scholarly journals Transplacental Innate Immune Training via Maternal Microbial Exposure: Role of XBP1-ERN1 Axis in Dendritic Cell Precursor Programming

2020 ◽  
Vol 11 ◽  
Author(s):  
Kyle T. Mincham ◽  
Anya C. Jones ◽  
Marie Bodinier ◽  
Naomi M. Scott ◽  
Jean-Francois Lauzon-Joset ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Large Scale ◽  
Innate Immune ◽  
Mucosal Tissue ◽  
Treatment Target ◽  
Tissue Microenvironment ◽  
Pathogen Challenge ◽  
Progenitor Compartment ◽  
Airways Inflammation

We recently reported that offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance to allergic airways inflammation, and localized the potential treatment target to fetal conventional dendritic cell (cDC) progenitors. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis. Additionally, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has been shown to be crucial for tissue survival of cDC, particularly within the lungs. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. We suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of OM-85-mediated transplacental innate immune training which results in postnatal resistance to airway inflammatory disease.

scholarly journals Transplacental innate immune training via maternal microbial exposure: the XBP1-ERN1 axis in programming dendritic cell precursors

2019 ◽  
Author(s):  
Kyle T. Mincham ◽  
Anya C. Jones ◽  
Marie Bodinier ◽  
Naomi M. Scott ◽  
Jean-Francois Lauzon-Joset ◽  
...  
Keyword(s):  
Large Scale ◽  
Postnatal Period ◽  
Innate Immune ◽  
Treatment Target ◽  
Tissue Microenvironment ◽  
Enhanced Resistance ◽  
Pathogen Challenge ◽  
Immunological Homeostasis ◽  
Progenitor Compartment ◽  
Airways Inflammation

AbstractWe recently reported that the offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance postnatally to allergic airways inflammation, and localised the potential treatment target to the fetal cDC progenitor compartment which expands to increase the pool of precursors available at birth, enabling accelerated postnatal seeding of the lung mucosal cDC network required for establishment of immunological homeostasis in the airways. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis, that are hallmarks of classical “immune training”. In addition, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has previously been shown to be essential for tissue survival of cDC, particularly within the lung microenvironment. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. XBP1-ERN1 signalling plays a key role in mitigation of ER stress-associated toxicity which frequently accompanies DC hyper-activation during intense immunoinflammatory responses, and we suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of the OM-85-mediated transplacental “innate immune training” process which results in enhanced resistance to airway inflammatory disease during the high-risk early postnatal period.

DOCK8-Deficient Mice Reveal a Crucial Role for Dendritic Cell Activity in the Initiation of the Allogeneic Response to Transfused Red Blood Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 658-658
Author(s):  
Stephanie C. Eisenbarth ◽  
Jeanne E. Hendrickson ◽  
Samuele Calabro ◽  
Antonia Gallman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Innate Immune ◽  
Allogeneic Response ◽  
Deficient Mice

Abstract The generation of antibodies against transfused red blood cells (RBCs) can pose a serious health risk, especially in chronically transfused patients requiring life-long transfusion support; yet our understanding of what immune signals or cells dictate when someone will become alloimmunized is lacking. The relative role of dendritic cells, B cells and macrophages in the induction of RBC alloimmunization remain unclear. Given the now well established role of innate immune signals in regulating adaptive immunity, understanding if and how innate immunity is triggered during transfusion may allow development of therapies to prevent alloimmunization in chronically transfused subjects such as those with myelodysplasia or hemoglobinopathies. We have established a murine model system in which we can evaluate both the role of particular innate immune stimuli as well as particular cells of the immune system in regulating the allogeneic response to transfused RBCs. A particularly useful transgenic "HOD mouse" has been engineered, which encodes a triple fusion protein and provides a unique tool to directly assess both RBC-specific T and B cell responses. This RBC-specific antigen contains the model protein antigen hen egg lysozyme (HEL) fused to chicken ovalbumin (OVA) fused to the human Duffyb blood group antigen (HEL-OVA-Duffy) as an integral membrane protein under control of the beta globin promoter. Transfusion of genetically targeted mice lacking various innate immune cells or receptors allows us to screen for important immune pathways regulating the response to allogeneic RBCs. Using these models, we recently discovered that mice lacking the GEF (guanine nucleotide exchange factor) DOCK8 fail to develop alloimmunity to transfused RBCs. Dendritic cells in these knockout mice fail to migrate to T cells due to lack of coordinated actin rearrangement governed by this GEF. Both B cell and T cell activation in the spleen to the transgenic transfused RBCs is abrogated. Inclusion of OVA in the alloantigen of the HOD mice allows us to readily study naïve CD4+ T cell activation following transfusion by using the OTII T cell receptor (TCR) transgenic mice in which essentially all T cells express one antigen receptor specific for a peptide of OVA. By tracking rounds of cell division we found that adoptively transferred OTII undergo more than 5-8 rounds of division in the spleen three days following transfusion of HOD RBCs in WT recipients. In contrast, no OTII proliferation was observed in DOCK8-deficient mice following OTII adoptive transfer and HOD RBC transfusion, suggesting that T cells are failing to receive activation signals by splenic antigen presenting cells. Our preliminary data now suggest that DOCK8-deficient dendritic cells are able to process and present RBC-derived antigens, but do not migrate to T cell zones in the spleen to prime naïve RBC-specific T cells. The need for dendritic cell migration within the spleen in the induction of alloimmunity to transfused RBCs has not been addressed; these mice allow us for the first time to answer these fundamental immunologic questions during transfusion. Future work will aim to determine how dendritic cell movement within the spleen is regulated during transfusion and the specific role of splenic dendritic cell subsets in CD4+ T cell priming to allogeneic RBCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of PI3K/AKT Pathway and NADPH Oxidase 4 in Host ROS Manipulation by Toxoplasma gondii

2020 ◽  
Vol 58 (3) ◽  
pp. 237-247
Author(s):  
Hei Gwon Choi ◽  
Fei-Fei Gao ◽  
Wei Zhou ◽  
Pu-Reum Sun ◽  
Jae-Min Yuk ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Nadph Oxidase ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Innate Immune ◽  
Akt Pathway ◽  
Akt Signaling Pathway ◽  
Nadph Oxidase 4 ◽  
Pathway Activation

Dendritic cell is one of the first innate immune cell to encounter T. gondii after the parasite crosses the host intestinal epithelium. T. gondii requires intact DC as a carrier to infiltrate into host central nervous system (CNS) without being detected or eliminated by host defense system. The mechanism by which T. gondii avoids innate immune defense of host cell, especially in the dendritic cell is unknown. Therefore, we examined the role of host PI3K/AKT signaling pathway activation by T. gondii in dendritic cell. T. gondii infection or T. gondii excretory/secretory antigen (TgESA) treatment to the murine dendritic cell line DC2.4 induced AKT phosphorylation, and treatment of PI3K inhibitors effectively suppressed the T. gondii proliferation but had no effect on infection rate or invasion rate. Furthermore, it is found that T. gondii or TgESA can reduce H2O2-induced intracellular reactive oxygen species (ROS) as well as host endogenous ROS via PI3K/AKT pathway activation. While searching for the main source of the ROS, we found that NADPH oxidase 4 (NOX4) expression was controlled by T. gondii infection or TgESA treatment, which is in correlation with previous observation of the ROS reduction by identical treatments. These findings suggest that the manipulation of the host PI3K/AKT signaling pathway and NOX4 expression is an essential mechanism for the down-regulation of ROS, and therefore, for the survival and the proliferation of T. gondii.

scholarly journals Evidence of Pathogen-Induced Immunogenetic Selection across the Large Geographic Range of a Wild Seabird

2020 ◽  
Vol 37 (6) ◽  
pp. 1708-1726
Author(s):  
Hila Levy ◽  
Steven R Fiddaman ◽  
Juliana A Vianna ◽  
Daly Noll ◽  
Gemma V Clucas ◽  
...  
Keyword(s):  
Geographic Range ◽  
Gentoo Penguin ◽  
Innate Immune ◽  
Evolutionary Time ◽  
Immune Genes ◽  
Changing Environments ◽  
Pathogen Challenge ◽  
Innate Immune Genes ◽  
Latitudinal Range

Abstract Over evolutionary time, pathogen challenge shapes the immune phenotype of the host to better respond to an incipient threat. The extent and direction of this selection pressure depend on the local pathogen composition, which is in turn determined by biotic and abiotic features of the environment. However, little is known about adaptation to local pathogen threats in wild animals. The Gentoo penguin (Pygoscelis papua) is a species complex that lends itself to the study of immune adaptation because of its circumpolar distribution over a large latitudinal range, with little or no admixture between different clades. In this study, we examine the diversity in a key family of innate immune genes—the Toll-like receptors (TLRs)—across the range of the Gentoo penguin. The three TLRs that we investigated present varying levels of diversity, with TLR4 and TLR5 greatly exceeding the diversity of TLR7. We present evidence of positive selection in TLR4 and TLR5, which points to pathogen-driven adaptation to the local pathogen milieu. Finally, we demonstrate that two positively selected cosegregating sites in TLR5 are sufficient to alter the responsiveness of the receptor to its bacterial ligand, flagellin. Taken together, these results suggest that Gentoo penguins have experienced distinct pathogen-driven selection pressures in different environments, which may be important given the role of the Gentoo penguin as a sentinel species in some of the world’s most rapidly changing environments.

The Role of Sense of Direction and Other Factors During Navigation in a Large-Scale, Unconstrained Environment

2013 ◽  
Author(s):  
Elisabeth J. Ploran ◽  
Ericka Rovira ◽  
James C. Thompson ◽  
Raja Parasuraman
Keyword(s):  
Large Scale ◽  
Sense Of Direction

Role of Innate Immune Sensors, TLRs, and NALP3 in Rheumatoid Arthritis and Osteoarthritis

2014 ◽  
Vol 24 (4) ◽  
pp. 243-251 ◽  
Author(s):  
Yuya Takakubo ◽  
G. Barreto ◽  
Yrjo T. Konttinen ◽  
H. Oki ◽  
Michiaki Takagi
Keyword(s):  
Rheumatoid Arthritis ◽  
Innate Immune

Magnetic Properties of xCeO2•(50 − x) PbO•50B2O3 Glasses and Glass Ceramics

2017 ◽  
Vol 13 (1) ◽  
pp. 4486-4494 ◽  
Author(s):  
G.El Damrawi ◽  
F. Gharghar
Keyword(s):  
Magnetic Properties ◽  
Large Scale ◽  
Glass Ceramics ◽  
Magnetic Behavior ◽  
Crystal Formation ◽  
Dual Roles ◽  
Effective Agent ◽  
Ordered Structures ◽  
Essential Change

Cerium oxide in borate glasses of composition xCeO2·(50 − x)PbO·50B2O3 plays an important role in changing both microstructure and magnetic behaviors of the system. The structural role of CeO2 as an effective agent for cluster and crystal formation in borate network is clearly evidenced by XRD technique. Both structure and size of well-formed cerium separated clusters have an effective influence on the structural properties. The cluster aggregations are documented to be found in different range ordered structures, intermediate and long range orders are the most structures in which cerium phases are involved. The nano-sized crystallized cerium species in lead borate phase are evidenced to have magnetic behavior.  The criteria of building new specific borate phase enriched with cerium as ferrimagnetism has been found to keep the magnetization in large scale even at extremely high temperature. Treating the glass thermally or exposing it to an effective dose of ionized radiation is evidenced to have an essential change in magnetic properties. Thermal heat treatment for some of investigated materials is observed to play dual roles in the glass matrix. It can not only enhance alignment processes of the magnetic moment but also increases the capacity of the crystallite species in the magnetic phases. On the other hand, reverse processes are remarked under the effect of irradiation. The magnetization was found to be lowered, since several types of the trap centers which are regarded as defective states can be produced by effect of ionized radiation. 

The Impact of Quantitative Easing on Emerging Markets – Literature Review

e-Finanse ◽  
2018 ◽  
Vol 14 (4) ◽  
pp. 67-76
Author(s):  
Piotr Bartkiewicz
Keyword(s):  
Emerging Markets ◽  
Large Scale ◽  
Empirical Literature ◽  
Quantitative Easing ◽  
Methodological Choices ◽  
The Subject ◽  
Methodological Approaches ◽  
The Impact ◽  
Sufficient Precision

AbstractThe article presents the results of the review of the empirical literature regarding the impact of quantitative easing (QE) on emerging markets (EMs). The subject is of interest to policymakers and researchers due to the increasingly larger role of EMs in the world economy and the large-scale capital flows occurring after 2009. The review is conducted in a systematic manner and takes into consideration different methodological choices, samples and measurement issues. The paper puts the summarized results in the context of transmission channels identified in the literature. There are few distinct methodological approaches present in the literature. While there is a consensus regarding the direction of the impact of QE on EMs, its size and durability have not yet been assessed with sufficient precision. In addition, there are clear gaps in the empirical findings, not least related to relative underrepresentation of the CEE region (in particular, Poland).

Age Advantages of Emotional Experience during the COVID-19 Pandemic are Robust, but Diminished Compared to Pre-pandemic Conditions

2020 ◽  
Author(s):  
Rui Sun ◽  
Disa Sauter
Keyword(s):  
Older Adults ◽  
Large Scale ◽  
Negative Emotion ◽  
Emotional Experience ◽  
Negative Emotions ◽  
Older Individuals ◽  
Selection Strategies ◽  
Scale Test ◽  
Prolonged Stress

Getting old is generally seen as unappealing, yet aging confers considerable advantages in several psychological domains (North & Fiske, 2015). In particular, older adults are better off emotionally than younger adults, with aging associated with the so-called “age advantages,” that is, more positive and less negative emotional experiences (Carstensen et al., 2011). Although the age advantages are well established, it is less clear whether they occur under conditions of prolonged stress. In a recent study, Carstensen et al (2020) demonstrated that the age advantages persist during the COVID-19 pandemic, suggesting that older adults are able to utilise cognitive and behavioural strategies to ameliorate even sustained stress. Here, we build on Carstensen and colleagues’ work with two studies. In Study 1, we provide a large-scale test of the robustness of Carstensen and colleagues’ finding that older individuals experience more positive and less negative emotions during the COVID-19 pandemic. We measured positive and negative emotions along with age information in 23,629 participants in 63 countries in April-May 2020. In Study 2, we provide a comparison of the age advantages using representative samples collected before and during the COVID-19 pandemic. We demonstrate that older people experience less negative emotion than younger people during the prolonged stress of the COVID-19 pandemic. However, the advantage of older adults was diminished during the pandemic, pointing to a likely role of older adults use of situation selection strategies (Charles, 2010).

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