ID: 34051025	2021
Predictive role of endometrial T-bet/GATA3 ratio during mid-luteal phase for live birth in patients undergoing in vitro fertilization: A retrospective observational study. Journal of reproductive immunology\| PubMed ID: 34953324	2022
Chronic endometritis impairs embryo implantation in patients with repeated implantation failure: A retrospective study. Taiwanese journal of obstetrics & gynecology\| PubMed ID: 36428002	2022
Establishment of reference intervals of endometrial immune cells during the mid-luteal phase. Journal of reproductive immunology\| PubMed ID: 36758471	2023
Impact of body mass index on peripheral and uterine immune status in the window of implantation in patients with recurrent reproductive failure. Human fertility (Cambridge, England)\| PubMed ID: 36946060	2023
Comparing the peri-implantation endometrial T-bet/GATA3 ratio between control fertile women and patients with recurrent miscarriage: establishment and application of a reference range. Human reproduction (Oxford, England)\| PubMed ID: 37353913	2023

Shuyi Yu

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