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. 2023 Jul 24:14:1228647.
doi: 10.3389/fimmu.2023.1228647. eCollection 2023.

Immune-checkpoint proteins, cytokines, and microbiome impact on patients with cervical insufficiency and preterm birth

Seri Jeong  1 , Won Kyong Cho  2 , Yeonhwa Jo  2 , Soo-Ran Choi  3 , Nuri Lee  1 , Kibum Jeon  4 , Min-Jeong Park  1 , Wonkeun Song  1 , Keun-Young Lee  5
Affiliations

Immune-checkpoint proteins, cytokines, and microbiome impact on patients with cervical insufficiency and preterm birth

Seri Jeong et al. Front Immunol. .

Abstract

Background: Microenvironmental factors, including microbe-induced inflammation and immune-checkpoint proteins that modulate immune cells have been associated with both cervical insufficiency and preterm delivery. These factors are incompletely understood. This study aimed to explore and compare interactions among microbiome and inflammatory factors, such as cytokines and immune-checkpoint proteins, in patients with cervical insufficiency and preterm birth. In particular, factors related to predicting preterm birth were identified and the performance of the combination of these factors was evaluated.

Methods: A total of 220 swab samples from 110 pregnant women, prospectively recruited at the High-Risk Maternal Neonatal Intensive Care Center, were collected between February 2020 and March 2021. This study included 63 patients with cervical insufficiency receiving cerclage and 47 control participants. Endo- and exocervical swabs and fluids were collected simultaneously. Shotgun metagenomic sequencing for the microbiome and the measurement of 34 immune-checkpoint proteins and inflammatory cytokines were performed.

Results: First, we demonstrated that immune-checkpoint proteins, the key immune-regulatory molecules, could be measured in endocervical and exocervical samples. Secondly, we identified significantly different microenvironments in cervical insufficiency and preterm birth, with precise cervical locations, to provide information about practically useful cervical locations in clinical settings. Finally, the presence of Moraxella osloensis (odds ratio = 14.785; P = 0.037) and chemokine CC motif ligand 2 levels higher than 73 pg/mL (odds ratio = 40.049; P = 0.005) in endocervical samples were associated with preterm birth. Combining M. osloensis and chemokine CC motif ligand 2 yielded excellent performance for predicting preterm birth (area under the receiver operating characteristic curve = 0.846, 95% confidence interval = 0.733-0.925).

Conclusion: Multiple relationships between microbiomes, immune-checkpoint proteins, and inflammatory cytokines in the cervical microenvironment were identified. We focus on these factors to aid in the comprehensive understanding and therapeutic modulation of local microbial and immunologic compositions for the management of cervical insufficiency and preterm birth.

Keywords: cervical insufficiency; cervix; cytokines; immune-checkpoint proteins; inflammation; microbiome; preterm birth.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Principal component analysis plots for soluble immune-checkpoint proteins and inflammatory cytokines according to sampling location, cervical insufficiency, and preterm birth. (A) Endocervical samples; (B) Exocervical samples. Prediction ellipses illustrated as red and blue lines represent probabilities of 0.95.
Figure 2
Figure 2
Distribution of total microbiome reads and levels of soluble immune-checkpoint proteins according to sampling locations such as the endocervix and exocervix. Plots for (A) total reads; (B) CD28; (C) TIM-3; (D) HVEM; (E) CD40; (F) LAG-3; (G) PD-1; and (H) PD-L2.
Figure 3
Figure 3
Distribution of soluble immune-checkpoint protein levels in the cervical insufficiency, prophylactic cerclage, and normal pregnant women groups. Plots for (A) Endocervical TIM-3; and (B) Endocervical LAG-3.
Figure 4
Figure 4
Distribution of soluble immune-checkpoint protein and inflammatory cytokine levels between participants with preterm and term birth. Plots for (A) Endocervical TIM-3; (B) Endocervical CCL2; (C) Endocervical IL-6; (D) Exocervical CD80/B7-1; (E) Exocervical PD-L2; and (F) Exocervical IL-6.
Figure 5
Figure 5
Receiver operating characteristic analysis for the performance of combined variables (Moraxella osloensis and CCL2 from endocervical samples) for predicting preterm delivery.
Figure 6
Figure 6
Correlations of soluble immune-checkpoint proteins with microbiomes and inflammatory cytokines based on Spearman’s rank correlation analyses. (A) Soluble immune-checkpoint proteins with microbiomes in endocervical samples; (B) Soluble immune-checkpoint proteins with inflammatory cytokines in endocervical samples. (C) Soluble immune-checkpoint proteins with microbiome in exocervical samples; (D) Soluble immune-checkpoint proteins with inflammatory cytokines in exocervical samples.
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