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Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway.
Gobert AP, Latour YL, Asim M, Finley JL, Verriere TG, Barry DP, Milne GL, Luis PB, Schneider C, Rivera ES, Lindsey-Rose K, Schey KL, Delgado AG, Sierra JC, Piazuelo MB, Wilson KT
(2019) mBio 10:
MeSH Terms: Animals, Bacteria, Gene Silencing, Helicobacter pylori, Histones, Humans, Immune Evasion, Immunity, Innate, Immunoglobulins, Macrophages, Male, Metabolic Networks and Pathways, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type II, Phosphatidylinositol 3-Kinases, Polyamines, RAW 264.7 Cells, Spermidine, Spermine, Sulfur, Transcription Factors
Show Abstract · Added November 1, 2019
The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of -adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape. Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.
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22 MeSH Terms
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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Drug-specific upregulation of CD137 on CD8+ T cells aids in the diagnosis of multiple antibiotic toxic epidermal necrolysis.
Trubiano JA, Redwood A, Strautins K, Pavlos R, Woolnough E, Chang CC, Phillips E
(2017) J Allergy Clin Immunol Pract 5: 823-826
MeSH Terms: Adult, Allergens, Anti-Bacterial Agents, CD8-Positive T-Lymphocytes, Cells, Cultured, Drug Substitution, Humans, Immunoglobulins, Intravenous, Male, Steroids, Stevens-Johnson Syndrome, Tumor Necrosis Factor Receptor Superfamily, Member 9, Up-Regulation, Vesicular Transport Proteins, Young Adult
Added March 30, 2020
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Transcriptional Control of Synaptic Remodeling through Regulated Expression of an Immunoglobulin Superfamily Protein.
He S, Philbrook A, McWhirter R, Gabel CV, Taub DG, Carter MH, Hanna IM, Francis MM, Miller DM
(2015) Curr Biol 25: 2541-8
MeSH Terms: Acetylcholine, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, GABAergic Neurons, Gene Expression Regulation, Immunoglobulins, Motor Neurons, Nerve Tissue Proteins, Receptors, Cholinergic, Synapses, Transcription Factors
Show Abstract · Added March 26, 2019
Neural circuits are actively remodeled during brain development, but the molecular mechanisms that trigger circuit refinement are poorly understood. Here, we describe a transcriptional program in C. elegans that regulates expression of an Ig domain protein, OIG-1, to control the timing of synaptic remodeling. DD GABAergic neurons reverse polarity during larval development by exchanging the locations of pre- and postsynaptic components. In newly born larvae, DDs receive cholinergic inputs in the dorsal nerve cord. These inputs are switched to the ventral side by the end of the first larval (L1) stage. VD class GABAergic neurons are generated in the late L1 and are postsynaptic to cholinergic neurons in the dorsal nerve cord but do not remodel. We investigated remodeling of the postsynaptic apparatus in DD and VD neurons using targeted expression of the acetylcholine receptor (AChR) subunit, ACR-12::GFP. We determined that OIG-1 antagonizes the relocation of ACR-12 from the dorsal side in L1 DD neurons. During the L1/L2 transition, OIG-1 is downregulated in DD neurons by the transcription factor IRX-1/Iroquois, allowing the repositioning of synaptic inputs to the ventral side. In VD class neurons, which normally do not remodel, the transcription factor UNC-55/COUP-TF turns off IRX-1, thus maintaining high levels of OIG-1 to block the removal of dorsally located ACR-12 receptors. OIG-1 is secreted from GABA neurons, but its anti-plasticity function is cell autonomous and may not require secretion. Our study provides a novel mechanism by which synaptic remodeling is set in motion through regulated expression of an Ig domain protein.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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The Ancient Immunoglobulin Domains of Peroxidasin Are Required to Form Sulfilimine Cross-links in Collagen IV.
Ero-Tolliver IA, Hudson BG, Bhave G
(2015) J Biol Chem 290: 21741-8
MeSH Terms: Collagen Type IV, Cross-Linking Reagents, Evolution, Molecular, Extracellular Matrix, Extracellular Matrix Proteins, HEK293 Cells, Heme, Humans, Imines, Immunoglobulins, Models, Biological, Peroxidase, Peroxidases, Protein Binding, Protein Structure, Tertiary
Show Abstract · Added August 12, 2015
The collagen IV sulfilimine cross-link and its catalyzing enzyme, peroxidasin, represent a dyad critical for tissue development, which is conserved throughout the animal kingdom. Peroxidasin forms novel sulfilimine bonds between opposing methionine and hydroxylysine residues to structurally reinforce the collagen IV scaffold, a function critical for basement membrane and tissue integrity. However, the molecular mechanism underlying cross-link formation remains unclear. In this work, we demonstrate that the catalytic domain of peroxidasin and its immunoglobulin (Ig) domains are required for efficient sulfilimine bond formation. Thus, these molecular features underlie the evolutionarily conserved function of peroxidasin in tissue development and integrity and distinguish peroxidasin from other peroxidases, such as myeloperoxidase (MPO) and eosinophil peroxidase (EPO).
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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15 MeSH Terms
Inflammatory cytokine TSLP stimulates platelet secretion and potentiates platelet aggregation via a TSLPR-dependent PI3K/Akt signaling pathway.
Dong J, Dong J, Lin J, Wang B, He S, Wu C, Kushwaha KK, Mohabeer N, Su Y, Fang H, Huang K, Li D
(2015) Cell Physiol Biochem 35: 160-74
MeSH Terms: Androstadienes, Animals, Blood Platelets, Carotid Artery Thrombosis, Chlorides, Chromones, Cytokines, Disease Models, Animal, Ferric Compounds, Humans, Immunoglobulins, Mice, Mice, Inbred C57BL, Mice, Knockout, Morpholines, P-Selectin, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Platelet Activation, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex, Proto-Oncogene Proteins c-akt, Receptors, Cytokine, Signal Transduction, Wortmannin
Show Abstract · Added January 20, 2015
AIMS - Thymic stromal lymphopoietin (TSLP) plays an important role in inflammatory diseases and is over-expressed in human atherosclerotic artery specimens. The present study investigated the role of TSLP in platelet activation and thrombosis models in vitro and in vivo, as well as the underlying mechanism and signaling pathway.
METHODS AND RESULTS - Western blotting and flow cytometry demonstrated that the TSLP receptor was expressed on murine platelets. According to flow cytometry, platelet stimulation with TSLP induced platelet degranulation and integrin αIIbβ3 activation. A TSLPR deficiency caused defective platelet aggregation, defective platelet secretion and markedly blunted thrombus growth in perfusion chambers at both low and high shear rates. TSLPR KO mice exhibited defective carotid artery thrombus formation after exposure to FeCl3. TSLP increased Akt phosphorylation, an effect that was abrogated by the PI3K inhibitors wortmannin and LY294002. The PI3K inhibitors further diminished TSLP-induced platelet activation. TSLP-mediated platelet degranulation, integrin αIIbβ3 activation and Akt phosphorylation were blunted in platelets that lacked the TSLP receptor.
CONCLUSION - This study demonstrated that the functional TSLPR was surface-expressed on murine platelets. The inflammatory cytokine TSLP triggered platelet activation and thrombus formation via TSLP-dependent PI3K/Akt signaling, which suggests an important role for TSLP in linking vascular inflammation and thrombo-occlusive diseases.
© 2015 S. Karger AG, Basel.
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26 MeSH Terms
Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells.
Bonami RH, Sullivan AM, Case JB, Steinberg HE, Hoek KL, Khan WN, Kendall PL
(2014) J Immunol 192: 1459-70
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, B-Lymphocytes, Cells, Cultured, Diabetes Mellitus, Type 1, Immunoglobulins, Insulin, Insulin Antibodies, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Transgenic, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell
Show Abstract · Added May 19, 2014
Autoreactive B lymphocytes are essential for the development of T cell-mediated type 1 diabetes (T1D). Cytoplasmic Bruton's tyrosine kinase (BTK) is a key component of B cell signaling, and its deletion in T1D-prone NOD mice significantly reduces diabetes. However, the role of BTK in the survival and function of autoreactive B cells is not clear. To evaluate the contributions of BTK, we used mice in which B cells express an anti-insulin BCR (125Tg) and promote T1D, despite being anergic. Crossing Btk deficiency onto 125Tg mice reveals that, in contrast to immature B cells, mature anti-insulin B cells are exquisitely dependent upon BTK, because their numbers are reduced by 95%. BTK kinase domain inhibition reproduces this effect in mature anti-insulin B cells, with less impact at transitional stages. The increased dependence of anti-insulin B cells on BTK became particularly evident in an Igκ locus site-directed model, in which 50% of B cells edit their BCRs to noninsulin specificities; Btk deficiency preferentially depletes insulin binders from the follicular and marginal zone B cell subsets. The persistent few Btk-deficient anti-insulin B cells remain competent to internalize Ag and invade pancreatic islets. As such, loss of BTK does not significantly reduce diabetes incidence in 125Tg/NOD mice as it does in NOD mice with a normal B cell repertoire. Thus, BTK targeting may not impair autoreactive anti-insulin B cell function, yet it may provide protection in an endogenous repertoire by decreasing the relative availability of mature autoreactive B cells.
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14 MeSH Terms
Diagnostic and therapeutic aspects of Hashimoto's encephalopathy.
Olmez I, Moses H, Sriram S, Kirshner H, Lagrange AH, Pawate S
(2013) J Neurol Sci 331: 67-71
MeSH Terms: Adult, Aged, Autoantibodies, Azathioprine, Brain Diseases, Child, Child, Preschool, Electroencephalography, Encephalitis, Enzyme Inhibitors, Female, Hashimoto Disease, Humans, Immunoglobulins, Intravenous, Male, Methotrexate, Middle Aged, Retrospective Studies, Steroids
Show Abstract · Added August 14, 2014
OBJECTIVE - To share our experience on clinical presentation and management of patients diagnosed with Hashimoto's Encephalopathy (HE) at Vanderbilt Medical Center between 1999 and 2012.
BACKGROUND - HE is a rare disorder characterized by encephalopathy and central nervous system (CNS) dysfunction, elevated antithyroid antibodies, the absence of infection or structural abnormalities in the CNS, and a response to treatment with steroids. The relationship between thyroid antibodies and encephalopathy has remained unresolved.
DESIGN/METHODS - Retrospective chart review.
RESULTS - We identified 13 patients who met the criteria for the diagnosis of HE. The median age was 49 years (range, 2-66) and all except one were women. Encephalopathy in the form of altered mental status, stroke-like symptoms or seizures, with prompt resolution of symptoms upon receiving steroids, was the commonest presentation, seen in 7 patients. The second commonest presentation was subacute progressive decrease in cognitive function, which reversed within days to weeks after steroid therapy, seen in 4 patients. Electroencephalogram (EEG) was available in 12 patients and was abnormal in 8, showing nonspecific cerebral dysfunction in all 8 and epileptiform activity in 3. Treatment consisted of steroids in the acute phase for 12 of 13 patients with rapid improvement in symptoms. Maintenance therapy was rituximab in 7 patients, intravenous immunoglobulin (IVIg) in 7, azathioprine in 4, mycophenolate mofetil in 3, and methotrexate in 1 (some patients received sequential therapy with different agents). There was complete or near complete resolution of symptoms in 12 of the 13 patients.
CONCLUSIONS - We present a cohort of patients in whom CNS dysfunction was associated with elevated antithyroid antibodies and reversal of disease followed immunomodulatory therapies.
Copyright © 2013 Elsevier B.V. All rights reserved.
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19 MeSH Terms
Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies.
Borte M, Bernatowska E, Ochs HD, Roifman CM, Vivaglobin Study Group
(2011) Clin Exp Immunol 164: 357-64
MeSH Terms: Brazil, Child, Child, Preschool, Disease-Free Survival, Europe, Female, Follow-Up Studies, Home Infusion Therapy, Humans, Immunoglobulins, Immunologic Deficiency Syndromes, Infections, Injections, Subcutaneous, Male, North America
Show Abstract · Added January 20, 2015
Subcutaneous immunoglobulin infusions are effective, safe and well tolerated in the treatment of primary immunodeficiencies, but only limited data on the treatment of children are available. We investigated the efficacy, safety and pharmacokinetics of home therapy with a 16% liquid human immunoglobulin G preparation (Vivaglobin®) when administered subcutaneously in children with primary immunodeficiencies. Data were analysed from 22 children (2-<12 years) who participated in two prospective, open-label studies (one in Europe/Brazil, one in North America). All children had previously received intravenous immunoglobulins. They started weekly subcutaneous immunoglobulin infusions with an approximately 3-month wash-in/wash-out period, followed by a 6-month (Europe/Brazil) or 12-month (North America) efficacy evaluation period. In Europe/Brazil, subcutaneous doses generally equalled the previous weekly equivalent intravenous doses. In North America, subcutaneous doses during the efficacy evaluation period were 126% (median) of the previous weekly equivalent intravenous doses. Efficacy end-points in both studies included the occurrence of serious bacterial infections and any infections, and serum immunoglobulin G trough levels. Median serum immunoglobulin G trough levels exceeded those during previous intravenous therapy by 13% (North America) and 16% (Europe/Brazil). During the efficacy evaluation period of both studies, none of the children had a serious bacterial infection; the mean overall infection rate/patient year was 4·7 in Europe/Brazil and 5·6 in North America, concurring with previous reports in adults. The adverse event profile was comparable to previous reports in adults. Both studies confirmed the efficacy and safety of subcutaneous immunoglobulin therapy with Vivaglobin in children with primary immunodeficiencies.
© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.
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15 MeSH Terms
Immunotherapy with a combination of intravenous immune globulin and p4 peptide rescues mice from postinfluenza pneumococcal pneumonia.
Weeks JN, Boyd KL, Rajam G, Ades EW, McCullers JA
(2011) Antimicrob Agents Chemother 55: 2276-81
MeSH Terms: Animals, Female, Immunoglobulins, Intravenous, Immunotherapy, Mice, Mice, Inbred BALB C, Pneumonia, Pneumococcal, Streptococcus pneumoniae
Show Abstract · Added March 20, 2014
Alternate therapies are needed for treatment of secondary bacterial pneumonia following influenza. The immunomodulatory peptide P4 has shown promise in mouse models of primary pneumococcal infection. Mice infected with influenza virus and then challenged with Streptococcus pneumoniae were treated with a combination of P4 peptide and intravenous immune globulin. Survival was improved from 20% to 80% in treated mice relative to controls. Clinical cure correlated with increased clearance of bacteria and decreased lung consolidation. Greater trafficking of professional phagocytic cells to the site of pneumococcal infection coupled with enhanced opsonophagocytosis as manifest by decreased surface display of Fcγ receptors (FcγR) on neutrophils and macrophages were associated with P4 peptide treatment. This suggests that the mechanism of action for improved clearance of bacteria engendered by P4 is through improved uptake by phagocytes mediated by IgG Fc-Fcγ receptor interactions following antibody-mediated opsonophagocytosis of bacteria. Antibody-based therapies, when coupled with immune modulators, such as P4 peptide, may be an effective tool together with antibiotics in our armamentarium against severe pneumonia.
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8 MeSH Terms