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Dhir, Varun. "Mesenchymal Stem Cells: The New Immunosuppressants?" Journal of Postgraduate Medicine, Education and Research 46, no. 2 (2012): 63–68. http://dx.doi.org/10.5005/jp-journals-10028-1015.
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ABSTRACT Mesenchymal stem cells are adult stem cells which can differentiate into cells of mesodermal lineage. osteoblasts, chondroblasts and adipocytes. They have an important property of immunosuppression which is mediated mainly through soluble mediators, like interleukin-1, transforming growth factor-β, nitric oxide, indoleamine 2,3 dioxegenase, etc. They have been shown to suppress both naive and antigen experienced T cells, lead to T cell arrest, and suppress Th1 and Th17 responses. They have also been shown to lead to development of tolerogenic dendritic cells, Th2 response and expansion of T regulatory cells. Importantly, MSCs are cells with a low immunogenic potential and hence have been used both in allogenic as well as xenogenic settings. MSCs have shown efficacy in suppressing the development of autoimmune disease in various animal models, like collagen induced arthritis, MRL-lpr mice, EAE mice, etc. They have been used in small human studies, some of which have shown benefit like in systemic lupus erythematosus. Also, they have been used in graft-verus-host disease in humans with promising results. However, a single randomized controlled trial has been done and, thus, their current status remains investigational. It is hoped that they may become part of the armamentarium to control and abberant or excessive immune reponse. Key messages (1) Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate only in one lineage (mesodermal). (2) They were first discovered in the bone marrow and this remains a common source, followed by adipose tissue. There are other sources: Synovial fluid, umbilical cord blood, amniotic fluid, placenta, fetal liver. (3) MSCs are immunosuppressive, the mechanism of which is not fully elucidated, but involves action on other cells mainly through soluble mediators, like TGFβ, IDO, IL-1, NO, etc. (4) MSCs have shown efficacy in various animal models of autoimmune diseases. There have been small human studies, some of which showed benefit, however, a single randomized controlled trial has been done. (5) MSCs may have a role in autoimmune diseases refractory to treatment or as an add onto prevent treatment side effects. How to cite this article Dhir V. Mesenchymal Stem Cells: The New Immunosuppressants? J Postgrad Med Edu Res 2012;46(2):63-68.
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Zhang, Xingqi, Joanna H. Sliwowska, and Joanne Weinberg. "Prenatal Alcohol Exposure and Fetal Programming: Effects on Neuroendocrine and Immune Function." Experimental Biology and Medicine 230, no. 6 (June 2005): 376–88. http://dx.doi.org/10.1177/15353702-0323006-05.
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Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female’s ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.
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Saito, Mika, Earl Silverman, Fraser Golding, Vitor Guerra, Linda Hiraki, Varsha Thakur, and Edgar Jaeggi. "Effects of Transplacental Dexamethasone Therapy on Fetal Immune-Mediated Complete Heart Block." Fetal Diagnosis and Therapy 48, no. 3 (2021): 183–88. http://dx.doi.org/10.1159/000513202.
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<b><i>Introduction:</i></b> Antibody-mediated complete atrioventricular block (CAVB) is considered irreversible. We sought to examine the effects of transplacental steroids on fetal AV conduction. <b><i>Methods:</i></b> Fifty-nine fetuses diagnosed with CAVB at our center from 1996 to 2018 were reviewed. Routine dexamethasone administration to birth was used to limit cardiac inflammatory damage. Restoration of fetal AV conduction was classified as “unexpected” treatment response. <b><i>Results:</i></b> CAVB resolved in 5/29 (17%) fetuses first treated ≤24-week gestation with 8 mg/day of dexamethasone, when compared with 0/30 (0%) when treatment was initiated later and/or at a starting dose of 4 mg/day (odds ratio 13.69; 95% confidence interval 0.72–260.13; <i>p</i> = 0.024). Treatment response was also associated with a faster ventricular rate at diagnosis (median [range]: 80 [60–97] beats per minute [bpm] vs. 58 [38–92] bpm; <i>p</i> = 0.0036). CAVB reappeared in all 5 responders either prenatally (<i>n</i> = 1) or postnatally before (<i>n</i> = 3) or after (<i>n</i> = 1) the first year of life. When compared with infants with treatment-resistant CAVB (median follow-up 10.3 years), responders (median follow-up 12.3 years) required postnatal pacing less frequent (2/5 [40%] vs. 45/49 [92%]; <i>p</i> = 0.013). <b><i>Conclusions:</i></b> In a subgroup of CAVB fetuses, dexamethasone transiently restored AV conduction. This was associated with a lower rate of postnatal pacing when compared with nonresponders.
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Ghanmi, Z., M. Rouabhia, O. Othmane, and P. A. Deschaux. "5.3 Effects of metal ions on cyprinid fish immune response: in vitro effects of Zn2+ and Mn2+ on the mitogenic reponse of carp pronephros lymphocytes." Developmental & Comparative Immunology 13, no. 4 (September 1989): 398. http://dx.doi.org/10.1016/0145-305x(89)90115-8.
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Childs, Caroline E., Tessa Romijn, Uta Enke, Samuel Hoile, and Philip C. Calder. "Maternal diet during pregnancy has tissue-specific effects upon fetal fatty acid composition and alters fetal immune parameters." Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA) 83, no. 4-6 (October 2010): 179–84. http://dx.doi.org/10.1016/j.plefa.2010.08.007.
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Arneth, Borros. "Neonatal Immune Incompatibilities between Newborn and Mother." Journal of Clinical Medicine 9, no. 5 (May 14, 2020): 1470. http://dx.doi.org/10.3390/jcm9051470.
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Background: Incompatibilities between the mother and unborn baby can cause complications that must be identified early to initiate the appropriate treatment. For example, neonatal alloimmune thrombocytopenia (NAIT), neonatal alloimmune neutropenia (NAIN), and morbus hemolyticus neonatorum affect children worldwide. Aim: This literature review aims to depict the similarities and differences between these three disorders from a clinical and mechanistic point of view. Material and Methods: The current literature review entailed conducting a systematic search to locate articles on the three conditions. Different electronic databases, including PsycINFO, PubMed, Web of Science, and CINAHL, were searched using the search terms “neonatal alloimmune thrombocytopenia”, “neonatal alloimmune neutropenia”, “morbus hemolyticus neonatorum”, “NAIT”, “FNAIT”, “fetal”, “NAIN”, and “hemolytic disease of the newborn”. Results: This review shows that these three diseases are caused by incompatibilities between the maternal and fetal immune systems. Furthermore, these conditions can lead to severe complications that hinder fetal development and cause death if not well managed. Discussion: The current literature review shows that NAIT, NAIN, and morbus hemolyticus neonatorum are rare conditions that occur when the mother produces antibodies against the fetal immune system. Thus, there is a need for the early detection of these conditions to initiate appropriate treatment before the child experiences adverse effects. Conclusion: The development of NAIT, NAIN, and morbus hemolyticus neonatorum is linked to the production of antibodies against the fetal immune system and fetal antigens. Further studies are required to determine potential interventions to reduce the risk of developing these three conditions.
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Garbett, K. A., E. Y. Hsiao, S. Kálmán, P. H. Patterson, and K. Mirnics. "Effects of maternal immune activation on gene expression patterns in the fetal brain." Translational Psychiatry 2, no. 4 (April 2012): e98-e98. http://dx.doi.org/10.1038/tp.2012.24.
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Ehninger, Dan. "Tsc2Haploinsufficiency Has Limited Effects on Fetal Brain Cytokine Levels during Gestational Immune Activation." Autism Research and Treatment 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/761279.
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Dysregulated TSC/mTOR signaling may play a pathogenetic role in forms of syndromic autism, such as autism associated with tuberous sclerosis, a genetic disorder caused by heterozygousTSC1orTSC2mutations. Environmental risk factors, such as gestational viral infections, may, in some cases, also contribute to the pathogenesis of autism and related neuropsychiatric disorders. We have recently found that a heterozygousTsc2mutation and the poly I:C model of maternal immune activation (MIA) interactively perturb fetal development and adult social behavior in mice, suggesting that these factors converge on shared pathways. TSC/mTOR signaling plays an important role in the modulation of immune responses, raising the possibility that the damage caused by MIA was greater inTsc2+/−than in wildtype fetuses because of an exacerbated immune response in the mutants. Here, cytokine antibody arrays were employed to measure relative cytokine abundances in the fetal brain and the placenta during MIA. Cytokines were induced by gestational poly I:C but there was no obvious modulatory effect ofTsc2haploinsufficiency. The data indicate that cytokine exposure during MIA is comparable inTsc2haploinsufficient and wildtype control fetuses, suggesting that downstream molecular and cellular processes may account for the interactive effects ofTsc2haploinsufficiency and MIA.
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McLaurin, J., JP Antel, and VW Yong. "Immune and non-immune actions of interferon-β-1b on primary human neural cells." Multiple Sclerosis Journal 1, no. 1 (April 1995): 10–19. http://dx.doi.org/10.1177/135245859500100103.
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Systemic interferon-β-1b (IFN-β-1b) reduces the frequency of clinical exacerbations and the number of magnetic resonance imaging (MRI)-defined lesions in patients with relapsing—remitting MS. The basis for this clinical effect is not understood. While IFN-β-1b has been demonstrated to have antiproliferative and immunomodulatory effects on the sytemic immune system, its actions on neural cells could also contribute to its therapeutic efficacy. In this study, we hove examined possible immune and non-immune effects of IFN-β-1b on CNS-derived primary human cells. With respect to immune-related effects, application of IFN-β-1b did not decrease basal expression of HLA-DR on astrocytes or microglia, and it reduced the IFN-γ-enhanced HLA-DR expression on adult human astrocytes only at high concentrations (1000 IU ml-1); IFN-β-1b at all concentrations tested did not reduce the IFN-γ-enhanced HLA-DR expression by fetal astrocytes or adult microglial cells. In contrast, but in correspondence with the literature, the IFN-γ-enhanced HLA-DR expression on a glioma cell line was attenuated by IFN-β-1b in a dose-dependent manner. With respect to non-immune effects, the number of adult human oligodendrocytes and their state of morphological differentiation were not affected by IFN-β-1b. Proliferation of the mitotically active fetal human astrocytes, however, was reduced by IFN-β-1b treatment Lactate dehydrogenase assays revealed that IFN-β-1b was not toxic to neural cells, including adult oligodendrocytes and fetal human neurons. We conclude that IFN-β-1b lacks efficacy in down-regulating HLA-DR expression by primary human neural cells and that regulation of MHC class II antigens is unlikely to be a mechanism for its beneficial effect in MS. Finally, the lack of toxicity of IFN-β-1b on human neural cells is important for a drug that will probably be used widely.
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Knapek, Katie J., Hanah M. Georges, Hana Van Campen, Jeanette V. Bishop, Helle Bielefeldt-Ohmann, Natalia P. Smirnova, and Thomas R. Hansen. "Fetal Lymphoid Organ Immune Responses to Transient and Persistent Infection with Bovine Viral Diarrhea Virus." Viruses 12, no. 8 (July 28, 2020): 816. http://dx.doi.org/10.3390/v12080816.
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Bovine Viral Diarrhea Virus (BVDV) fetal infections occur in two forms; persistent infection (PI) or transient infection (TI), depending on what stage of gestation the fetus is infected. Examination of lymphoid organs from both PI and TI fetuses reveals drastically different fetal responses, dependent upon the developmental stage of the fetal immune system. Total RNA was extracted from the thymuses and spleens of uninfected control, PI, and TI fetuses collected on day 190 of gestation to test the hypothesis that BVDV infection impairs the innate and adaptive immune response in the fetal thymus and spleen of both infection types. Transcripts of genes representing the innate immune response and adaptive immune response genes were assayed by Reverse Transcription quatitative PCR (RT-qPCR) (2−ΔΔCq; fold change). Genes of the innate immune response, interferon (IFN) inducible genes, antigen presentation to lymphocytes, and activation of B cells were downregulated in day 190 fetal PI thymuses compared to controls. In contrast, innate immune response genes were upregulated in TI fetal thymuses compared to controls and tended to be upregulated in TI fetal spleens. Genes associated with the innate immune system were not different in PI fetal spleens; however, adaptive immune system genes were downregulated, indicating that PI fetal BVDV infection has profound inhibitory effects on the expression of genes involved in the innate and adaptive immune response. The downregulation of these genes in lymphocytes and antigen-presenting cells in the developing thymus and spleen may explain the incomplete clearance of BVDV and the persistence of the virus in PI animals while the upregulation of the TI innate immune response indicates a more mature immune system, able to clear the virus.
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Yockey, Laura J., Carolina Lucas, and Akiko Iwasaki. "Contributions of maternal and fetal antiviral immunity in congenital disease." Science 368, no. 6491 (May 7, 2020): 608–12. http://dx.doi.org/10.1126/science.aaz1960.
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Viral infections during pregnancy can have devastating consequences on pregnancy outcomes, fetal development, and maternal health. In this review, we examine fetal and maternal immune defense mechanisms that mediate resistance against viral infections and discuss the range of syndromes that ensue when such mechanisms fail, from fetal developmental defects to establishment of chronic infection. Further, we highlight the role of maternal immune activation, or uncontrolled inflammation triggered by viral infections during pregnancy, and its potential downstream pathological effects, including tissue damage and fetal demise. Insights into the respective contributions of direct viral toxicity versus fetal and maternal immune responses that underlie the pathogenesis of congenital disease will guide future treatment strategies.
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Boyle, R. J., L.-J. Mah, A. Chen, S. Kivivuori, R. M. Robins-Browne, and M. L.-K. Tang. "Effects ofLactobacillusGG treatment during pregnancy on the development of fetal antigen-specific immune responses." Clinical & Experimental Allergy 38, no. 12 (December 2008): 1882–90. http://dx.doi.org/10.1111/j.1365-2222.2008.03100.x.
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Holladay, S. D., L. Sharova, B. J. Smith, R. M. Gogal, D. L. Ward, and B. L. Blaylock. "Nonspecific stimulation of the maternal immune system. I. Effects on teratogen-induced fetal malformations." Teratology 62, no. 6 (2000): 413–19. http://dx.doi.org/10.1002/1096-9926(200012)62:6<413::aid-tera8>3.0.co;2-b.
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Fisher, R. E., M. Steele, and N. A. Karrow. "Fetal Programming of the Neuroendocrine-Immune System and Metabolic Disease." Journal of Pregnancy 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/792934.
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Adverse uterine environments experienced during fetal development can alter the projected growth pattern of various organs and systems of the body, leaving the offspring at an increased risk of metabolic disease. The thrifty phenotype hypothesis has been demonstrated as an alteration to the growth trajectory to improve the survival and reproductive fitness of the individual. However, when the intrauterine environment does not match the extrauterine environment problems can arise. With the increase in metabolic diseases in both Westernized and developing countries, it is becoming apparent that there is an environmental disconnect with the extrauterine environment. Therefore, the focus of this paper will be to explore the effects of maternal malnutrition on the offspring’s susceptibility to metabolic disorders such as obesity, cardiovascular disease, and diabetes with emphasis on programming of the neuroendocrine-immune system.
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Chen, Jingfei, Jialei Duan, Alina Montalbano, Boxun Li, Gary Hon, and Carole R. Mendelson. "Single-Cell RNA-Seq of Mouse Decidual Leukocytes Reveals Intriguing Gestational Changes in the Immune Cell Landscape and Effects of SRC-1/-2 Double-Deficiency." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A753—A754. http://dx.doi.org/10.1210/jendso/bvab048.1532.
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Abstract Single-cell RNA-seq of Mouse Decidual Leukocytes Reveals Intriguing Gestational Changes in the Immune Cell Landscape and Effects of SRC-1/-2 Double-DeficiencyOur previous findings suggest that the fetus signals the mother when it is ready to be born through secretion of surfactant components/immune modulators, surfactant protein A (SP-A) and platelet-activating factor (PAF) by the fetal lung into amniotic fluid (AF). This occurs with increased proinflammatory cytokine expression by fetal AF macrophages (Mϕ), increased myometrial NF-κB activation and contractile (CAP) gene expression. Steroid receptor coactivator (Src)-1 and Src-2 are critical for developmental induction SP-A and PAF by the fetal lung. The finding that pregnant wild-type (WT) mice carrying Src-1 and Src-2 double-deficient fetuses (Src-1/-2d/d) manifested a marked delay (~38h) in parturition, further suggests that signals for parturition arise from the fetus and that Src-1 and Src-2 serve a critical role. Infiltrating leukocytes at the maternal-fetal interface (MFI)/decidua are known to play a central role in pregnancy maintenance and parturition timing. However, there is limited knowledge regarding gestational changes in immune cell composition toward term. To analyze gestational changes in the composition of immune cells within decidua and effects of Src-1/-2d/d, we conducted single-cell RNA-seq of ~17,000 decidual leukocytes (CD45+) from pregnant mice at 15.5 and 18.5 dpc carrying WT or Src-1/-2d/d fetuses. Unsupervised clustering identified 22 distinct decidual immune cell clusters, comprised of Mϕ, B cells, natural killer cells, neutrophils, dendritic cells and monocytes. Significant differences in cell type composition and transcriptional profiles were found across study groups (WT @ 15.5 dpc vs. 18.5 dpc; Src-1/-2d/dvs. WT @15.5 dpc and 18.5 dpc). Interestingly, in deciduas of pregnant mice carrying WT fetuses, Mϕ and B cell clusters markedly increased between 15.5 and 18.5 dpc, whereas, neutrophils declined; however, these gestational changes did not occur in pregnant mice carrying Src-1/-2d/d fetuses. Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns distinguishing these immune cell subtypes to uncover their putative functions. These findings highlight the complexity and dynamics of the decidual immune cell landscape during the transition from myometrial quiescence to contractility, and the fetal-maternal interactions leading to parturition. Support: NIH grants R01-HL050022 (CRM) and P01-HD087150 (CRM), Burroughs Wellcome Preterm Birth Grant #1019823 (CRM).
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Tamblyn, J. A., M. Hewison, C. L. Wagner, J. N. Bulmer, and M. D. Kilby. "Immunological role of vitamin D at the maternal–fetal interface." Journal of Endocrinology 224, no. 3 (March 2015): R107—R121. http://dx.doi.org/10.1530/joe-14-0642.
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During pregnancy, immune activity is tightly regulated so that antimicrobial protection of the mother and fetus is balanced with the need for immune tolerance to prevent fetal rejection. In this setting, the maternal–fetal interface, in the form of the uterine decidua, provides a heterogeneous immune cell population with the potential to mediate diverse activities throughout pregnancy. Recent studies have suggested that vitamin D may be a key regulator of immune function during pregnancy, with the fetal–maternal interface representing a prominent target. Among its non-classical actions are potent immunomodulatory effects, including induction of antibacterial responses and modulation of T-lymphocytes to suppress inflammation and promote tolerogenesis. Thus, vitamin D may play a pivotal role in normal decidual immune function by promoting innate responses to infection, while simultaneously preventing an over-elaboration of inflammatory adaptive immunity. Research to date has focused upon the potential role of vitamin D in preventing infectious diseases such as tuberculosis, as well as possibly suppressing of autoimmune disease. Nevertheless, vitamin D may also influence facets of immune function not immediately associated with primary innate responses. This review summarises our current understanding of decidual immune function with respect to the vitamin D metabolism and signalling, and as to how this may be affected by variations in maternal vitamin D status. There has recently been much interest in vitamin D supplementation of pregnant women, but our knowledge of how this may influence the function of decidua remains limited. Further insight into the immunomodulatory actions of vitamin D during pregnancy will help shed light upon this.
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Garbett, Krassimira A., Elaine Y. Hsiao, Sara Kálmán, Paul H. Patterson, and Károly Mirnics. "Poster #10 EFFECTS OF MATERNAL IMMUNE ACTIVATION ON GENE EXPRESSION PATTERNS IN THE FETAL BRAIN." Schizophrenia Research 136 (April 2012): S188. http://dx.doi.org/10.1016/s0920-9964(12)70582-0.
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Chaiwangyen, Wittaya, José M. Murrieta-Coxca, Rodolfo R. Favaro, Stella M. Photini, Ruby N. Gutiérrez-Samudio, Ekkehard Schleussner, Udo R. Markert, and Diana M. Morales-Prieto. "MiR-519d-3p in Trophoblastic Cells: Effects, Targets and Transfer to Allogeneic Immune Cells via Extracellular Vesicles." International Journal of Molecular Sciences 21, no. 10 (May 14, 2020): 3458. http://dx.doi.org/10.3390/ijms21103458.
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Members of the placenta-specific miRNA cluster C19MC, including miR-519d, are secreted by fetal trophoblast cells within extracellular vesicles (EVs). Trophoblast-derived EVs can be internalized by the autologous trophoblast and surrounding maternal immune cells, resulting in coordination of cellular responses. The study of functions and targets of placental miRNAs in the donor and recipient cells may contribute to the understanding of the immune tolerance essential in pregnancy. Here, we report that miR-519d-3p levels correlate positively with cell proliferation and negatively with migration in trophoblastic cell lines. Inhibition of miR-519d-3p in JEG-3 cells increases caspase-3 activation and apoptosis. PDCD4 and PTEN are targeted by miR-519d-3p in a cell type-specific manner. Transfection of trophoblastic cell lines with miR-519d mimic results in secretion of EVs containing elevated levels of this miRNA (EVmiR-519d). Autologous cells enhance their proliferation and decrease their migration ability when treated with EVmiR-519d. NK92 cells incorporate EV-delivered miR-519d-3p at higher levels than Jurkat T cells. EVmiR-519d increases the proliferation of Jurkat T cells but decreases that of NK92 cells. Altogether, miR-519d-3p regulates pivotal trophoblast cell functions, can be transferred horizontally via EVs to maternal immune cells and exerts functions therein. Vesicular miRNA transfer from fetal trophoblasts to maternal immune cells may contribute to the immune tolerance in pregnancy.
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Prescott, Susan L. "Allergic disease: understanding how in utero events set the scene." Proceedings of the Nutrition Society 69, no. 3 (June 29, 2010): 366–72. http://dx.doi.org/10.1017/s0029665110001874.
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Events and exposures in pregnancy can have critical effects on fetal development with lasting implications for subsequent health and disease susceptibility. There is growing interest in how modern environmental changes influence fetal immune development and contribute to the recent epidemic of allergy and other immune disorders. Rising rates of allergic disease in early infancy, together with pre-symptomatic differences in immune function at birth, suggest that antenatal events play a predisposing role in the development of disease. A number of environmental exposures in pregnancy can modify neonatal immune function including diet, microbial exposure and maternal smoking, and there is emerging evidence from animal models that these factors may have epigenetic effects on immune gene expression and disease susceptibility. Furthermore, functional genetic polymorphisms also alter individual vulnerability to the effects of these environmental exposures, highlighting the complexity of gene–environmental interactions in this period. All these observations underscore the need for ongoing research to understand the pathogenesis and rising incidence of disease in the hope of better strategies to reverse this.
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Bulgaru, Cristina Valeria, Daniela Eliza Marin, Gina Cecilia Pistol, and Ionelia Taranu. "Zearalenone and the Immune Response." Toxins 13, no. 4 (March 31, 2021): 248. http://dx.doi.org/10.3390/toxins13040248.
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Zearalenone (ZEA) is an estrogenic fusariotoxin, being classified as a phytoestrogen, or as a mycoestrogen. ZEA and its metabolites are able to bind to estrogen receptors, 17β-estradiol specific receptors, leading to reproductive disorders which include low fertility, abnormal fetal development, reduced litter size and modification at the level of reproductive hormones especially in female pigs. ZEA has also significant effects on immune response with immunostimulatory or immunosuppressive results. This review presents the effects of ZEA and its derivatives on all levels of the immune response such as innate immunity with its principal component inflammatory response as well as the acquired immunity with two components, humoral and cellular immune response. The mechanisms involved by ZEA in triggering its effects are addressed. The review cited more than 150 publications and discuss the results obtained from in vitro and in vivo experiments exploring the immunotoxicity produced by ZEA on different type of immune cells (phagocytes related to innate immunity and lymphocytes related to acquired immunity) as well as on immune organs. The review indicates that despite the increasing number of studies analyzing the mechanisms used by ZEA to modulate the immune response the available data are unsubstantial and needs further works.
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Yoshida, Seiichi, Hirohisa Takano, Masataka Nishikawa, He Miao, and Takamichi Ichinose. "Effects of Fetal Exposure to Urban Particulate Matter on the Immune System of Male Mouse Offspring." Biological and Pharmaceutical Bulletin 35, no. 8 (2012): 1238–43. http://dx.doi.org/10.1248/bpb.b110708.
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Kieffer, Tom EC, Peck Y. Chin, Ella S. Green, Lachlan M. Moldenhauer, Jelmer R. Prins, and Sarah A. Robertson. "Prednisolone in early pregnancy inhibits regulatory T cell generation and alters fetal and placental development in mice." Molecular Human Reproduction 26, no. 5 (March 11, 2020): 340–52. http://dx.doi.org/10.1093/molehr/gaaa019.
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Abstract Corticosteroids have been utilised in the assisted reproduction setting with the expectation of suppressing aberrant immune activation and improving fertility in women. However, the effects of corticosteroids on fertility, and on pregnancy and offspring outcomes, are unclear. In this study, mice were administered prednisolone (1 mg/kg) or PBS daily in the pre-implantation phase, and effects on the adaptive immune response, the implantation rate, fetal development and postnatal outcomes were investigated. Prednisolone disrupted the expected expansion of CD4+ T cells in early pregnancy, inhibiting generation of both regulatory T cells (Treg cells) and effector T cells and suppressing IFNG required for T cell functional competence. Prednisolone caused an 8–20% increase in the embryo implantation rate and increased the number of viable pups per litter. In late gestation, fetal and placental weights were reduced in a litter size-dependent manner, and the canonical inverse relationship between litter size and fetal weight was lost. The duration of pregnancy was extended by ~ 0.5 day and birth weight was reduced by ~ 5% after prednisolone treatment. Viability of prednisolone-exposed offspring was comparable to controls, but body weight was altered in adulthood, particularly in male offspring. Thus, while prednisolone given in the pre-implantation phase in mice increases maternal receptivity to implantation and resource investment in fetal growth, there is a trade-off in long-term consequences for fetal development, birth weight and offspring health. These effects are associated with, and likely caused by, prednisolone suppression of the adaptive immune response at the outset of pregnancy.
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Jeschke, Laura, Clarisa Guillermina Santamaria, Nicole Meyer, Ana Claudia Zenclussen, Julia Bartley, and Anne Schumacher. "Early-Pregnancy Dydrogesterone Supplementation Mimicking Luteal-Phase Support in ART Patients Did Not Provoke Major Reproductive Disorders in Pregnant Mice and Their Progeny." International Journal of Molecular Sciences 22, no. 10 (May 20, 2021): 5403. http://dx.doi.org/10.3390/ijms22105403.
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Progestogens are frequently administered during early pregnancy to patients undergoing assisted reproductive techniques (ART) to overcome progesterone deficits following ART procedures. Orally administered dydrogesterone (DG) shows equal efficacy to other progestogens with a higher level of patient compliance. However, potential harmful effects of DG on critical pregnancy processes and on the health of the progeny are not yet completely ruled out. We treated pregnant mice with DG in the mode, duration, and doses comparable to ART patients. Subsequently, we studied DG effects on embryo implantation, placental and fetal growth, fetal-maternal circulation, fetal survival, and the uterine immune status. After birth of in utero DG-exposed progeny, we assessed their sex ratios, weight gain, and reproductive performance. Early-pregnancy DG administration did not interfere with placental and fetal development, fetal-maternal circulation, or fetal survival, and provoked only minor changes in the uterine immune compartment. DG-exposed offspring grew normally, were fertile, and showed no reproductive abnormalities with the exception of an altered spermiogram in male progeny. Notably, DG shifted the sex ratio in favor of female progeny. Even though our data may be reassuring for the use of DG in ART patients, the detrimental effects on spermatogenesis in mice warrants further investigations and may be a reason for caution for routine DG supplementation in early pregnancy.
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Papait, Andrea, Elsa Vertua, Marta Magatti, Sabrina Ceccariglia, Silvia De Munari, Antonietta Rosa Silini, Michal Sheleg, Racheli Ofir, and Ornella Parolini. "Mesenchymal Stromal Cells from Fetal and Maternal Placenta Possess Key Similarities and Differences: Potential Implications for Their Applications in Regenerative Medicine." Cells 9, no. 1 (January 6, 2020): 127. http://dx.doi.org/10.3390/cells9010127.
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Placenta-derived mesenchymal stromal cells (MSC) have attracted more attention for their immune modulatory properties and poor immunogenicity, which makes them suitable for allogeneic transplantation. Although MSC isolated from different areas of the placenta share several features, they also present significant biological differences, which might point to distinct clinical applications. Hence, we compared cells from full term placenta distinguishing them on the basis of their origin, either maternal or fetal. We used cells developed by Pluristem LTD: PLacenta expanded mesenchymal-like adherent stromal cells (PLX), maternal-derived cells (PLX-PAD), fetal-derived cells (PLX-R18), and amniotic membrane-derived MSC (hAMSC). We compared immune modulatory properties evaluating effects on T-lymphocyte proliferation, expression of cytotoxicity markers, T-helper and T-regulatory cell polarization, and monocyte differentiation toward antigen presenting cells (APC). Furthermore, we investigated cell immunogenicity. We show that MSCs and MSC-like cells from both fetal and maternal sources present immune modulatory properties versus lymphoid (T cells) and myeloid (APC) cells, whereby fetal-derived cells (PLX-R18 and hAMSC) have a stronger capacity to modulate immune cell proliferation and differentiation. Our results emphasize the importance of understanding the cell origin and characteristics in order to obtain a desired result, such as modulation of the inflammatory response that is critical in fostering regenerative processes.
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Izvolskaia, Marina, Viktoria Sharova, and Liudmila Zakharova. "Prenatal Programming of Neuroendocrine System Development by Lipopolysaccharide: Long-Term Effects." International Journal of Molecular Sciences 19, no. 11 (November 21, 2018): 3695. http://dx.doi.org/10.3390/ijms19113695.
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Various stress factors during critical periods of fetal development modulate the epigenetic mechanisms controlling specific genes, which can affect the structure and function of physiological systems. Maternal immune stress by bacterial infection simulated by lipopolysaccharide (LPS) in an experiment is considered to be a powerful programming factor of fetal development. Studies of the molecular mechanisms controlling the formation and functioning of physiological systems are in the pilot stage. LPSs are the most potent natural inflammation factors. LPS-induced increases in fetal levels of pro- and anti-inflammatory cytokines can affect brain development and have long-term effects on behavior and neuroendocrine functions. The degradation of serotonergic neurons induced by LPS in the fetus is attributed to the increased levels of interleukin (IL)-6 and tumor necrosis factor (TNFα) as well as to anxiety and depression in children. Dopamine deficiency causes dysthymia, learning disability, and Parkinson’s disease. According to our data, an LPS-induced increase in the levels of IL-6, leukemia inhibitory factor (LIF), and monocyte chemotactic protein (MCP-1) in maternal and fetal rats during early pregnancy disturbs the development and functioning of gonadotropin-releasing hormone production and reproductive systems. It is important to note the high responsiveness of epigenetic developmental mechanisms to many regulatory factors, which offers opportunities to correct the defects.
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Eltaweel, Nashwa, Samuel Lockley, Irshad Ahmed, and Bee K. Tan. "SARS-CoV-2: do corticosteroids for fetal lung maturation worsen maternal or fetal outcomes?" British Journal of Midwifery 29, no. 2 (February 2, 2021): 90–92. http://dx.doi.org/10.12968/bjom.2021.29.2.90.
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Immune system changes during pregnancy could make pregnant women more susceptible to SARS-Cov-2 infection. The use of corticosteroids within obstetrics has been shown to reduce the risks of respiratory distress syndrome, intraventricular haemorrhage, necrotizing enterocolitis and neonatal death in the baby associated with premature delivery. During the COVID-19 pandemic, corticosteroids have been trialled as a treatment to dampen the ‘cytokine storm’ and associated inflammatory processes. Corticosteroids have long been known to have immunosuppressive effects that could hinder the body's ability to mount a defence against COVID-19 and thereby delaying viral clearance. In this clinical case studies, antenatal steroids for fetal lung maturation appear to be of benefit and did not result in a deterioration of maternal disease. Our clinical case studies support the current recommendations from the Royal College of Obstetricians and Gynaecologists ie corticosteroids for fetal lung maturation is appropriate in patients who are suspected or have confirmed SARS-CoV-2 infection.
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Gershwin, Laurel J. "Effects of Air Pollutants on Development of Allergic Immune Responses in the Respiratory Tract." Clinical and Developmental Immunology 10, no. 2-4 (2003): 119–26. http://dx.doi.org/10.1080/10446670310001626535.
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The increased incidence of allergic asthma in the human population worldwide has stimulated many explanatory theories. A concomitant decrease in air quality leads to epidemiological and laboratory-based studies to demonstrate a link between air pollutants and asthma. Specifically, ozone, environmental tobacco smoke, and diesel exhaust are associated with enhancement of respiratory allergy to inhaled allergens. This review summarizes the state of the knowledge, both human epidemiology and laboratory animal experiments, linking air pollution to allergy. Critical issues involve development of the lung and the fetal immune response, and the potential for substances like ozone and ETS in the air to modulate early immune responses with lifelong consequences.
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Hové, Carmen, Benjamin C. Trumble, Amy S. Anderson, Jonathan Stieglitz, Hillard Kaplan, Michael D. Gurven, and Aaron D. Blackwell. "Immune function during pregnancy varies between ecologically distinct populations." Evolution, Medicine, and Public Health 2020, no. 1 (January 1, 2020): 114–28. http://dx.doi.org/10.1093/emph/eoaa022.
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Abstract Background and objectives Among placental mammals, females undergo immunological shifts during pregnancy to accommodate the fetus (i.e. fetal tolerance). Fetal tolerance has primarily been characterized within post-industrial populations experiencing evolutionarily novel conditions (e.g. reduced pathogen exposure), which may shape maternal response to fetal antigens. This study investigates how ecological conditions affect maternal immune status during pregnancy by comparing the direction and magnitude of immunological changes associated with each trimester among the Tsimane (a subsistence population subjected to high pathogen load) and women in the USA. Methodology Data from the Tsimane Health and Life History Project (N = 935) and the National Health and Nutrition Examination Survey (N = 1395) were used to estimate population-specific effects of trimester on differential leukocyte count and C-reactive protein (CRP), a marker of systemic inflammation. Results In both populations, pregnancy was associated with increased neutrophil prevalence, reduced lymphocyte and eosinophil count and elevated CRP. Compared to their US counterparts, pregnant Tsimane women exhibited elevated lymphocyte and eosinophil counts, fewer neutrophils and monocytes and lower CRP. Total leukocyte count remained high and unchanged among pregnant Tsimane women while pregnant US women exhibited substantially elevated counts, resulting in overlapping leukocyte prevalence among all third-trimester individuals. Conclusions and implications Our findings indicate that ecological conditions shape non-pregnant immune baselines and the magnitude of immunological shifts during pregnancy via developmental constraints and current trade-offs. Future research should investigate how such flexibility impacts maternal health and disease susceptibility, particularly the degree to which chronic pathogen exposure might dampen inflammatory response to fetal antigens. Lay Summary This study compares immunological changes associated with pregnancy between the Tsimane (an Amazonian subsistence population) and individuals in the USA. Results suggest that while pregnancy enhances non-specific defenses and dampens both antigen-specific immunity and parasite/allergy response, ecological conditions strongly influence immune baselines and the magnitude of shifts during gestation.
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West-Eberhard, Mary Jane. "Nutrition, the visceral immune system, and the evolutionary origins of pathogenic obesity." Proceedings of the National Academy of Sciences 116, no. 3 (December 31, 2018): 723–31. http://dx.doi.org/10.1073/pnas.1809046116.
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The global obesity epidemic is the subject of an immense, diversely specialized research effort. An evolutionary analysis reveals connections among disparate findings, starting with two well-documented facts: Obesity-associated illnesses (e.g., type-2 diabetes and cardiovascular disease), are especially common in: (i) adults with abdominal obesity, especially enlargement of visceral adipose tissue (VAT), a tissue with important immune functions; and (ii) individuals with poor fetal nutrition whose nutritional input increases later in life. I hypothesize that selection favored the evolution of increased lifelong investment in VAT in individuals likely to suffer lifelong malnutrition because of its importance in fighting intraabdominal infections. Then, when increased nutrition violates the adaptive fetal prediction of lifelong nutritional deficit, preferential VAT investment could contribute to abdominal obesity and chronic inflammatory disease. VAT prioritization may help explain several patterns of nutrition-related disease: the paradoxical increase of chronic disease with increased food availability in recently urbanized and migrant populations; correlations between poor fetal nutrition, improved childhood (catch-up) growth, and adult metabolic syndrome; and survival differences between children with marasmus and kwashiorkor malnutrition. Fats and sugars can aggravate chronic inflammation via effects on intestinal bacteria regulating gut permeability to visceral pathogens. The extremes in a nutrition-sensitive trade-off between visceral (immune-function) vs. subcutaneous (body shape) adiposity may have been favored by selection in highly stratified premedicine societies. Altered adipose allocation in populations with long histories of social stratification and malnutrition may be the result of genetic accommodation of developmental responses to poor maternal/fetal conditions, increasing their vulnerability to inflammatory disease.
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Derevtsova, Anastasia, Andrey Kaviev, Sardorbek Makhkamov, Bakhtiyor Abdulazizov, and Alexandra Shevtsova. "Effect of pesticides on fetal development in the intrauterine and early postnatal periods." E3S Web of Conferences 258 (2021): 04008. http://dx.doi.org/10.1051/e3sconf/202125804008.
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The main objective of this study was to determine the level of toxic effects of pesticides on the development of immune and endocrine systems in offspring during intrauterine and early postnatal development. During the experiment, preparations containing the pesticide lambda-Cyhalothring (LCP) and fipronil were injected into white laboratory rats during pregnancy and lactation. The study was carried out using electron microscopy and morphological and biochemical studies. From the results of this study, it is concluded that the toxic effect of pesticide exposure during pregnancy and lactation is manifested by stunted growth of the thyroid gland (lymph nodes), thymus, lymph node and spleen development. Cell proliferation and apoptosis caused by direct toxic effects of drugs, developed hypothyroidism, oxidative stress reactions in both mother-nature and offspring are the main cause of toxic effects of industrial pesticides on the immune and endocrine systems. It follows from the data obtained that early detection of hypothyroidism and oxidative stress states in pregnant women and infants and then their correction with drugs is an important aspect of public health.
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Vodopivec, Ivana. "The Neurology of Immune-Mediated Disorders in Women." Seminars in Neurology 37, no. 06 (December 2017): 705–11. http://dx.doi.org/10.1055/s-0037-1607456.
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AbstractMany neuroinflammatory disorders have a predilection for women; even if there is no female predominance, neuroinflammatory conditions in women pose a management challenge for several reasons. Disease activity of these conditions may change during pregnancy and commonly increases in the postpartum period. Uncontrolled disease activity may affect pregnancy outcomes. Moreover, immunomodulating agents that are used to suppress the disease activity may have a negative impact on fertility, pregnancy, and fetal outcomes, and on infants who are breastfed. Adverse effects of immunosuppressants extend beyond the reproductive issues and may include bone loss, increased risk of cancers, and infectious complications. The successful management of women with these disorders requires that not only practitioners understand and recognize the adverse effects of immunosuppressants, but also seek to prevent adverse outcomes through counseling about contraceptive choices, safety monitoring, risk surveillance, and other strategies.
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Armin, Sabiha, and Kenneth Nugent. "Effects of COVID-19 infection during pregnancy." Southwest Respiratory and Critical Care Chronicles 9, no. 39 (April 19, 2021): 28–34. http://dx.doi.org/10.12746/swrccc.v9i39.851.
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Women develop important changes in their cardiovascular and respiratory systems during pregnancy. They also have important changes in their immune system which are necessary to tolerate foreign fetal tissue. These expected alterations can increase the likelihood of poor outcomes with certain respiratory infections, especially viral infection. There is extensive literature describing COVID-19 in pregnant women, and there is evidence that this virus can infect the placenta, raising implications for maternal-fetal transmission. Women who contract COVID-19 during pregnancy are at increased risk of preterm labor and other perinatal complications when compared to non-pregnant women. Trials on the safety and efficacy of the COVID-19 vaccines during pregnancy are in progress; several reproductive societies have recommended that women who are planning to get pregnant or are pregnant should get vaccination since there are few reports of adverse events in pregnant women who have received vaccines. Healthcare providers will need to address concerns of infertility, the possibility of vertical transmission, and neonatal infection with women regarding timely vaccination against this disease and other necessary precautions.
Keywords: coronavirus, COVID-19, pregnancy, placental pathology, vertical transmission
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Felsburg, P. J. "Overview of immune system development in the dog: comparison with humans." Human & Experimental Toxicology 21, no. 9-10 (September 2002): 487–92. http://dx.doi.org/10.1191/0960327102ht286oa.
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Dogs play an important role in toxicology because of their importance as a large animal, pre-clinical model for evaluating potential toxicity in human drug development including the effects of investigational drugs on the immune system. The purpose of this paper is to review the development of the canine immune system during the fetal, neonatal and postnatal periods and to compare it with that of the human immune system. Unlike rodents, the development of the canine immune system shares many similarities to that of the human. In both dogs and humans, the immune system, including the mucosal immune system, is fully developed before birth although the maturity of the immune response may continue into the postnatal period.
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Zacharasiewicz, Angela. "Maternal smoking in pregnancy and its influence on childhood asthma." ERJ Open Research 2, no. 3 (July 2016): 00042–2016. http://dx.doi.org/10.1183/23120541.00042-2016.
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Maternal smoking in pregnancy (MSP) is a large modifiable risk factor for pregnancy related mortality and morbidity and also the most important known modifiable risk factor for asthma.This review summarises the effects of MSP throughout infancy, childhood and adolescence with regards to asthma (development and severity). Firstly, the direct damage caused by nicotine on fetal lung development, fetal growth and neuronal differentiation is discussed, as well as the indirect effects of nicotine on placental functioning. Secondly, the effects of MSP on later immune functioning resulting in increased infection rate are summarised and details are given on the effects of MSP modulating airway hyperreactivity, reducing lung function and therefore increasing asthma morbidity.Furthermore, epigenetic effects are increasingly being recognised. These can also result in transgenerational detrimental effects induced by cigarette smoke.In summary, the causal relationship between MSP and asthma development is well documented and presents a major health problem for generations to come. The high prevalence of MSP is alarming and epigenetic effects of nicotine on immune functioning potentiate this danger. A considerable part of the increase in asthma prevalence worldwide is due to MSP.
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Meng, Di, Weishu Zhu, Kriston Ganguli, Hai Ning Shi, and W. Allan Walker. "Anti-inflammatory effects of Bifidobacterium longum subsp infantis secretions on fetal human enterocytes are mediated by TLR-4 receptors." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 4 (October 1, 2016): G744—G753. http://dx.doi.org/10.1152/ajpgi.00090.2016.
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The therapeutic and preventive application of probiotics for necrotizing enterocolitis (NEC) has been supported by more and more experimental and clinical evidence in which Toll-like receptor 4 (TLR-4) exerts a significant role. In immune cells, probiotics not only regulate the expression of TLR-4 but also use the TLR-4 to modulate the immune response. Probiotics may also use the TLR-4 in immature enterocytes for anti-inflammation. Here we demonstrate that probiotic conditioned media (PCM) from Bifidobacterium longum supp infantis but not isolated organisms attenuates interleukin-6 (IL-6) induction in response to IL-1β by using TLR-4 in a human fetal small intestinal epithelial cell line (H4 cells), human fetal small intestinal xenografts, mouse fetal small intestinal organ culture tissues, and primary NEC enterocytes. Furthermore, we show that PCM, using TLR-4, downregulates the mRNA expression of interleukin-1 receptor-associated kinase 2 (IRAK-2), a common adapter protein shared by IL-1β and TLR-4 signaling. PCM also reduces the phosphorylation of the activator-protein 1 (AP-1) transcription factors c-Jun and c-Fos in response to IL-1β stimulation in a TLR-4-dependent manner. This study suggests that PCM may use TLR-4 through IRAK-2 and via AP-1 to prevent IL-1β-induced IL-6 induction in immature enterocytes. Based on these observations, the combined use of probiotics and anti-TLR-4 therapy to prevent NEC may not be a good strategy.
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Lingman, Goran, Magnus Stangenberg, Jesper Legarth, and Feryal Rahman. "Albumin Transfusion in Non-Immune Fetal Hydrops: Doppler Ultrasound Evaluation of the Acute Effects on Blood Circulation in the Fetal Aorta and the Umbilical Arteries." Fetal Diagnosis and Therapy 4, no. 2-3 (1989): 120–25. http://dx.doi.org/10.1159/000263433.
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Palmer, Christina G. S. "Evidence for Maternal-Fetal Genotype Incompatibility as a Risk Factor for Schizophrenia." Journal of Biomedicine and Biotechnology 2010 (2010): 1–12. http://dx.doi.org/10.1155/2010/576318.
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Prenatal/obstetric complications are implicated in schizophrenia susceptibility. Some complications may arise from maternal-fetal genotype incompatibility, a term used to describe maternal-fetal genotype combinations that produce an adverse prenatal environment. A review of maternal-fetal genotype incompatibility studies suggests that schizophrenia susceptibility is increased by maternal-fetal genotype combinations at theRHDandHLA-Bloci. Maternal-fetal genotype combinations at these loci are hypothesized to have an effect on the maternal immune system during pregnancy which can affect fetal neurodevelopment and increase schizophrenia susceptibility. This article reviews maternal-fetal genotype incompatibility studies and schizophrenia and discusses the hypothesized biological role of these ‘‘incompatibility genes’’. It concludes that research is needed to further elucidate the role ofRHDandHLA-Bmaternal-fetal genotype incompatibility in schizophrenia and to identify other genes that produce an adverse prenatal environment through a maternal-fetal genotype incompatibility mechanism. Efforts to develop more sophisticated study designs and data analysis techniques for modeling maternal-fetal genotype incompatibility effects are warranted.
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MacKenzie, Tippi, Erin Jarvis, Amar Nijagal, Tom Le, Marta Wegorzewska, and Qizhi Tang. "The Maternal Immune Response to in Utero Hematopoietic Stem Cell Transplantation." Blood 114, no. 22 (November 20, 2009): 64. http://dx.doi.org/10.1182/blood.v114.22.64.64.
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Abstract Abstract 64 In utero hematopoietic stem cell transplantation (IUHSCTx) is a promising treatment strategy for many congenital hematopoietic disorders such as immunodeficiencies. However, clinical applications have been hampered by lack of engraftment, possibly secondary to a host immune response. This has been a conundrum in the field, since the fetus can also be tolerized to allogeneic cells in some circumstances. We hypothesized that it is the maternal immune response which limits engraftment of in utero transplanted cells. Methods: Fetal BALB/c mice at 14 days' gestation were transplanted with age-matched fetal liver (FL) cells (2.5 × 106 cells/fetus) from allogeneic C57B6 mice and levels of circulating donor cell chimerism were determined serially starting at 4 weeks after in utero transplantation. Rates of engraftment (number of chimeric pups/number of surviving pups) and levels of chimerism (donor CD45 cells/total CD45 cells) were compared to controls in which animals were transplanted with congenic cells (C57B6 (CD45.2) fetal hosts transplanted with C57B6 (CD45.1) FL). In order to determine the role of the maternal adaptive immune system, immunodeficient BALB/c.Rag−/− mothers (deficient in T and B cells) were bred to wild type BALB/c males, such that the fetuses (BALB/c.Rag+/−) would be immunocompetent. These fetuses were transplanted with C57B6 FL and rates of engraftment and levels of chimerism in these transplants were compared to those in wild type allogeneic transplants. In order to determine whether the maternal influence is caused by maternal lymphocytes trafficking into the fetus, C57B6 (CD45.2) females were bred to C57B6 (CD45.1) males, such that the fetal cells (CD45.1+/CD45.2+) could be distinguished from maternal cells (CD45.1−/CD45.2+). Fetal blood and tissues were examined for the presence of maternal cells by flow cytometry at various gestational ages. Results: The rate of engraftment after IUHSCTx in control animals transplanted with congenic cells was 14/16 (88%) and average levels of chimerism were 9.9±8.4%. In contrast, the rate of engraftment in wild-type BALB/c fetuses transplanted with allogeneic B6 cells was 11/25 (44%; p<0.05 compared to congenic), and levels of chimerism were 21±19 (p=NS), confirming there is an adaptive immune response to fetal stem cell transplantation. As expected, chimeric animals were tolerant to the donor strain by mixed lymphocyte reaction while injected, non-chimeric animals were sensitized. However, in the absence of a maternal adaptive immune system, rates of chimerism (in immunocompetent BALB/c.Rag+/− pups) increased to 100% (n=10, p<0.05 compared to wild type allogeneic) and levels of chimerism were significantly higher (44±18, p<0.05). Levels of chimerism in engrafted animals declined over time after allogeneic transplantation but not after congenic transplantation, indicating there is a second, late phase immune response to allogeneic cells. However, chimerism levels did not decline in the BALB/c.Rag+/− recipients, suggesting that the maternal immune system has long-lasting effects on the success of fetal transplantation, perhaps by priming the host immune system. In our analysis of maternal/fetal cellular trafficking, we detected maternal lymphocytes in the blood of midgestation fetuses (14±7% at E12.5–E14.5, n=9) which declined gradually and was undetectable after birth. Lineage analysis demonstrated that 45±15 % of maternal cells are Gr-1+ granulocytes and 21±15% are B cells. Trafficking of maternal cells into the fetus was increased following fetal manipulation (injection of PBS < injection of allogeneic HSC). Conclusions: There is an adaptive immune response which limits early engraftment after in utero transplantation of allogeneic cells and leads to a gradual decline in levels of chimerism in engrafted animals. However, in the selective absence of maternal T and B cells, all fetuses transplanted with allogeneic FL cells show long-term, multilineage engraftment and demonstrate donor-specific tolerance. These results indicate that the maternal immune system plays a significant role in the success of fetal HSC transplantation. Cellular trafficking between the mother and fetus may be a mechanism by which maternal lymphocytes encounter cells transplanted into the fetus. Our findings have clinical implications in that the success of IUHSCTx may be improved by harvesting cells from the mother or HLA-matching cells to the mother. Disclosures: No relevant conflicts of interest to declare.
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Koehn, Liam M., Yifan Huang, Mark D. Habgood, Kai Kysenius, Peter J. Crouch, Katarzyna M. Dziegielewska, and Norman R. Saunders. "Effects of paracetamol (acetaminophen) on gene expression and permeability properties of the rat placenta and fetal brain." F1000Research 9 (June 8, 2020): 573. http://dx.doi.org/10.12688/f1000research.24119.1.
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Background: Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as “safe” by regulatory authorities. Methods: Clinically relevant doses of paracetamol were administered intraperitoneally to pregnant rats twice daily from embryonic day E15 to 19 (chronic) or as a single dose at E19 (acute). Control samples were from un-treated age-matched animals. At E19, rats were anaesthetised, administered a final paracetamol dose, uteruses were opened and fetuses exposed for sample collection. For RNA sequencing, placentas and fetal brains were removed and flash frozen. Fetal and maternal plasma and cerebrospinal fluid were assayed for ⍺-fetoprotein and interleukin 1β (IL1β). Brains were fixed and examined (immunohistochemistry) for plasma protein distribution. Placental permeability to a small molecule (14C-sucrose) was tested by injection into either mother or individual fetuses; fetal and maternal blood was sampled at regular intervals to 90 minutes. Results: RNA sequencing revealed a large number of genes up- or down-regulated in placentas from acutely or chronically treated animals compared to controls. Most notable was down-regulation of three acute phase plasma proteins (⍺-fetoprotein, transferrin, transthyretin) in acute and especially chronic experiments and marked up-regulation of immune-related genes, particularly cytokines, again especially in chronically treated dams. IL1β increased in plasma of most fetuses from treated dams but to variable levels and no IL1β was detectable in plasma of control fetuses or any of the dams. Increased placental permeability appeared to be only from fetus to mother for both 14C-sucrose and ⍺-fetoprotein, but not in the reverse direction. In the fetal brain, gene regulatory changes were less prominent than in the placenta of treated fetuses and did not involve inflammatory-related genes; there was no evidence of increased blood-brain barrier permeability. Conclusion: Results suggest that paracetamol may induce an immune-inflammatory-like response in placenta and more caution should be exercised in use of paracetamol in pregnancy.
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Koehn, Liam M., Yifan Huang, Mark D. Habgood, Kai Kysenius, Peter J. Crouch, Katarzyna M. Dziegielewska, and Norman R. Saunders. "Effects of paracetamol (acetaminophen) on gene expression and permeability properties of the rat placenta and fetal brain." F1000Research 9 (August 19, 2020): 573. http://dx.doi.org/10.12688/f1000research.24119.2.
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Background: Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as “safe” by regulatory authorities. Methods: Clinically relevant doses of paracetamol were administered intraperitoneally to pregnant rats twice daily from embryonic day E15 to 19 (chronic) or as a single dose at E19 (acute). Control samples were from un-treated age-matched animals. At E19, rats were anaesthetised, administered a final paracetamol dose, uteruses were opened and fetuses exposed for sample collection. For RNA sequencing, placentas and fetal brains were removed and flash frozen. Fetal and maternal plasma and cerebrospinal fluid were assayed for α-fetoprotein and interleukin 1β (IL1β). Brains were fixed and examined (immunohistochemistry) for plasma protein distribution. Placental permeability to a small molecule (14C-sucrose) was tested by injection into either mother or individual fetuses; fetal and maternal blood was sampled at regular intervals to 90 minutes. Results: RNA sequencing revealed a large number of genes up- or down-regulated in placentas from acutely or chronically treated animals compared to controls. Most notable was down-regulation of three acute phase plasma proteins (α-fetoprotein, transferrin, transthyretin) in acute and especially chronic experiments and marked up-regulation of immune-related genes, particularly cytokines, again especially in chronically treated dams. IL1β increased in plasma of most fetuses from treated dams but to variable levels and no IL1β was detectable in plasma of control fetuses or any of the dams. Increased placental permeability appeared to be only from fetus to mother for both 14C-sucrose and α-fetoprotein, but not in the reverse direction. In the fetal brain, gene regulatory changes were less prominent than in the placenta of treated fetuses and did not involve inflammatory-related genes; there was no evidence of increased blood-brain barrier permeability. Conclusion: Results suggest that paracetamol may induce an immune-inflammatory-like response in placenta and more caution should be exercised in use of paracetamol in pregnancy.
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Chase, Christopher C. L., Neelu Thakur, Mahmoud F. Darweesh, Susan E. Morarie-Kane, and Mrigendra K. Rajput. "Immune response to bovine viral diarrhea virus—looking at newly defined targets." Animal Health Research Reviews 16, no. 1 (June 2015): 4–14. http://dx.doi.org/10.1017/s1466252315000110.
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AbstractBovine viral diarrhea virus (BVDV) has long been associated with a wide variety of clinical syndromes and immune dysregulation, many which result in secondary bacterial infections. Current understanding of immune cell interactions that result in activation and tolerance are explored in light of BVDV infection including: depletion of lymphocytes, effects on neutrophils, natural killer cells, and the role of receptors and cytokines. In addition, we review some new information on the effect of BVDV on immune development in the fetal liver, the role of resident macrophages, and greater implications for persistent infection.
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Wooldridge, Amy L., Robert J. Bischof, Els N. Meeusen, Hong Liu, Gary K. Heinemann, Damien S. Hunter, Lynne C. Giles, et al. "Placental restriction of fetal growth reduces cutaneous responses to antigen after sensitization in sheep." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 306, no. 7 (April 1, 2014): R441—R446. http://dx.doi.org/10.1152/ajpregu.00432.2013.
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Prenatal and early childhood exposures are implicated as causes of allergy, but the effects of intrauterine growth restriction on immune function and allergy are poorly defined. We therefore evaluated effects of experimental restriction of fetal growth on immune function and allergic sensitization in adolescent sheep. Immune function (circulating total red and white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and the antibody response to Clostridial vaccination) and responses to house dust mite (HDM) allergen and ovalbumin (OVA) antigen sensitization (specific total Ig, IgG1, and IgE antibodies, and cutaneous hypersensitivity) were investigated in adolescent sheep from placentally restricted (PR, n = 23) and control ( n = 40) pregnancies. Increases in circulating HDM-specific IgE ( P = 0.007) and OVA-specific IgE ( P = 0.038) were greater in PR than control progeny. PR did not alter total Ig, IgG1, or IgM responses to either antigen. PR increased OVA-specific but not HDM-specific IgA responses in females only ( P = 0.023). Multiple birth increased Ig responses to OVA in a sex-specific manner. PR decreased the proportion of positive cutaneous hypersensitivity responders to OVA at 24 h ( P = 0.030) but had no effect on cutaneous responses to HDM. Acute wheal responses to intradermal histamine correlated positively with birth weight in singletons ( P = 0.023). Intrauterine growth restriction may suppress inflammatory responses in skin downstream of IgE induction, without impairment in antibody responses to a nonpolysaccharide vaccine. Discord between cutaneous and IgE responses following sensitization suggests new mechanisms for prenatal allergy programming.
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WHITEHEAD, N. E. "AN ANTIBOY ANTIBODY? RE-EXAMINATION OF THE MATERNAL IMMUNE HYPOTHESIS." Journal of Biosocial Science 39, no. 6 (November 2007): 905–21. http://dx.doi.org/10.1017/s0021932007001903.
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SummaryThe maternal immune hypothesis (MIH) argues same sex attraction (SSA) results from maternal immune attack on fetal male-specific brain structures and involves the previous biological influence of elder brothers. One of the surveys supporting this is shown to be based on an unsuitable sample and to contain some strong contrary evidence. The hypothesis relies on at least four speculative ideas and there is evidence against each. (1) Likely immune response prevalence is too low compared with calculated SSA prevalence resulting from the fraternal birth order effect. (2) Testis immune attack would be more likely than brain attack but is not known. (3) Fetal brain structures are practically indistinguishable at birth and subsequent brain anatomical gender differentiation only occurs after birth when no attack is occurring. (4) The hypothesis also predicts unfavourable biology for late birth-order males but in fact the reverse is generally true, and neurological effects are very minor. Studies show aborted fetuses caused by likely maternal immune attack are predominantly girls rather than boys, which also argues against the theory. Studies on identical twins show that common factors such as uterine environment are only a small influence on SSA and post-natal idiosyncratic reactions and non-shared environmental factors are much larger influences.
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Jawor, Paulina, John F. Mee, and Tadeusz Stefaniak. "Role of Infection and Immunity in Bovine Perinatal Mortality: Part 2. Fetomaternal Response to Infection and Novel Diagnostic Perspectives." Animals 11, no. 7 (July 15, 2021): 2102. http://dx.doi.org/10.3390/ani11072102.
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Bovine perinatal mortality due to infection may result either from the direct effects of intrauterine infection and/or the fetal response to such infection, leading to the fetal inflammatory response syndrome (FIRS). Both intrauterine infection and FIRS, which causes multi-organ damage and involution of immune organs, compromise fetal survivability, sometimes fatally. Organ injury associated with FIRS may, in addition to causing fetal mortality, irreversibly compromise extrauterine adaptation of the neonate, a recognized problem in human fetuses. Diagnosis of intrauterine infection and of FIRS requires related, but independent analytical approaches. In addition to detection of pathogens, the immune and inflammatory responses of the bovine fetus may be utilized to diagnose intrauterine infection. This can be done by detection of specific changes in internal organs and the measurement of antibodies and/or elements of the acute phase reaction. Currently our ability to diagnose FIRS in bovine fetuses and neonates is limited to research studies. This review focuses on both the fetomaternal response to infection and diagnostic methods which rely on the response of the fetus to infection and inflammatory changes, as well other methods which may improve diagnosis of intrauterine infection in cases of bovine perinatal mortality.
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Bronson, Stefanie L., and Tracy L. Bale. "Prenatal Stress-Induced Increases in Placental Inflammation and Offspring Hyperactivity Are Male-Specific and Ameliorated by Maternal Antiinflammatory Treatment." Endocrinology 155, no. 7 (July 1, 2014): 2635–46. http://dx.doi.org/10.1210/en.2014-1040.
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Adverse experiences during gestation such as maternal stress and infection are known risk factors for neurodevelopmental disorders, including schizophrenia, autism, and attention deficit/hyperactivity disorder. The mechanisms by which these distinct exposures may confer similar psychiatric vulnerability remain unclear, although likely involve pathways common to both stress and immune responses at the maternal-fetal interface. We hypothesized that maternal stress-induced activation of immune pathways within the placenta, the sex-specific maternal-fetal intermediary, may contribute to prenatal stress programming effects on the offspring. Therefore, we assessed for markers indicative of stress-induced placental inflammation, and examined the ability of maternal nonsteroidal antiinflammatory drug (NSAID) treatment to ameliorate placental effects and thereby rescue the stress-dysregulation phenotype observed in our established mouse model of early prenatal stress (EPS). As expected, placental gene expression analyses revealed increased levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, specifically in male placentas. NSAID treatment partially ameliorated these EPS effects. Similarly, in adult offspring, males displayed stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal NSAID treatment. Fitting with these outcomes and supportive of dopamine pathway involvement, expression of dopamine D1 and D2 receptors was altered by EPS in males. These studies support an important interaction between maternal stress and a proinflammatory state in the long-term programming effects of maternal stress.
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Yu, Yang, Hui Wang, Xianhua Meng, Lu Hao, Yue Fu, Linlin Fang, Dan Shen, Xiaomeng Yu, and Jingshung Li. "Immunomodulatory Effects of Cinobufagin on Murine Lymphocytes and Macrophages." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/835263.
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Cinobufagin (CBG), a major bioactive component of the traditional Chinese medicine ChanSu, has been reported to have potent pharmacological activity. In this study, we aimed to elucidate the effects of CBG on the activity of immune cells in mice. Peritoneal macrophages and splenocytes from mice were prepared and cultured in RPMI1640 supplemented with 10% fetal bovine serum. Concanavalin (ConA), lipopolysaccharide (LPS), and CBG (0.0125, 0.05, 0.15, or 0.25 μg/mL) were added to the culture medium, and the phagocytic activity of macrophages was detected by MTT assays. Additionally, lymphocyte secretion of interleukin- (IL-)2 and IL-10 was detected by enzyme-linked immunosorbent assay, and the cell cycle distribution and cell surface markers were detected by flow cytometry. Our results demonstrated that CBG promoted lymphocyte proliferation; this effect was suppressed by combined treatment with ConA or LPS. Moreover, CBG also significantly improved the CD4+/CD8+ratio in spleen lymphocytes and increased the percentage of spleen lymphocytes in the S phase. Finally, we found that CBG enhanced the secretion of IL-2 and IL-10 and increased the phagocytosis ability of macrophages. In summary, CBG could enhance activity of immune cells.
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Fröhlich, Carolin, Jens Ehrhardt, Diana Krüger, Dominika Trojnarska, Marek Zygmunt, and Damián Oscar Muzzio. "Pregnancy status alters IL-21-mediated effects on murine B lymphocytes." Reproduction 159, no. 3 (March 2020): 351–59. http://dx.doi.org/10.1530/rep-19-0407.
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A favorable outcome of pregnancy depends greatly on an adequate balance of immune protection and fetal tolerance at the fetomaternal interface. IL-21 is a pro-inflammatory cytokine associated with altering immune responses in autoimmune diseases. IL-21 has pleiotropic functions, including induction of Th17 T cells, inhibition of Treg development, and modulation of antibody responses of B lymphocytes. Genetic polymorphisms of IL21 have been associated to poor pregnancy outcomes. However, the mechanism of IL-21 actions needs further evaluation. Here, we postulate that IL-21 affects splenic B cell function during pregnancy and shapes immune responses. We show that splenic B cells from CBA/J × BALB/c mice with favorable pregnancy outcome expressed lower IL21R levels than in CBA/J × DBA/2J mice, a mouse model for immune-induced bad pregnancy outcome. As a consequence, B cells from CBA/J × BALB/c mice reacted less sensitively to IL-21 than B cells from non-pregnant mice (NPM) or from CBA/J × DBA/2J mice. Also, LPS-induced apoptotic rates were altered in NPM and CBA/J × DBA/2J but not in CBA/J × BALB/c mice. This is accompanied by improved survival of B cells that produce the anti-inflammatory cytokine IL-10 upon stimulation with LPS. We also observed lower numbers of CD4+CXCR5+Bcl-6+ follicular T-helper cells (Tfh) in normal pregnant mice, compared to non-pregnant and mice with disturbed pregnancies. Our data indicate that alterations of the Tfh/IL-21/IL-10 axis may have important influence on pregnancy outcome.
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Barton, James C., Mansoor N. Saleh, Charles M. Stedman, and Albert F. Lobuglio. "Case Report: Immune Thrombocytopenia: Effects of Maternal Gamma Globulin Infusion on Maternal and Fetal Serum, Platelet, and Monocyte IgG." American Journal of the Medical Sciences 293, no. 2 (February 1987): 112–18. http://dx.doi.org/10.1097/00000441-198702000-00008.
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Mao, Guanping, Junpeng Wang, Youmin Kang, Ping Tai, Jing Wen, Qiang Zou, Ge Li, Hong Ouyang, Guoliang Xia, and Bin Wang. "Progesterone Increases Systemic and Local Uterine Proportions of CD4+CD25+ Treg Cells during Midterm Pregnancy in Mice." Endocrinology 151, no. 11 (September 15, 2010): 5477–88. http://dx.doi.org/10.1210/en.2010-0426.
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Mechanisms maintaining the growth of a “semi-foreign” fetus within the maternal uterus via immune tolerance remain unclear. CD4+CD25+ regulatory T (Treg) cells have been implicated in the maintenance of maternal-fetal immune tolerance. Additionally, 17β-estradiol (E2) is able to initiate immune suppression through CD4+CD25+ Treg cells during early pregnancy. Little is known, however, regarding the relationship between progesterone (P4) and immune tolerance during midterm pregnancy, an important period, characterized by higher levels of P4 but lower levels of E2 in the serum. Here, we examined the effects of P4 on the expansion and function of systemic and local uterine CD4+CD25+ Treg cells during midterm pregnancy in mice. Using in vivo and in vitro models, we provide the first evidence that P4 not only increases the proportion of CD4+CD25+ Treg cells and IL-10 expression but also enhances their suppressive function. Moreover, at physiological doses relevant to midterm pregnancy, P4, but not E2, converts CD4+CD25− T cells into CD4+CD25+ Treg cells. This conversion was inhibited in vitro by the nuclear P4 receptors antagonist RU 486 and in vivo in P4-treated ovariectomized and pseudopregnant mice models, suggesting that P4 expands Treg populations via nuclear P4 receptors. Furthermore, RU 486 significantly reduced the quantity and function of Treg cells in the fetal-maternal interface before the onset of induced abortion. Interestingly, with decreasing Foxp3, proinflammatory factors increased. Together, the present results demonstrate that P4 is an important regulator of systemic and local CD4+CD25+ Treg cells, which are involved in maintaining maternal-fetal immune tolerance during midterm pregnancy.
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Chavatte-Palmer, P., Y. Heyman, and I. Schwartz. "26 EFFECTS OF SOMATIC CLONING ON THE IMMUNE RESPONSE IN YOUNG AND ADULT CATTLE." Reproduction, Fertility and Development 18, no. 2 (2006): 121. http://dx.doi.org/10.1071/rdv18n2ab26.
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Somatic cloning in cattle is associated with important gestational abnormalities, including implantation delay during the first 2 months of pregnancy and abnormal fetal and placental growth (known as large offspring syndrome, or LOS) in the third trimester. In our laboratory, between 3 and 25% of the cloned blastocysts transferred to recipient cows reach term, depending on genotype. About 20% of the newborns die rapidly due to various causes that appear to be direct consequences of the LOS. We previously reported on a thymic atrophy resulting from nuclear transfer (Renard et al. 1999 Lancet 353, 1459-1491) and have further diagnosed distinct pathological events occurring in the infancy and adult age of clones, including death due to apparently benign infections (despite treatment) and also thymic atrophy in approximately 20% of the postmortem cases. These observations in clones have led us to investigate the immune function of apparently normal bovine clones. Holstein cows housed in the same farm were used. Circulating lymphocyte populations during the resting state were marked, counted in 17 clones and 17 contemporary controls ranging from 15 days to 5 years of age, and allotted to one of three groups: 1 (0.5-2 months, n = 4 clones, n = 6 controls), 2 (3-9 months, n = 7 clones, n = 5 controls) and 3 (1.5-5 years, n = 6 clones, n = 6 controls). Clones originated from adult fibroblast cells from four different genotypes distributed in the three groups. Peripheral mononuclear blood cells (PMBCs) were collected, marked, and counted by flow cytometry. The specific markers were CD2, CD3, CD4, CD8, CD14, CD11b, CD25, CD45RO, P46 (NK cells), ��, PanB, MHC1, and MHC2. In a second experiment, six clones from three different genotypes and six controls aged 8-9 months were vaccinated with 10 mg ovalbumin in alum to evaluate the na�ve immune response. The cell subset proportions were not different between clones and controls. There was no difference between groups for antibody response to vaccination. However, T cell restimulation with specific antigens after immunization with evalbumin was significantly lower in clones compared to controls (P < 0.05). Furthermore, nonspecific stimulation with phytohemagglutinin (PHA) was also lower in clones (P < 0.05). These results show that lymphocyte populations are normally represented in apparently healthy clones. Bovine clones presented, however, a reduced capacity to build up a cellular immune response against a newly encountered antigen, such as ovalbumin. It remains to be determined whether these functional alterations are a result of defective reprogramming of immune functions during the cloning process or the consequence of an abnormal placental development leading to altered feto-placental interactions during pregnancy and fetal programming. Previous work by others has shown that there may be an abnormal expression of MHC1 in the placenta of bovine clones (Hill et al. 2002 Biol. Reprod. 67, 55-63), and this may well be part of the same phenomenon affecting overall immune regulation in clones.