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. 2023 Aug 22;24(17):13071.
doi: 10.3390/ijms241713071.

Immune Checkpoints in Recurrent Pregnancy Loss: New Insights into a Detrimental and Elusive Disorder

Luca Marozio  1 , Anna Maria Nuzzo  2 , Eugenio Gullo  1 , Laura Moretti  2 , Emilie M Canuto  1 , Annalisa Tancredi  1 , Margherita Goia  3 , Stefano Cosma  1 , Alberto Revelli  4 , Alessandro Rolfo  2 , Chiara Benedetto  1
Affiliations

Immune Checkpoints in Recurrent Pregnancy Loss: New Insights into a Detrimental and Elusive Disorder

Luca Marozio et al. Int J Mol Sci. .

Abstract

Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1-2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to a lack of pregnancy-induced immune tolerance. It is unknown whether immune activity is deranged in the endometrium of women with RPL. We studied the gene expression and the quantitative tissue protein levels of three immune checkpoints (CD276, which enhances cytotoxic T-cell activity, cytotoxic T-lymphocyte-associated antigen-4 [CTL-4], which reduces Th1 cytokine production, and lymphocyte activation gene-3 [LAG-3], which shows suppressive activity on Tregs and CD4+ T-cells) in endometrial samples from 27 women with unexplained RPL and in 29 women with dysfunctional uterine bleeding and previous uneventful pregnancies as controls. RNA isolation, real-time PCR, protein isolation, and ELISA were performed. CD276 gene expression and protein tissue levels were significantly lower in the endometrium of the RPL group than in the controls, whereas both CTL-4 and LAG-3 were significantly higher. This difference suggests defective endometrial immune regulation and overactivation of immune response in women with a history of RPL, at least in relation to controls with dysfunctional uterine bleeding and previous normal reproductive history.

Keywords: T-cell activity; endometrium; immune activity; immune tolerance; placentation; pregnancy; recurrent pregnancy loss.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CD276 gene (A) and protein (B) expression levels in endometrial biopsies. (A) Fold change of CD276 mRNA in endometrium tissue samples from the RPL and the control group. (B) Fold change of CD276 protein in endometrium tissue samples from the RPL and the control group. Data are presented as mean ± SE. Significance was calculated using Student’s t-test (* p < 0.05). RPL denotes recurrent pregnancy loss; CTRL-END: endometrial tissue from the control group; RPL-END: endometrial tissue from the RPL group.
Figure 2
Figure 2
CTLA4 gene (A) and protein (B) expression levels in endometrial biopsies. (A) Fold change of CTLA4 mRNA in endometrium tissue samples from the RPL and the control group. (B) Fold change of CTLA4 protein in endometrium tissue samples from the RPL and the control group. Data are presented as mean ± SE. Significance was calculated using Student’s t-test (* p < 0.05). RPL denotes recurrent pregnancy loss; CTRL-END: endometrial tissue from the control group; RPL-END endometrial tissue from the RPL group.
Figure 3
Figure 3
LAG3 gene (A) and protein (B) expression levels in endometrial biopsies. (A) Fold change of LAG3 mRNA in endometrium tissue samples from the RPL and the control group. (B) Fold change of LAG3 protein in endometrium tissue samples from the RPL and the control group. Data are presented as mean ± SE. Significance was calculated using Student’s t-test (* p < 0.05). RPL denotes recurrent pregnancy loss; CTRL-END: endometrial tissue from the control group; RPL-END endometrial tissue from the RPL group.
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