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A dysregulated immune microenvironment at the maternal-fetal interface in early pregnancy may lead to early pregnancy loss, fetal growth restriction, and preeclampsia. However, major questions about how epigenetic modifications regulate the immune microenvironment during the decidualization process and embryo implantation remain unanswered. DNA methylation, the main epigenetic mechanism involved in the endometrial cycle, is crucial for specific transcriptional networks associated with endometrial stromal cell (ESC) proliferation, hormone response, decidualization, and embryo implantation. Ten-eleven translocation (TET) enzymes, responsible for catalyzing the conversion of 5-methylcytosine to 5-hydroxymethylcyosine, 5-formylytosine, and 5-carboxylcyosine to achieve the DNA demethylation process, appear to play a critical role in decidualization and embryo implantation. Here, we provide a comprehensive view of their structural similarities and the common mechanism of regulation in the microenvironment at the maternal-fetal interface during decidualization and early pregnancy. We also discuss their physiological role in the decidual immune microenvironment. Finally, we propose a key hypothesis regarding TET enzymes at the maternal-fetal interface between decidual immune cells and ESCs. Future work is needed to elucidate their functional role and examine therapeutic strategies targeting these enzymes in pregnancy-related disease preclinical models, which would be of great value for future implications in disease diagnosis or treatment.

Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by a high prevalence of autoantibodies and lymphocyte-mediated exocrine gland damage. To enhance our understanding of the mechanisms underlying the progression of the disease and to discover potential biomarkers for the early diagnosis of pSS, we applied RNA sequencing to compare the gene expression patterns in minor salivary glands between pSS patients and non-pSS. A total of 293 differentially expressed genes (DEGs) were detected in pSS vs. non-pSS (FDR < 0.05, fold changes > 2). Of these DEGs, 285 (97.26%) were up-regulated, with most being involved in immune system activation, especially in the formation of the immunological synapse. Significantly elevated CCL19/CCR7 expression in the salivary gland was found to be related to anti-Sjögren's syndrome-related antigen A (SSA) antibody and IgG levels in pSS patients, which was further confirmed in a larger cohort. Up-regulated gene expression showed strong discriminatory accuracy in identifying pSS with area under the curve of 0.98 using receiver operating characteristic curve analysis. In conclusion, gene expression changes in pSS include strong markers of immunological activation and have good discriminatory power in identifying patients with pSS.

Our previous investigations indicated that in vitro polarization of mouse macrophages by Toxoplasma gondii type II strain dense granule protein 15 (GRA15II), one of the genotype-associated effectors of T. gondii, induced the phenotypes of classically activated macrophage (M1). Transfusion of the cells to mice may effectively alleviated hepatic fibrosis caused by schistosomiasis. The purpose of the study was to identify whether liver macrophages can be in vivo driven to M1 macrophages by lentiviral vector (LV) carrying GRA15II gene (LV-gra15II) and to explore the potential mechanism by which the LV-gra15II-activated liver macrophage (LV-gra15II-M) ameliorates the hepatic fibrosis in schistosomiasis. The mice were treated with LV-gra15II by hydrodynamic injection via the tail vein followed by challenge of Schistosoma japonicum (S. japonicum). Our experiments showed that LV-gra15II was successfully delivered to liver macrophages and GRA15II was persistently expressed in the macrophages of mice for at least 2 months. Furthermore, the LV-gra15II infected macrophages were polarized to M1 macrophages in vivo. Consequently, mice with schistosomiasis receiving LV-gra15II injection displayed a remarkable amelioration of liver granuloma formation and collagen deposition in association with downregulated expression of transforming growth factor-beta1, arginase 1 (Arg-1), α-smooth muscle actin, and an increased expression of matrix metalloproteinase 13 (MMP13). Simultaneously, no negative effects of liver function and vitality of mice were noted. The in vitro experiments indicated that the C-C motif chemokine ligand 2 and nitric oxide level were elevated in LV-gra15II-M cultural supernatants; hepatocyte growth factor expression was enhanced in LV-gra15II-M. In addition, LV-gra15II-M not only secreted MMP13, which greatly degraded type I collagen, but also induced murine hepatic stellate cell (HSC) line (JS1) apoptosis in the co-culture system. Taken together, we identified for the first time that LV-gra15II may in vivo drive liver macrophages to M1 macrophage phenotypes, which helps for alteration of the liver fibrotic microenvironment with collagen dissolution, HSC deactivation, apoptosis and hepatocyte protection. Our study gives an insight into the use of gene delivery with parasite-derived immunomodulatory factor as a potential immune cell activating agent to re-equilibrate the other pathogen-induced immune response in some chronic diseases.