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      Immunological Tolerance, Pregnancy, and Preeclampsia: The Roles of Semen Microbes and the Father

      1 , 2 , 3 , 4 , 5 , *

      Frontiers in Medicine

      Frontiers Media S.A.

      preeclampsia, immunology, microbes, dormancy, semen, infection

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          Abstract

          Although it is widely considered, in many cases, to involve two separable stages (poor placentation followed by oxidative stress/inflammation), the precise originating causes of preeclampsia (PE) remain elusive. We have previously brought together some of the considerable evidence that a (dormant) microbial component is commonly a significant part of its etiology. However, apart from recognizing, consistent with this view, that the many inflammatory markers of PE are also increased in infection, we had little to say about immunity, whether innate or adaptive. In addition, we focused on the gut, oral and female urinary tract microbiomes as the main sources of the infection. We here marshall further evidence for an infectious component in PE, focusing on the immunological tolerance characteristic of pregnancy, and the well-established fact that increased exposure to the father’s semen assists this immunological tolerance. As well as these benefits, however, semen is not sterile, microbial tolerance mechanisms may exist, and we also review the evidence that semen may be responsible for inoculating the developing conceptus (and maybe the placenta) with microbes, not all of which are benign. It is suggested that when they are not, this may be a significant cause of PE. A variety of epidemiological and other evidence is entirely consistent with this, not least correlations between semen infection, infertility and PE. Our view also leads to a series of other, testable predictions. Overall, we argue for a significant paternal role in the development of PE through microbial infection of the mother via insemination.

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          Most cited references 741

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          For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.
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            Oscillations in NF-kappaB signaling control the dynamics of gene expression.

            Signaling by the transcription factor nuclear factor kappa B (NF-kappaB) involves its release from inhibitor kappa B (IkappaB) in the cytosol, followed by translocation into the nucleus. NF-kappaB regulation of IkappaBalpha transcription represents a delayed negative feedback loop that drives oscillations in NF-kappaB translocation. Single-cell time-lapse imaging and computational modeling of NF-kappaB (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased IkappaBalpha transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-kappaB signaling may thus depend on number, period, and amplitude of oscillations.
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              Pre-eclampsia

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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                04 January 2018
                2017
                : 4
                Affiliations
                1The Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork , Cork, Ireland
                2Department of Obstetrics and Gynecology, University College Cork , Cork, Ireland
                3Faculty of Health and Life Sciences, University of Liverpool , Liverpool, United Kingdom
                4School of Chemistry, The University of Manchester , Manchester, United Kingdom
                5The Manchester Institute of Biotechnology, The University of Manchester , Manchester, United Kingdom
                Author notes

                Edited by: Issam Lebbi, Dream Center, Tunisia

                Reviewed by: Stefan Gebhardt, Stellenbosch University, South Africa; Peter Sedlmayr, Medical University of Graz, Austria

                *Correspondence: Douglas B. Kell, dbk@ 123456manchester.ac.uk

                Paper 14 in the series “The dormant blood microbiome in chronic, inflammatory diseases.”

                Specialty section: This article was submitted to Obstetrics and Gynecology, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2017.00239
                5758600
                Copyright © 2018 Kenny and Kell.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 7, Tables: 5, Equations: 0, References: 867, Pages: 39, Words: 37606
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council 10.13039/501100000268
                Award ID: BB/L025752/1
                Funded by: Science Foundation Ireland 10.13039/501100001602
                Award ID: 08/IN.1/B2083, 12/RC/2272
                Categories
                Medicine
                Hypothesis and Theory

                preeclampsia, immunology, microbes, dormancy, semen, infection

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