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Dengue viruses are enhanced by distinct populations of serotype cross-reactive antibodies in human immune sera.
de Alwis R, Williams KL, Schmid MA, Lai CY, Patel B, Smith SA, Crowe JE, Wang WK, Harris E, de Silva AM
(2014) PLoS Pathog 10: e1004386
MeSH Terms: Animals, Antibodies, Neutralizing, Antibodies, Viral, Antibody-Dependent Enhancement, Cross Reactions, Dengue Virus, Epitopes, Humans, Immune Sera, Mice, Neutralization Tests
Show Abstract · Added February 2, 2015
Dengue viruses (DENV) are mosquito-borne flaviviruses of global importance. DENV exist as four serotypes, DENV1-DENV4. Following a primary infection, individuals produce DENV-specific antibodies that bind only to the serotype of infection and other antibodies that cross-react with two or more serotypes. People exposed to a secondary DENV infection with another serotype are at greater risk of developing more severe forms of dengue disease. The increased risk of severe dengue in people experiencing repeat DENV infections appear to be due, at least in part, to the ability of pre-existing serotype cross-reactive antibodies to form virus-antibody complexes that can productively infect Fcγ receptor-bearing target cells. While the theory of antibody-dependent enhancement (ADE) is supported by several human and small animal model studies, the specific viral antigens and epitopes recognized by enhancing human antibodies after natural infections have not been fully defined. We used antibody-depletion techniques to remove DENV-specific antibody sub-populations from primary DENV-immune human sera. The effects of removing specific antibody populations on ADE were tested both in vitro using K562 cells and in vivo using the AG129 mouse model. Removal of serotype cross-reactive antibodies ablated enhancement of heterotypic virus infection in vitro and antibody-enhanced mortality in vivo. Further depletion studies using recombinant viral antigens showed that although the removal of DENV E-specific antibodies using recombinant E (rE) protein resulted in a partial reduction in DENV enhancement, there was a significant residual enhancement remaining. Competition ADE studies using prM-specific Fab fragments in human immune sera showed that both rE-specific and prM-specific antibodies in primary DENV-immune sera significantly contribute to enhancement of heterotypic DENV infection in vitro. Identification of the targets of DENV-enhancing antibodies should contribute to the development of safe, non-enhancing vaccines against dengue.
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11 MeSH Terms
Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions.
de Alwis R, Smith SA, Olivarez NP, Messer WB, Huynh JP, Wahala WM, White LJ, Diamond MS, Baric RS, Crowe JE, de Silva AM
(2012) Proc Natl Acad Sci U S A 109: 7439-44
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antibody Specificity, Chlorocebus aethiops, Dengue, Dengue Virus, Enzyme-Linked Immunosorbent Assay, Epitopes, Humans, Immune Sera, Macaca mulatta, Models, Molecular, Molecular Sequence Data, Mutation, Neutralization Tests, Protein Binding, Protein Multimerization, Recombinant Proteins, Sequence Homology, Amino Acid, Vero Cells, Viral Envelope Proteins, Virion
Show Abstract · Added August 6, 2012
Dengue is a mosquito-borne flavivirus that is spreading at an unprecedented rate and has developed into a major health and economic burden in over 50 countries. Even though infected individuals develop potent and long-lasting serotype-specific neutralizing antibodies (Abs), the epitopes engaged by human neutralizing Abs have not been identified. Here, we demonstrate that the dengue virus (DENV)-specific serum Ab response in humans consists of a large fraction of cross-reactive, poorly neutralizing Abs and a small fraction of serotype-specific, potently inhibitory Abs. Although many mouse-generated, strongly neutralizing monoclonal antibodies (mAbs) recognize epitopes that are present on recombinant DENV envelope (E) proteins, unexpectedly, the majority of neutralizing Abs in human immune sera bound to intact virions but not to the ectodomain of purified soluble E proteins. These conclusions with polyclonal Abs were confirmed with newly generated human mAbs derived from DENV-immune individuals. Two of three strongly neutralizing human mAbs bound to E protein epitopes that were preserved on the virion but not on recombinant E (rE) protein. We propose that humans produce Abs that neutralize DENV infection by binding a complex, quaternary structure epitope that is expressed only when E proteins are assembled on a virus particle. Mapping studies indicate that this epitope has a footprint that spans adjacent E protein dimers and includes residues at the hinge between domains I and II of E protein. These results have significant implications for the DENV Ab and vaccine field.
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25 MeSH Terms
Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/Bl6 mice.
Clark JA, Flick RB, Pai LY, Szalayova I, Key S, Conley RK, Deutch AY, Hutson PH, Mezey E
(2008) Mol Psychiatry 13: 498-506
MeSH Terms: 5-Hydroxytryptophan, Amino Acid Sequence, Animals, Antibody Specificity, Dexamethasone, Enzyme Induction, Female, Frontal Lobe, Humans, Immune Sera, Mice, Mice, Inbred C57BL, Mifepristone, Molecular Sequence Data, Nerve Tissue Proteins, Ovariectomy, Peptide Fragments, Protein Isoforms, RNA, Messenger, Raphe Nuclei, Rats, Rats, Sprague-Dawley, Tryptophan Hydroxylase
Show Abstract · Added May 27, 2014
Considerable attention has focused on regulation of central tryptophan hydroxylase (TPH) activity and protein expression. At the time of these earlier studies, it was thought that there was a single central TPH isoform. However, with the recent identification of TPH2, it becomes important to distinguish between regulatory effects on the protein expression and activity of the two isoforms. We have generated a TPH2-specific polyclonal antiserum (TPH2-6361) to study regulation of TPH2 at the protein level and to examine the distribution of TPH2 expression in rodent and human brain. TPH2 immunoreactivity (IR) was detected throughout the raphe nuclei, in lateral hypothalamic nuclei and in the pineal body of rodent and human brain. In addition, a prominent TPH2-IR fiber network was found in the human median eminence. We recently reported that glucocorticoid treatment of C57/Bl6 mice for 4 days markedly decreased TPH2 messenger RNA levels in the raphe nuclei, whereas TPH1 mRNA was unaffected. The glucocorticoid-elicited inhibition of TPH2 gene expression was blocked by co-administration of the glucocorticoid receptor antagonist mifepristone (RU-486). Using TPH2-6361, we have extended these findings to show a dose-dependent decrease in raphe TPH2 protein levels in response to 4 days of treatment with dexamethasone; this effect was blocked by co-administration of mifepristone. Moreover, the glucocorticoid-elicited inhibition of TPH2 was functionally significant: serotonin synthesis was significantly reduced in the frontal cortex of glucocorticoid-treated mice, an effect that was blocked by mifepristone co-administration. This study provides further evidence for the glucocorticoid regulation of serotonin biosynthesis via inhibition of TPH2 expression, and suggest that elevated glucocorticoid levels may be relevant to the etiology of psychiatric diseases, such as depression, where hypothalamic-pituitary-adrenal axis dysregulation has been documented.
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23 MeSH Terms
IFN-gamma production is specifically regulated by IL-10 in mice made tolerant with anti-CD40 ligand antibody and intact active bone.
Yin D, Dujovny N, Ma L, Varghese A, Shen J, Bishop DK, Chong AS
(2003) J Immunol 170: 853-60
MeSH Terms: Animals, Antibodies, Monoclonal, Bone Transplantation, CD40 Ligand, Clonal Deletion, Heart Transplantation, Immune Sera, Immunosuppression, Injections, Intraperitoneal, Injections, Intravenous, Interferon-gamma, Interleukin-10, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Knockout, Skin Transplantation, Tissue Donors, Transplantation Tolerance, Transplantation, Homologous
Show Abstract · Added December 10, 2013
We have developed a strategy to induce tolerance to allografts, involving cotransplantation of allogeneic intact active bone and transient anti-CD40 ligand mAb therapy. Tolerance induced by this approach in C57BL/6 mice receiving BALB/c hearts is not mediated by deletional mechanisms, but by peripheral regulatory mechanisms. Tolerance is associated with diminished ex vivo IFN-gamma production that is donor specific, and a reduction in the frequency of IFN-gamma-producing cells. Splenocytes from mice tolerant to BALB/c grafts, but sensitized to third-party C3H skin grafts, demonstrated normally primed ex vivo IFN-gamma responses to C3H stimulators. Neutralizing anti-IL-10 and anti-IL-10R, but not anti-TGF-beta, anti-IL-4, or anti-CTLA-4, Abs restored the ex vivo IFN-gamma response to BALB/c stimulators. There was no significant difference in IL-2 or IL-4 production between tolerant and rejecting mice, and anti-IL-10 mAbs had no effect on IL-2 or IL-4 production. The Cincinnati cytokine capture assay was used to test whether suppression of IFN-gamma production in vivo was also a marker of tolerance. In naive mice, we observed a dramatic increase in serum IFN-gamma levels following challenge with allogeneic BALB/c splenocytes or hearts. Tolerant mice challenged with allogeneic BALB/c splenocytes or hearts made significantly less or undetectable amounts of IFN-gamma. No IL-4 or IL-10 production was detected in tolerant or rejecting mice. Collectively, our studies suggest that active suppression of IFN-gamma production by IL-10 is correlated with, and may contribute to, tolerance induced with intact active bone and anti-CD40 ligand mAbs.
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21 MeSH Terms
Lewis rat pancreas, but not cardiac xenografts, are resistant to anti-gal antibody mediated hyperacute rejection.
Yin DP, Sankary HN, Ma LL, Shen J, Qin Y, Blinder L, Williams JW, Chong AS
(2001) Transplantation 71: 1385-9
MeSH Terms: Acute Disease, Animals, Antibodies, Diabetes Mellitus, Experimental, Disaccharides, Disease Susceptibility, Galactosyltransferases, Graft Rejection, Heart Transplantation, Immune Sera, Immunosuppressive Agents, Mice, Mice, Knockout, Pancreas, Pancreas Transplantation, Rats, Rats, Inbred Lew, T-Lymphocytes, Tacrolimus, Tissue Donors, Transplantation, Heterologous
Show Abstract · Added December 10, 2013
BACKGROUND - The objective of this study was to evaluate the role of anti-Gal Abs and non-anti-Gal Abs in hyperacute rejection (HAR) of concordant pancreas xenografts compared with heart xenografts. In addition, we tested whether rejection of Lewis rat pancreas grafts was T-cell dependent and could be prevented by anti-T-cell treatment.
METHODS - To determine the role of anti-Gal Abs in the induction of HAR, Lewis rat pancreas and heart xenografts were transplanted into alpha1,3Galactosyltransferase knockout (GT-Ko) mice treated with normal human serum (NHS) or hyperimmune serum, or into presensitized GT-Ko mice. To investigate whether rejection of pancreas xenograft was mediated by a T-cell dependent response, Lewis rat pancreas grafts were transplanted into streptozotocin (STZ)-induced diabetic GT-Ko mice treated with FK506, anti-CD4 mAbs (GK1.5), and thymectomy. Antidonor-specific IgM and IgG and anti-Gal Abs were analyzed by flow cytometry. Rejected and long-term surviving pancreas xenografts were assessed by functional (blood glucose) and histopathological examination.
RESULTS - HAR of Lewis rat pancreas xenografts could not be induced by NHS (0.4 ml), whereas NHS (0.2 ml) resulted in HAR of Lewis heart xenografts. Infusion of Lewis rat-specific hyperimmune serum (0.2 ml) resulted in HAR of Lewis rat pancreas xenografts. In addition, second Lewis rat pancreas grafts were hyperacutely rejected by presensitized GT-Ko mice. Immunohistochemical staining showed a low expression of Galalpha1,3Gal antigen in the endocrine tissue compared with that in the cardiac grafts. The levels of anti-Gal Abs in pancreas xenograft transplantation did not increase in GT-Ko mice after pancreas xenograft transplantation that was significantly increased after heart transplantation. FK506 treatment induced long-term survival of Lewis pancreas xenografts (mean survival time (MST) >90 days). Anti-CD4 treatment delayed rejection of Lewis rat pancreas xenografts with MST of 34.3 days, whereas anti-CD4, in combination with thymectomy, synergistically prolonged survival of pancreas xenograft (MST=70.4 days).
CONCLUSION - Pancreas xenograft is resistant to anti-Gal Abs-induced HAR but is susceptible to anti-donor specific Abs. Rejection of Lewis pancreas xenograft in STZ-induced, diabetic, GT-Ko mice is T-cell dependent.
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21 MeSH Terms
Human immunodeficiency virus type 1 particles pseudotyped with envelope proteins that fuse at low pH no longer require Nef for optimal infectivity.
Chazal N, Singer G, Aiken C, Hammarskjöld ML, Rekosh D
(2001) J Virol 75: 4014-8
MeSH Terms: Animals, Anti-Bacterial Agents, Antibodies, Viral, Cell Line, Gene Deletion, Gene Products, nef, HIV Envelope Protein gp120, HIV-1, HeLa Cells, Humans, Hydrogen-Ion Concentration, Immune Sera, Macrolides, Membrane Fusion, Membrane Glycoproteins, Molecular Sequence Data, Neutralization Tests, Receptors, HIV, Viral Envelope Proteins, nef Gene Products, Human Immunodeficiency Virus
Show Abstract · Added February 19, 2015
We have investigated the effects of Nef on infectivity in the context of various viral envelope proteins. These experiments were performed with a minimal vector system where Nef is the only accessory protein present. Our results support the hypothesis that the route of entry influences the ability of Nef to enhance human immunodeficiency virus (HIV) infectivity. We show that HIV particles pseudotyped with Ebola virus glycoprotein or vesicular stomatitis virus glycoprotein (VSV-G), which fuse at low pH, do not require Nef for optimal infectivity. In contrast, Nef significantly enhances the infectivity of virus particles that contain envelope proteins that fuse at neutral pH (CCR5-dependent HIV Env, CXCR4-dependent HIV Env, or amphotropic murine leukemia virus Env). In addition, our results demonstrate that virus particles containing mixed CXCR4-dependent HIV and VSV-G envelope proteins show a conditional requirement for Nef for optimal infectivity, depending on which protein is allowed to facilitate entry.
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20 MeSH Terms
The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity.
Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, Xue YY, Buechi L, Walz A, Richmond A, Strieter RM
(2000) J Immunol 165: 5269-77
MeSH Terms: Administration, Topical, Amino Acid Motifs, Amino Acid Sequence, Angiogenesis Inhibitors, Animals, Antibodies, Blocking, Cell Migration Inhibition, Cells, Cultured, Chemokines, CXC, Cornea, Endothelium, Vascular, Humans, Immune Sera, Mice, Mice, Inbred C57BL, Mice, Knockout, Microcirculation, Molecular Sequence Data, Neovascularization, Physiologic, Pertussis Toxin, Rats, Receptors, Interleukin-8B, Virulence Factors, Bordetella
Show Abstract · Added May 31, 2013
We have previously shown that members of the ELR(+) CXC chemokine family, including IL-8; growth-related oncogenes alpha, beta, and gamma; granulocyte chemotactic protein 2; and epithelial neutrophil-activating protein-78, can mediate angiogenesis in the absence of preceding inflammation. To date, the receptor on endothelial cells responsible for chemotaxis and neovascularization mediated by these ELR(+) CXC chemokines has not been determined. Because all ELR(+) CXC chemokines bind to CXC chemokine receptor 2 (CXCR2), we hypothesized that CXCR2 is the putative receptor for ELR(+) CXC chemokine-mediated angiogenesis. To test this postulate, we first determined whether cultured human microvascular endothelial cells expressed CXCR2. CXCR2 was detected in human microvascular endothelial cells at the protein level by both Western blot analysis and immunohistochemistry using polyclonal Abs specific for human CXCR2. To determine whether CXCR2 played a functional role in angiogenesis, we determined whether this receptor was involved in endothelial cell chemotaxis. We found that microvascular endothelial cell chemotaxis in response to ELR(+) CXC chemokines was inhibited by anti-CXCR2 Abs. In addition, endothelial cell chemotaxis in response to ELR(+) CXC chemokines was sensitive to pertussis toxin, suggesting a role for G protein-linked receptor mechanisms in this biological response. The importance of CXCR2 in mediating ELR(+) CXC chemokine-induced angiogenesis in vivo was also demonstrated by the lack of angiogenic activity induced by ELR(+) CXC chemokines in the presence of neutralizing Abs to CXCR2 in the rat corneal micropocket assay, or in the corneas of CXCR2(-/-) mice. We thus conclude that CXCR2 is the receptor responsible for ELR(+) CXC chemokine-mediated angiogenesis.
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23 MeSH Terms
Activin receptor-like kinase 2 can mediate atrioventricular cushion transformation.
Lai YT, Beason KB, Brames GP, Desgrosellier JS, Cleggett MC, Shaw MV, Brown CB, Barnett JV
(2000) Dev Biol 222: 1-11
MeSH Terms: Activin Receptors, Type II, Amino Acid Sequence, Animals, Atrioventricular Node, Base Sequence, COS Cells, Chick Embryo, DNA Primers, DNA, Complementary, Immune Sera, Molecular Sequence Data, Morphogenesis, Protein-Serine-Threonine Kinases, Receptors, Growth Factor, Sequence Homology, Amino Acid
Show Abstract · Added February 21, 2016
Epithelial-mesenchymal transformation in the atrioventricular (AV) cushion of the tubular heart is a critical step in the formation of the valves and membranous septa. Transforming growth factor beta (TGFbeta) ligands are a primary signal of this transformation. To investigate the expression and function of specific Type I TGFbeta receptors during AV cushion transformation, we cloned and characterized the chicken homologues of two mammalian activin receptor-like kinases (ALK), ALK2 and ALK5, and generated specific, polyclonal antibodies against the extracellular binding domains of each. Both the chicken ALK2 (ChALK2) and the chicken ALK5 (ChALK5) cDNAs encode proteins that bind TGFbeta1 in the presence of the Type II TGFbeta receptor. However, as expected, only ChALK5 stimulated the TGFbeta-responsive PAI-1 promoter. These data establish that ChALK2 and ChALK5 are the chicken homologues of the mammalian receptors ALK2 and ALK5. Both ChALK2 and ChALK5 are expressed by AV endocardial cells. AV cushion explants harvested from stage 13-18 embryos were incubated with antisera to ChALK2 or ChALK5. Anti-ChALK2 antisera inhibited mesenchyme formation by 34-50% while neutralizing anti-ChALK5 antisera were without effect. These data demonstrate that ChALK2 can mediate transformation in the AV cushion.
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15 MeSH Terms
TCR and IL-12 receptor signals cooperate to activate an individual response element in the IFN-gamma promoter in effector Th cells.
Zhang F, Nakamura T, Aune TM
(1999) J Immunol 163: 728-35
MeSH Terms: Animals, CD3 Complex, Cells, Cultured, Immune Sera, Immune Tolerance, Interferon-gamma, Interleukin-12, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Mitogens, Nuclear Proteins, Promoter Regions, Genetic, Receptors, Antigen, T-Cell, Receptors, Interleukin, Receptors, Interleukin-12, Response Elements, Signal Transduction, T-Lymphocytes, Helper-Inducer
Show Abstract · Added December 10, 2013
IFN-gamma is a key regulatory cytokine of the immune system. Reporter transgenic mice expressing the luciferase gene under the control of separate TCR-response elements (TCR-RE) from the IFN-gamma promoter or expressing the green fluorescent protein gene under the control of an IFN-gamma "minigene" were employed to explore the basis for IL-12 regulation of IFN-gamma gene transcription. In the absence of TCR stimulation, IL-12 did not activate the TCR-REs but did induce green fluorescent protein expression. TCR plus IL-12R stimulation of effector Th cells resulted in: 1) enhanced activation of the proximal, but not the distal, TCR-RE, and 2) increased induction of cJun-proximal TCR-RE complexes and c-Jun protein expression. Overexpression of cJun, but not cFos, increased activity of the proximal TCR-RE in T cells. These results suggest that IL-12R signaling affects IFN-gamma gene transcription by at least two separate mechanisms; IL-12R signaling without TCR signaling targets promoter regions outside of the approximately 100-bp IFN-gamma TCR-RE, and IL-12R signaling also stimulates TCR-induced activity of the proximal TCR-RE.
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21 MeSH Terms
The goodpasture autoantigen. Mapping the major conformational epitope(s) of alpha3(IV) collagen to residues 17-31 and 127-141 of the NC1 domain.
Netzer KO, Leinonen A, Boutaud A, Borza DB, Todd P, Gunwar S, Langeveld JP, Hudson BG
(1999) J Biol Chem 274: 11267-74
MeSH Terms: Amino Acid Sequence, Autoantigens, Base Sequence, Cell Line, Collagen, Collagen Type IV, DNA Primers, Epitopes, Humans, Immune Sera, Molecular Sequence Data, Mutagenesis, Protein Conformation, Recombinant Fusion Proteins
Show Abstract · Added December 10, 2013
The Goodpasture (GP) autoantigen has been identified as the alpha3(IV) collagen chain, one of six homologous chains designated alpha1-alpha6 that comprise type IV collagen (Hudson, B. G., Reeders, S. T., and Tryggvason, K. (1993) J. Biol. Chem. 268, 26033-26036). In this study, chimeric proteins were used to map the location of the major conformational, disulfide bond-dependent GP autoepitope(s) that has been previously localized to the noncollagenous (NC1) domain of alpha3(IV) chain. Fourteen alpha1/alpha3 NC1 chimeras were constructed by substituting one or more short sequences of alpha3(IV)NC1 at the corresponding positions in the non-immunoreactive alpha1(IV)NC1 domain and expressed in mammalian cells for proper folding. The interaction between the chimeras and eight GP sera was assessed by both direct and inhibition enzyme-linked immunosorbent assay. Two chimeras, C2 containing residues 17-31 of alpha3(IV)NC1 and C6 containing residues 127-141 of alpha3(IV)NC1, bound autoantibodies, as did combination chimeras containing these regions. The epitope(s) that encompasses these sequences is immunodominant, showing strong reactivity with all GP sera and accounting for 50-90% of the autoantibody reactivity toward alpha3(IV)NC1. The conformational nature of the epitope(s) in the C2 and C6 chimeras was established by reduction of the disulfide bonds and by PEPSCAN analysis of overlapping 12-mer peptides derived from alpha1- and alpha3(IV)NC1 sequences. The amino acid sequences 17-31 and 127-141 in alpha3(IV)NC1 have thus been shown to contain the critical residues of one or two disulfide bond-dependent conformational autoepitopes that bind GP autoantibodies.
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14 MeSH Terms