Immunological mechanisms in preeclampsia: A narrative review.

Maternal immunologic mechanisms for tolerance are essential for a successful pregnancy because they prevent maladaptive immune responses to the placenta and semi-allogeneic fetus and promote fetal growth. Preeclampsia is a major global cause of fetal mortality and morbidity. It is characterized by new-onset hypertension and proteinuria that occurs at twenty weeks of pregnancy or later. Preeclampsia is defined by a rise in cytokines that are pro-inflammatory and antiangiogenic components in the fetoplacental unit and the vascular endothelium of pregnant women, as well as an excessive and increasing stimulation of the immune system. Crucially, inflammation can result in low birth weight and inadequate placental perfusion in neonates. Preeclampsia, which is ultimately connected to inflammatory responses, can be impacted by several immunological mechanisms. Our goal in this work was to compile the most recent research on the pathoimmunology of preeclampsia, including studies on angiogenic variables and, in particular, immunological components.

The evaluation of CD39, CD73, and HIF-1 α expression besides their related miRNAs in PBMCs of women with recurrent pregnancy loss.

The molecular mechanisms involved in the pathogenesis of recurrent pregnancy loss (RPL) are not completely recognized. The present study aimed to assess the molecules associated with ATP catabolism and hypoxia besides their related miRNAs in patients with RPL. The frequency of Th17 and Treg cells in PBMCs of RPL women and healthy pregnant women were evaluated with Flow cytometry. The expression levels of CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-1α), miR-18a, miR-30a, and miR-206 in PBMCs of two groups were measured with real-time PCR and western blotting. Then, serum levels of IGF-1, TGF-ß, and HIF-1α were measured by ELISA. Our results indicated a higher (p = 0.0002) and lower (p < 0.0001) frequency of Th17 and Treg lymphocytes in RPL women, respectively. The expression level of CD39 decreased in PBMCs of RPL women whereas the level of CD73 and HIF-α increased (p = 0.0010, 0.0023, 0.0006 respectively). The results of CD39 and CD37 were also confirmed by protein analysis (p = 0.0047, 0.0364 respectively). Almost, the same results for CD39 and CD73 expression at mRNA and protein levels were observed in isolated Treg cells. Moreover, we found the higher expression of miR-206 and miRNA-30a (p = 0.0038, 0.0123), but the lower expression of miRNA-18a (p = 0.0101) in RPL. The concentration level of IGF-1, and TGF-ß reduced (p = 0.0017, 0.0065 respectively) while the level of HIF-α elevated (p = 0.0235) in serum samples of RPL. In conclusion, we observed the dysregulation of molecules that are involved in ATP catabolism and hypoxia, including CD39, CD73, and HIF-1a which is related to miR-18a, miR-30a, and miR-206 change in RPL women. It may be potentially used for RPL prognosis by more comprehensive future studies.

Evaluation of CD39, CD73, HIF-1α, and their related miRNAs expression in decidua of preeclampsia cases compared to healthy pregnant women.

BACKGROUND: The Preeclampsia (PE) molecular mechanisms are not fully revealed and different biological processes are involved in the pathogenesis of PE. We aimed to evaluate adenosine and hypoxia-related signaling molecules in PE patients in the current study. METHODS: Decidua tissue and peripheral blood samples were taken from 25 healthy pregnant and 25 PE women at delivery time. CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-α) were evaluated in mRNA and protein level using real-time PCR and western blotting techniques, respectively. Also, miR-30a, miR-206, and miR-18a expression were evaluated by real-time PCR. At last, secretion levels of IGF and TGF-ß in the taken serum of blood samples were measured by ELISA. RESULTS: Our results revealed that Expression of CD39 is decreased in PE cases versus healthy controls at mRNA and protein levels (p = 0.0003 for both). CD73 and HIF-α showed an increased level of expression in PE patients at RNA and protein status (p = 0.0157 and p < 0.0001 for protein evaluation of CD73 and HIF-α, respectively). The miRNA-30a (p = 0.0037) and miR-206 (p = 0.0113) showed elevated expression in the decidua of the PE group. The concentration of secreted IGF-1 (p = 0.0002) and TGF-ß (p = 0.0101) in serum samples of PE cases compared to the healthy group were decreased. CONCLUSION: In conclusion, our results showed that aberrant expression of molecules that are involved in ATP catabolism and the hypoxic conditions is observed in PE cases and involved in their hypertension and inflammation could be served as PE prognosis by more confirming in comprehensive future studies. miR-206 and miR-30a play a role by regulating CD39 and CD73 as molecules that are involved in ATP catabolism as well as regulating the production of IGF-1 in the process of hypertension, which is the main feature in patients with preeclampsia. On the other hand, decreased level of miR-18a lead to upregulation of HIF-1a, and the consequence condition of hypoxia increases hypertension and inflammation in these patients.

A comprehensive evaluation of the immune system response and type-I Interferon signaling pathway in hospitalized COVID-19 patients.

BACKGROUND: The COVID-19 pandemic has become the world's main life-threatening challenge in the third decade of the twenty-first century. Numerous studies have been conducted on SARS-CoV2 virus structure and pathogenesis to find reliable treatments and vaccines. The present study aimed to evaluate the immune-phenotype and IFN-I signaling pathways of COVID-19 patients with mild and severe conditions. MATERIAL AND METHODS: A total of 100 COVID-19 patients (50 with mild and 50 with severe conditions) were enrolled in this study. The frequency of CD4 + T, CD8 + T, Th17, Treg, and B lymphocytes beside NK cells was evaluated using flow cytometry. IFN-I downstream signaling molecules, including JAK-1, TYK-2, STAT-1, and STAT-2, and Interferon regulatory factors (IRF) 3 and 7 expressions at RNA and protein status were investigated using real-time PCR and western blotting techniques, respectively. Immune levels of cytokines (e.g., IL-1ß, IL-6, IL-17, TNF-α, IL-2R, IL-10, IFN-α, and IFN-ß) and the existence of anti-IFN-α autoantibodies were evaluated via enzyme-linked immunosorbent assay (ELISA). RESULTS: Immune-phenotyping results showed a significant decrease in the absolute count of NK cells, CD4 + T, CD8 + T, and B lymphocytes in COVID-19 patients. The frequency of Th17 and Treg cells showed a remarkable increase and decrease, respectively. All signaling molecules of the IFN-I downstream pathway and IRFs (i.e., JAK-1, TYK-2, STAT-1, STAT-2, IRF-3, and IRF-7) showed very reduced expression levels in COVID-19 patients with the severe condition compared to healthy individuals at both RNA and protein levels. Of 50 patients with severe conditions, 14 had anti-IFN-α autoantibodies in sera. Meanwhile, this result was 2 and 0 for patients with mild symptoms and healthy controls, respectively. CONCLUSION: Our results indicate a positive association of the existence of anti-IFN-α autoantibodies and immune cells dysregulation with the severity of illness in COVID-19 patients. However, comprehensive studies are necessary to find out more about this context. Video abstract.

Fetomaternal Immune Tolerance: Crucial Mechanisms of Tolerance for Successful Pregnancy in Humans.

For many years, the question of how the maternal immune system tolerates the foreign fetus has remained unanswered, and numerous studies have considerably attempted to elucidate underlying mechanisms for fetomaternal tolerance. This review aimed at discussing various significant mechanisms in fetomaternal compatibility. At the fetomaternal interface, in addition to having efficient control against infections, innate and adaptive maternal immune systems selectively prevent fetal rejection. In general, understanding the complex mechanisms of fetomaternal tolerance is critical for immunologic tolerance induction and spontaneous abortion prevention in high-risk populations. Different cells and molecules, such as regulatory T-cells, dendritic cells, decidua cells, IDO, Class I HLA molecules, TGF-ß, and IL-10, induce maternal immune tolerance in the fetus in numerous ways. The findings on fetomaternal immune tolerance have remained controversial and require further research.

TIGIT and CD155 as Immune-Modulator Receptor and Ligand on CD4+ T cells in Preeclampsia Patients.

One of the main characteristics of preeclampsia (PE) is systemic inflammation. CD4+ FoxP3+ cells play a critical role in both fetomaternal tolerance and successful pregnancy. T-cell immunoglobulin, as well as immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT)/CD155 pathway, possesses critical parts in the development of normal pregnancy by promoting regulatory T (Treg) cells. However, in PE, the relationship between TIGIT/CD155 and Treg differentiation has not been entirely clarified. In the current report, we aimed to assess the frequency of TIGIT and CD155 expressing TCD4+ cells in both PE and healthy pregnant women, as well as evaluating the amount of inflammatory and inhibitory cytokines at both mRNA and protein levels before and after blocking TIGIT and CD155. In the present report, 59 healthy, and 52 PE patients were designated to obtain their venous blood. The isolation of peripheral blood mononuclear cells (PBMCs) was performed from the blood samples, and PBMCs were then cultured in the RPMI1640 medium. The percentage of CD155+ and TIGIT+ CD4+ cells was assessed by flow cytometry in PBMCs. Cell culture supernatants were utilized to evaluate the secretory levels of transforming growth factor beta (TGF-ß), interleukin (IL)-10, IL-17, tumor necrosis factor alpha (TNF-α), and IL-1 ß, using enzyme-linked immunosorbent assay technique in pregnant women with or without PE both before and after blocking TIGIT and CD155. The mRNA expression of Foxp3, TIGIT, CD155, SHP-1, TGF-ß, IL-10, IL-17, TNF-α, and IL-1ß was also assessed by qRT-PCR in PBMCs before and after blocking TIGIT and CD155 in both populations. The data showed a significant decrease in the frequency of TIGIT+ CD4+ and CD155+ CD4+ T cells in PE women, compared to the control group. Our results showed decreased protein and mRNA levels of TIGIT, CD155, IL-10, FOXP3, and SHP-1 in PE patients. In addition, significant improvements in the levels of IL-17, TNF-α, and IL-1ß were observed in PE patients, as compared with the controls. However, blocking TIGIT and CD155 could increase these inflammatory cytokines and decrease anti-inflammatory cytokines. The data obtained in this report illustrated that there existed an imbalance between inflammatory and anti-inflammatory profiles, with an inflammatory status polarization, in PE patients. Additionally, TIGIT/CD155 showed a positive effect on immune regulation by activating ITIM, demonstrating the potential therapeutic value of the TIGIT/CD155 pathway in PE treatment. Also, using some proteins or materials that increased TIGIT/CD155 pathways activity and can be a therapeutic approach in PE.

Exosomes: Emerging biomarkers and targets in folliculogenesis and endometriosis.

An appropriate connection of the cells in the ovary follicles is vital for a healthy ovule maturation and fertilization, and also for endometrium preparation for implantation that can cause endometriosis. Cellular communication within the follicle and endometrial epithelium involve many signaling molecules. Recent studies indicate that cellular communication can be enclosed by secretion and absorption of small membrane carriers which are named extracellular vesicles including exosomes and microvesicles. Understanding and defining these EVs (Extracellular vesicles) population are important for future studies and clinical translation. Here, we describe the various important cargos which are carried by exosomes during folliculogenesis and endometriosis. Additionally, the current knowledge of exosomes and their cargo within the FF (Follicular fluid) during the folliculogenesis and also in the intrauterine cavity which are involved in endometriosis lesions have also been summarized. Considering the potential importance of this form of the cell to cell communication in the reproductive system, the vital issues under discussion lead to a new insight in this rapidly expanding field and it may be an interesting approach for diagnostic, prognostic and especially therapeutic strategies in the field of infertility and assisted reproductive technology (ART).

Tumor associated macrophages in the molecular pathogenesis of ovarian cancer.

The tumor microenvironment is a critical factor that enhances cancer progression, drug resistance, and failure of therapeutic approaches. Several cellular and non-cellular factors are involved in cancer promotion. Among the several cell populations in the tumor microenvironment, macrophages, as one of the most abundant innate immune cells within the tumor milieu, have attracted extensive attention among several researchers because of their critical role in innate pathophysiology of multiple disorders, as well as ovarian cancer. High plasticity and consequent high ability to adapt to environmental alternations by adjusting their cellular metabolism and immunological phenotype is the notable characteristic of macrophages. Therefore, the critical function of tumor-associated macrophages in ovarian cancer is highlighted in the growing body of recent studies. In this article, we will comprehensively focus on significant impacts of the macrophages on ovarian cancer progression, by discussing the role of macrophages as one of the fundamental immune cells present in tumor milieu, in metabolic reprogramming of transformed cells, and involvement of these cells in the ovarian cancer initiation, progression, invasion, and angiogenesis. Moreover, we will summarise recent studies evaluating the effects of targeting macrophages in ovarian cancer.

MicroRNAs: Small molecules with a large impact on pre-eclampsia.

As critical mediators in biological processes, microRNAs (miRNAs) which are small and endogenous noncoding RNAs have been associated with disease progression, cell proliferation, and development. Pre-eclampsia (PE), a pregnancy-related disorder with no early markers or symptoms is recognized as the main reason for fetal and maternal mortality and morbidity in the initial steps or even during pregnancy, worldwide. Clinical symptoms usually appear in the third trimester of the pregnancy. Although numerous research have unraveled several aspects of placenta development abnormalities associated with abnormal trophoblastic invasion and angiogenesis modification, many questions about the PE pathogenesis remains unanswered. A large number of studies have shown the important role of miRNAs as potential biomarkers in the PE prognosis and diagnosis. Here, the latest investigations about the PE and placental miRNAs expression, as well as, the crucial role of miRNA molecules including miR-210 and miR-155 which are deregulated in patients with PE, will be argued.

Vaccination of diffuse large B- cell lymphoma patients with antigen-primed dendritic cells.

Dendritic cells (DCs) are professional antigen presenting cells that have a potential role in the initiating of immune responses. The cell vaccination is a new strategy in treatment of infectious diseases and cancers. In this study, we have generated monocyte-derived dendritic cells of lymphoma patient's peripheral blood mononuclear cells then; these cells were used as vaccine in lymphoma patients. We generated dendritic cell vaccine from lymphoma patient's blood monocytes with human interleukin-4, granulocyte monocyte colony stimulating factor and then, antigen-primed Dcs were administrated subcutaneously close to the inguinal lymph nodes after maturation of dendritic cells. After 7 days, we analyzed immune response in lymphoma patients with determining of LDH, Beta 2 Microglobulin, CD4+T cell percent, CD8+ Tcell percent and Tumor size before and after vaccination. Furthermore, phenotypic and functional analysis of dendritic cells was performed using anti CD83-FITC monoclonal antibodies. Before vaccination, the mean ± SD of LDH was 530.62±140.65 but after vaccination it was 459±109.45 that significantly different between experimental groups (P=0.002). In addition, the CD8+ T cells percentage significantly different between two groups (P=0.002). We concluded that the use of dendritic cell probably is one of the suitable noninvasive treatments for lymphoma patients that they have not response to chemical drugs.

MICB gene expression on peripheral blood mononuclear cells and susceptibility to multiple sclerosis in north of Iran.

Multiple sclerosis (MS) is an autoimmune multifactorial degenerative disease with detrimental affliction on central nervous system. MHC class I chain- related geneA,B(MICA and MICB) are nonclassical human leukocyte antigens that can affect on some diseases and also on transplantation. The purpose of this study was to evaluate the MICA and MICB MRNA expression in multiple sclerosis patients. In this study, we evaluated MICA and MICB MRNA expression in the peripheral blood mononuclear cells by reverse transcryptase-polymerase chain reaction(RT-PCR) in MS patients and normal controls. The results of this study showed that 32.6% of patients with progressive clinical outcome over expressed MICB genes in comparison with controls ( p=0.002). It is concluded that the high expression of MICB gene in MS patients is an important criterion of MS disease that it may be due to the interaction between MICB and its receptor on CD8+T or NK cells.

Comparison of several maturation inducing factors in dendritic cell differentiation.

BACKGROUND: Dendritic cells (DCs) are professional antigen presenting cells that have an important role in the initiation of immune response. The use of maturation factors in dendritic cell differentiation provides a promising approach in immunotherapy. OBJECTIVE: In this study, we compared tumor necrosis factor-α, polyribocytidylic acid, lipopolysacharide and CpG oligonucleotides in inducing dendritic cell maturation. METHODS: We generated immature dendritic cells with GM-CSF in combination with IL-4 from peripheral blood mononuclear adherent cells and used tumor necrosis factor-α, polyribocytidylic acid, lipopolysacharide and CpG for the induction of dendritic cell maturation. CD83 maturation marker on the dendritic cells was analyzed by flowcytometry after 7 days. In addition, mixed leukocyte reaction between dendritic cells and T cells was performed by MTT proliferation assay. RESULTS: Flow cytometry results demonstrated a comparable high level of CD83 expression on the mature dendritic cells generated by TNF-α, CpG, Poly I:C, and LPS treatment of the immature dendritic cells. However, a significantly poorer proliferation of lymphocytes cocultured with the Poly I:C-treated DCs was observed compared to the CpG-treated DCs in mixed leukocyte reaction (p=0.026). Conversely, a significantly stronger proliferation of lymphocytes was observed when cocultured with TNF-α-treated DCs compared to the LPS-treated DCs (p=0.025). CONCLUSION: Our results indicated that all of studied maturation inducing factors can be used in DC maturation but TNF-α and CpG were the preferred in vitro maturation factors. It is concluded that maturation of dendritic cells by CpG motif and TNF-α can be used to regulate immune responses.