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Central EP3 (E Prostanoid 3) Receptors Mediate Salt-Sensitive Hypertension and Immune Activation.
Xiao L, Itani HA, do Carmo LS, Carver LS, Breyer RM, Harrison DG
(2019) Hypertension 74: 1507-1515
MeSH Terms: Adaptive Immunity, Analysis of Variance, Animals, Biomarkers, Biopsy, Needle, Brain, Dinoprostone, Disease Models, Animal, Female, Flow Cytometry, Hypertension, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, NG-Nitroarginine Methyl Ester, Random Allocation, Real-Time Polymerase Chain Reaction, Receptors, Prostaglandin E, EP3 Subtype, Sodium, Dietary
Show Abstract · Added December 3, 2019
We recently identified a pathway underlying immune activation in hypertension. Proteins oxidatively modified by reactive isoLG (isolevuglandin) accumulate in dendritic cells (DCs). PGE (Prostaglandin E2) has been implicated in the inflammation associated with hypertension. We hypothesized that PGE via its EP (E prostanoid) 3 receptor contributes to DC activation in hypertension. EP3 mice and wild-type littermates were exposed to sequential hypertensive stimuli involving an initial 2-week exposure to the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester hydrochloride in drinking water, followed by a 2-week washout period, and a subsequent 4% high-salt diet for 3 weeks. In wild-type mice, this protocol increased systolic pressure from 123±2 to 148±8 mm Hg (<0.05). This was associated with marked renal inflammation and a striking accumulation of isoLG adducts in splenic DCs. However, the increases in blood pressure, renal T-cell infiltration, and DC isoLG formation were completely prevented in EP3 mice. Similar protective effects were also observed in wild-type mice that received intracerebroventricular injection of a lentiviral vector encoding shRNA targeting the EP3 receptor. Further, in vitro experiments indicated that PGE also acts directly on DCs via its EP1 receptors to stimulate intracellular isoLG formation. Together, these findings provide new insight into how EP receptors in both the central nervous system and peripherally on DCs promote inflammation in salt-induced hypertension.
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20 MeSH Terms
Human Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis.
Bennett MR, Dong J, Bombardi RG, Soto C, Parrington HM, Nargi RS, Schoeder CT, Nagel MB, Schey KL, Meiler J, Skaar EP, Crowe JE
(2019) mBio 10:
MeSH Terms: Adaptive Immunity, Antibodies, Monoclonal, Crystallography, X-Ray, Humans, Immunity, Humoral, Proteomics, Staphylococcus aureus
Show Abstract · Added March 21, 2020
is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of -encoded mAbs blocks heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of -encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against infection. The human pathogen causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region gene-encoded human monoclonal antibodies with the response against IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB.
Copyright © 2019 Bennett et al.
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7 MeSH Terms
Late immune consequences of combat trauma: a review of trauma-related immune dysfunction and potential therapies.
Thompson KB, Krispinsky LT, Stark RJ
(2019) Mil Med Res 6: 11
MeSH Terms: Adaptive Immunity, Humans, Immunity, Innate, Immunomodulation, Military Personnel, Multiple Organ Failure, Systemic Inflammatory Response Syndrome, Wound Healing, Wounds and Injuries
Show Abstract · Added April 25, 2019
With improvements in personnel and vehicular body armor, robust casualty evacuation capabilities, and damage control resuscitation strategies, more combat casualties are surviving to reach higher levels of care throughout the casualty evacuation system. As such, medical centers are becoming more accustomed to managing the deleterious late consequences of combat trauma related to the dysregulation of the immune system. In this review, we aim to highlight these late consequences and identify areas for future research and therapeutic strategies. Trauma leads to the dysregulation of both the innate and adaptive immune responses, which places the injured at risk for several late consequences, including delayed wound healing, late onset sepsis and infection, multi-organ dysfunction syndrome, and acute respiratory distress syndrome, which are significant for their association with the increased morbidity and mortality of wounded personnel. The mechanisms by which these consequences develop are complex but include an imbalance of the immune system leading to robust inflammatory responses, triggered by the presence of damage-associated molecules and other immune-modifying agents following trauma. Treatment strategies to improve outcomes have been difficult to develop as the immunophenotype of injured personnel following trauma is variable, fluid and difficult to determine. As more information regarding the triggers that lead to immune dysfunction following trauma is elucidated, it may be possible to identify the immunophenotype of injured personnel and provide targeted treatments to reduce the late consequences of trauma, which are known to lead to significant morbidity and mortality.
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9 MeSH Terms
The Innate Immune Protein S100A9 Protects from T-Helper Cell Type 2-mediated Allergic Airway Inflammation.
Palmer LD, Maloney KN, Boyd KL, Goleniewska AK, Toki S, Maxwell CN, Chazin WJ, Peebles RS, Newcomb DC, Skaar EP
(2019) Am J Respir Cell Mol Biol 61: 459-468
MeSH Terms: Adaptive Immunity, Allergens, Alternaria, Alveolitis, Extrinsic Allergic, Animals, Bronchial Hyperreactivity, Bronchoalveolar Lavage Fluid, Calgranulin A, Calgranulin B, Cytokines, Forkhead Transcription Factors, Immunoglobulin E, Inflammation, Leukocyte L1 Antigen Complex, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pulmonary Eosinophilia, Specific Pathogen-Free Organisms, T-Lymphocytes, Regulatory, Th2 Cells
Show Abstract · Added April 7, 2019
Calprotectin is a heterodimer of the proteins S100A8 and S100A9, and it is an abundant innate immune protein associated with inflammation. In humans, calprotectin transcription and protein abundance are associated with asthma and disease severity. However, mechanistic studies in experimental asthma models have been inconclusive, identifying both protective and pathogenic effects of calprotectin. To clarify the role of calprotectin in asthma, calprotectin-deficient and wild-type (WT) C57BL/6 mice were compared in a murine model of allergic airway inflammation. Mice were intranasally challenged with extracts of the clinically relevant allergen, (Alt Ext), or PBS every third day over 9 days. On Day 10, BAL fluid and lung tissue homogenates were harvested and allergic airway inflammation was assessed. Alt Ext challenge induced release of S100A8/S100A9 to the alveolar space and increased protein expression in the alveolar epithelium of WT mice. Compared with WT mice, mice displayed significantly enhanced allergic airway inflammation, including production of IL-13, CCL11, CCL24, serum IgE, eosinophil recruitment, and airway resistance and elastance. In response to Alt Ext, mice accumulated significantly more IL-13IL-5CD4 T-helper type 2 cells. mice also accumulated a significantly lower proportion of CD4 T regulatory (Treg) cells in the lung that had significantly lower expression of CD25. Calprotectin enhanced WT Treg cell suppressive activity . Therefore, this study identifies a role for the innate immune protein, S100A9, in protection from CD4 T-helper type 2 cell hyperinflammation in response to Alt Ext. This protection is mediated, at least in part, by CD4 Treg cell function.
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23 MeSH Terms
Extrinsic and Intrinsic Immunometabolism Converge: Perspectives on Future Research and Therapeutic Development for Obesity.
Caslin HL, Hasty AH
(2019) Curr Obes Rep 8: 210-219
MeSH Terms: Adaptive Immunity, Adipose Tissue, Animals, Energy Metabolism, Epigenesis, Genetic, Humans, Immunity, Immunologic Memory, Iron, Macrophages, Metabolic Diseases, Metabolic Networks and Pathways, MicroRNAs, Obesity
Show Abstract · Added March 3, 2020
PURPOSE OF REVIEW - Research over the past decade has shown that immunologic and metabolic pathways are intricately linked. This burgeoning field of immunometabolism includes intrinsic and extrinsic pathways and is known to be associated with obesity-accelerated metabolic disease. Intrinsic immunometabolism includes the study of fuel utilization and bioenergetic pathways that influence immune cell function. Extrinsic immunometabolism includes the study of immune cells and products that influence systemic metabolism.
RECENT FINDINGS - Th2 immunity, macrophage iron handling, adaptive immune memory, and epigenetic regulation of immunity, which all require intrinsic metabolic changes, play a role in systemic metabolism and metabolic function, linking the two arms of immunometabolism. Together, this suggests that targeting intrinsic immunometabolism can directly affect immune function and ultimately systemic metabolism. We highlight important questions for future basic research that will help improve translational research and provide therapeutic targets to help establish new treatments for obesity and associated metabolic disorders.
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Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE.
Van Kaer L, Postoak JL, Wang C, Yang G, Wu L
(2019) Cell Mol Immunol 16: 531-539
MeSH Terms: Adaptive Immunity, Animals, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Humans, Immunity, Innate, Multiple Sclerosis, T-Lymphocytes
Show Abstract · Added March 26, 2019
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons. A hallmark of MS and its animal model, experimental autoimmune encephalomyelitis (EAE), is autoimmunity against proteins of the myelin sheath. Most studies in this field have focused on the roles of CD4 T lymphocytes, which form part of the adaptive immune system as both mediators and regulators in disease pathogenesis. Consequently, the treatments for MS often target the inflammatory CD4 T-cell responses. However, many other lymphocyte subsets contribute to the pathophysiology of MS and EAE, and these subsets include CD8 T cells and B cells of the adaptive immune system, lymphocytes of the innate immune system such as natural killer cells, and subsets of innate-like T and B lymphocytes such as γδ T cells, natural killer T cells, and mucosal-associated invariant T cells. Several of these lymphocyte subsets can act as mediators of CNS inflammation, whereas others exhibit immunoregulatory functions in disease. Importantly, the efficacy of some MS treatments might be mediated in part by effects on lymphocytes other than CD4 T cells. Here we review the contributions of distinct subsets of lymphocytes on the pathogenesis of MS and EAE, with an emphasis on lymphocytes other than CD4 T cells. A better understanding of the distinct lymphocyte subsets that contribute to the pathophysiology of MS and its experimental models will inform the development of novel therapeutic approaches.
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8 MeSH Terms
Innate and adaptive immunity in necrotizing enterocolitis.
Mara MA, Good M, Weitkamp JH
(2018) Semin Fetal Neonatal Med 23: 394-399
MeSH Terms: Adaptive Immunity, Enterocolitis, Necrotizing, Humans, Immunity, Innate, Infant, Newborn, Infant, Premature, Intestinal Mucosa, Toll-Like Receptors
Show Abstract · Added April 16, 2021
Necrotizing enterocolitis (NEC) is the most frequent and devastating gastrointestinal disease of premature infants. Although the precise mechanisms are not fully understood, NEC is thought to develop following a combination of prematurity, formula feeding, and adverse microbial colonization. Within the last decade, studies increasingly support an important role of a heightened mucosal immune response initiating a pro-inflammatory signaling cascade, which can lead to the disruption of the intestinal epithelium and translocation of pathogenic species. In this review, we first describe the cellular composition of the intestinal epithelium and its critical role in maintaining epithelial integrity. We then discuss cell signaling during NEC, specifically, toll-like receptors and nucleotide oligomerization domain-like receptors. We further review cytokines and cellular components that characterize the innate and adaptive immune systems and how they interact to support or modulate NEC development.
© 2018 Published by Elsevier Ltd.
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Immunity drives regulation in cancer through NF-κB.
Collignon E, Canale A, Al Wardi C, Bizet M, Calonne E, Dedeurwaerder S, Garaud S, Naveaux C, Barham W, Wilson A, Bouchat S, Hubert P, Van Lint C, Yull F, Sotiriou C, Willard-Gallo K, Noel A, Fuks F
(2018) Sci Adv 4: eaap7309
MeSH Terms: Adaptive Immunity, Biomarkers, DNA Methylation, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunity, Immunity, Innate, Mixed Function Oxygenases, NF-kappa B, Neoplasms, Neoplasms, Basal Cell, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins
Show Abstract · Added March 31, 2020
Ten-eleven translocation enzymes (TET1, TET2, and TET3), which induce DNA demethylation and gene regulation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are often down-regulated in cancer. We uncover, in basal-like breast cancer (BLBC), genome-wide 5hmC changes related to regulation. We further demonstrate that repression is associated with high expression of immune markers and high infiltration by immune cells. We identify in BLBC tissues an anticorrelation between expression and the major immunoregulator family nuclear factor κB (NF-κB). In vitro and in mice, is down-regulated in breast cancer cells upon NF-κB activation through binding of p65 to its consensus sequence in the promoter. We lastly show that these findings extend to other cancer types, including melanoma, lung, and thyroid cancers. Together, our data suggest a novel mode of regulation for in cancer and highlight a new paradigm in which the immune system can influence cancer cell epigenetics.
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Links between Immunologic Memory and Metabolic Cycling.
Cottam MA, Itani HA, Beasley AA, Hasty AH
(2018) J Immunol 200: 3681-3689
MeSH Terms: Adaptive Immunity, Animals, Body Weight, Humans, Hypertension, Immunity, Innate, Immunologic Memory, Metabolic Diseases
Show Abstract · Added March 26, 2019
Treatments for metabolic diseases, such as diet and therapeutics, often provide short-term therapy for metabolic stressors, but relapse is common. Repeated bouts of exposure to, and relief from, metabolic stimuli results in a phenomenon we call "metabolic cycling." Recent human and rodent data suggest metabolic cycling promotes an exaggerated response and ultimately worsened metabolic health. This is particularly evident with cycling of body weight and hypertension. The innate and adaptive immune systems have a profound impact on development of metabolic disease, and current data suggest that immunologic memory may partially explain this association, especially in the context of metabolic cycling. In this Brief Review, we highlight recent work in this field and discuss potential immunologic mechanisms for worsened disease prognosis in individuals who experience metabolic cycling.
Copyright © 2018 by The American Association of Immunologists, Inc.
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Why are preterm newborns at increased risk of infection?
Collins A, Weitkamp JH, Wynn JL
(2018) Arch Dis Child Fetal Neonatal Ed 103: F391-F394
MeSH Terms: Adaptive Immunity, B-Lymphocytes, Humans, Immunity, Cellular, Immunity, Innate, Immunoglobulins, Infant, Premature, Infant, Premature, Diseases, Infections, Sepsis
Show Abstract · Added April 16, 2021
One in 10 newborns will be born before completion of 36 weeks' gestation (premature birth). Infection and sepsis in preterm infants remain a significant clinical problem that represents a substantial financial burden on the healthcare system. Many factors predispose premature infants for having the greatest risk of developing and succumbing to infection as compared with all other age groups across the age spectrum. It is clear that the immune system of preterm infants exhibits distinct, rather than simply deficient, function as compared with more mature and older humans and that the immune function in preterm infants contributes to infection risk. While no single review can cover all aspects of immune function in this population, we will discuss key aspects of preterm neonatal innate and adaptive immune function that place them at high risk for developing infections and sepsis, as well as sepsis-associated morbidity and mortality.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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