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Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance
Justin R. Bailey, … , Stuart C. Ray, James E. Crowe Jr.
Justin R. Bailey, … , Stuart C. Ray, James E. Crowe Jr.
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e92872. https://doi.org/10.1172/jci.insight.92872.
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Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance

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Abstract

Here, we report the isolation of broadly neutralizing mAbs (bNAbs) from persons with broadly neutralizing serum who spontaneously cleared hepatitis C virus (HCV) infection. We found that bNAbs from two donors bound the same epitope and were encoded by the same germline heavy chain variable gene segment. Remarkably, these bNAbs were encoded by antibody variable genes with sparse somatic mutations. For one of the most potent bNAbs, these somatic mutations were critical for antibody neutralizing breadth and for binding to autologous envelope variants circulating late in infection. However, somatic mutations were not necessary for binding of the bNAb unmutated ancestor to envelope proteins of early autologous transmitted/founder viruses. This study identifies a public B cell clonotype favoring early recognition of a conserved HCV epitope, proving that anti-HCV bNAbs can achieve substantial neutralizing breadth with relatively few somatic mutations, and identifies HCV envelope variants that favored selection and maturation of an anti-HCV bNAb in vivo. These data provide insight into the molecular mechanisms of immune-mediated clearance of HCV infection and present a roadmap to guide development of a vaccine capable of stimulating anti-HCV bNAbs with a physiologic number of somatic mutations characteristic of vaccine responses.

Authors

Justin R. Bailey, Andrew I. Flyak, Valerie J. Cohen, Hui Li, Lisa N. Wasilewski, Anna E. Snider, Shuyi Wang, Gerald H. Learn, Nurgun Kose, Leah Loerinc, Rebecca Lampley, Andrea L. Cox, Jennifer M. Pfaff, Benjamin J. Doranz, George M. Shaw, Stuart C. Ray, James E. Crowe Jr.

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GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients
Norimitsu Ban, … , Jun Yoshino, Rajendra S. Apte
Norimitsu Ban, … , Jun Yoshino, Rajendra S. Apte
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e91455. https://doi.org/10.1172/jci.insight.91455.
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GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

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Abstract

Glaucoma is the second leading cause of blindness worldwide. Physicians often use surrogate endpoints to monitor the progression of glaucomatous neurodegeneration. These approaches are limited in their ability to quantify disease severity and progression due to inherent subjectivity, unreliability, and limitations of normative databases. Therefore, there is a critical need to identify specific molecular markers that predict or measure glaucomatous neurodegeneration. Here, we demonstrate that growth differentiation factor 15 (GDF15) is associated with retinal ganglion cell death. Gdf15 expression in the retina is specifically increased after acute injury to retinal ganglion cell axons and in a murine chronic glaucoma model. We also demonstrate that the ganglion cell layer may be one of the sources of secreted GDF15 and that GDF15 diffuses to and can be detected in aqueous humor (AH). In validating these findings in human patients with glaucoma, we find not only that GDF15 is increased in AH of patients with primary open angle glaucoma (POAG), but also that elevated GDF15 levels are significantly associated with worse functional outcomes in glaucoma patients, as measured by visual field testing. Thus, GDF15 maybe a reliable metric of glaucomatous neurodegeneration, although further prospective validation studies will be necessary to determine if GDF15 can be used in clinical practice.

Authors

Norimitsu Ban, Carla J. Siegfried, Jonathan B. Lin, Ying-Bo Shui, Julia Sein, Wolfgang Pita-Thomas, Abdoulaye Sene, Andrea Santeford, Mae Gordon, Rachel Lamb, Zhenyu Dong, Shannon C. Kelly, Valeria Cavalli, Jun Yoshino, Rajendra S. Apte

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Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood
Jin Hyen Baek, … , Dominik J. Schaer, Paul W. Buehler
Jin Hyen Baek, … , Dominik J. Schaer, Paul W. Buehler
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e93577. https://doi.org/10.1172/jci.insight.93577.
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Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood

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Abstract

Non–transferrin-bound iron (NTBI) and free hemoglobin (Hb) accumulate in circulation following stored RBC transfusions. This study investigated transfusion, vascular disease, and mortality in guinea pigs after stored RBC transfusion alone and following cotransfusion with apo-transferrin (apo-Tf) and haptoglobin (Hp). The effects of RBC exchange transfusion dose (1, 3, and 9 units), storage period (14 days), and mortality were evaluated in guinea pigs with a vascular disease phenotype. Seven-day mortality and the interaction between iron and Hb as cocontributors to adverse outcome were studied. Concentrations of iron and free Hb were greatest after transfusion with 9 units of stored RBCs compared with fresh RBCs or stored RBCs at 1- and 3-unit volumes. Nine units of stored RBCs led to mortality in vascular diseased animals, but not normal animals. One and 3 units of stored RBCs did not cause a mortality effect, suggesting the concomitant relevance of NTBI and Hb on outcome. Cotransfusion with apo-Tf or Hp restored survival to 100% following 9-unit RBC transfusions in vascular diseased animals. Our data suggest that increases in plasma NTBI and Hb contribute to vascular disease–associated mortality through iron-enhanced Hb oxidation and enhanced tissue injury.

Authors

Jin Hyen Baek, Ayla Yalamanoglu, Yamei Gao, Ricardo Guenster, Donat R. Spahn, Dominik J. Schaer, Paul W. Buehler

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18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response
Ann-Marie Chacko, … , Jenny G.H. Low, Subhash G. Vasudevan
Ann-Marie Chacko, … , Jenny G.H. Low, Subhash G. Vasudevan
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e93474. https://doi.org/10.1172/jci.insight.93474.
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18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

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Abstract

Development of antiviral therapy against acute viral diseases, such as dengue virus (DENV), suffers from the narrow window of viral load detection in serum during onset and clearance of infection and fever. We explored a biomarker approach using 18F-fluorodeoxyglucose (18F-FDG) PET in established mouse models for primary and antibody-dependent enhancement infection with DENV. 18F-FDG uptake was most prominent in the intestines and correlated with increased virus load and proinflammatory cytokines. Furthermore, a significant temporal trend in 18F-FDG uptake was seen in intestines and selected tissues over the time course of infection. Notably, 18F-FDG uptake and visualization by PET robustly differentiated treatment-naive groups from drug-treated groups as well as nonlethal from lethal infections with a clinical strain of DENV2. Thus, 18F-FDG may serve as a novel DENV infection–associated inflammation biomarker for assessing treatment response during therapeutic intervention trials.

Authors

Ann-Marie Chacko, Satoru Watanabe, Keira J. Herr, Shirin Kalimuddin, Jing Yang Tham, Joanne Ong, Marie Reolo, Raymond M.F. Serrano, Yin Bun Cheung, Jenny G.H. Low, Subhash G. Vasudevan

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Imaging protective mast cells in living mice during severe contact hypersensitivity
Laurent L. Reber, … , Nicolas Gaudenzio, Stephen J. Galli
Laurent L. Reber, … , Nicolas Gaudenzio, Stephen J. Galli
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e92900. https://doi.org/10.1172/jci.insight.92900.
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Imaging protective mast cells in living mice during severe contact hypersensitivity

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Abstract

Contact hypersensitivity (CHS) is a common skin disease induced by epicutaneous sensitization to haptens. Conflicting results have been obtained regarding pathogenic versus protective roles of mast cells (MCs) in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. Here we describe a fluorescent imaging approach that enables in vivo selective labeling and tracking of MC secretory granules by real-time intravital 2-photon microscopy in living mice, and permits the identification of such MCs as a potential source of cytokines in different disease models. We show using this method that dermal MCs release their granules progressively into the surrounding microenvironment, but also represent an initial source of the antiinflammatory cytokine IL-10, during the early phase of severe CHS reactions. Finally, using 3 different types of MC-deficient mice, as well as mice in which IL-10 is ablated specifically in MCs, we show that IL-10 production by MCs can significantly limit the inflammation and tissue pathology observed in severe CHS reactions.

Authors

Laurent L. Reber, Riccardo Sibilano, Philipp Starkl, Axel Roers, Michele A. Grimbaldeston, Mindy Tsai, Nicolas Gaudenzio, Stephen J. Galli

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Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis
W. Taylor Kimberly, … , Kathleen E. Corey, Robert E. Gerszten
W. Taylor Kimberly, … , Kathleen E. Corey, Robert E. Gerszten
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e92989. https://doi.org/10.1172/jci.insight.92989.
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Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis

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Abstract

The discovery of metabolite-phenotype associations may highlight candidate biomarkers and metabolic pathways altered in disease states. We sought to identify novel metabolites associated with obesity and one of its major complications, nonalcoholic fatty liver disease (NAFLD), using a liquid chromatography–tandem mass spectrometry method. In 997 individuals in Framingham Heart Study Generation 3 (FHS Gen 3), we identified an association between anandamide (AEA) and BMI. Further examination revealed that AEA was associated with radiographic hepatic steatosis. In a histologically defined NAFLD cohort, AEA was associated with NAFLD severity, the presence of nonalcoholic steatohepatitis, and fibrosis. These data highlight AEA as a marker linking cardiometabolic disease and NAFLD severity.

Authors

W. Taylor Kimberly, John F. O’Sullivan, Anjali K. Nath, Michelle Keyes, Xu Shi, Martin G. Larson, Qiong Yang, Michelle T. Long, Ramachandran Vasan, Randall T. Peterson, Thomas J. Wang, Kathleen E. Corey, Robert E. Gerszten

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Increased de novo ceramide synthesis and accumulation in failing myocardium
Ruiping Ji, … , Ira J. Goldberg, P. Christian Schulze
Ruiping Ji, … , Ira J. Goldberg, P. Christian Schulze
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e82922. https://doi.org/10.1172/jci.insight.82922.
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Increased de novo ceramide synthesis and accumulation in failing myocardium

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Abstract

Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long–chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long–chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.

Authors

Ruiping Ji, Hirokazu Akashi, Konstantinos Drosatos, Xianghai Liao, Hongfeng Jiang, Peter J. Kennel, Danielle L. Brunjes, Estibaliz Castillero, Xiaokan Zhang, Lily Y. Deng, Shunichi Homma, Isaac J. George, Hiroo Takayama, Yoshifumi Naka, Ira J. Goldberg, P. Christian Schulze

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C3d regulates immune checkpoint blockade and enhances antitumor immunity
Jeffrey L. Platt, … , Michael C. Carroll, Marilia Cascalho
Jeffrey L. Platt, … , Michael C. Carroll, Marilia Cascalho
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e90201. https://doi.org/10.1172/jci.insight.90201.
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C3d regulates immune checkpoint blockade and enhances antitumor immunity

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Abstract

Despite expression of immunogenic polypeptides, tumors escape immune surveillance by engaging T cell checkpoint regulators and expanding Tregs, among other mechanisms. What orchestrates these controls is unknown. We report that free C3d, a fragment of the third component of complement, inside tumor cells — or associated with irradiated tumor cells and unattached to antigen — recruits, accelerates, and amplifies antitumor T cell responses, allowing immunity to reverse or even to prevent tumor growth. C3d enhances antitumor immunity independently of B cells, NK cells, or antibodies, but it does so by increasing tumor infiltrating CD8+ lymphocytes, by depleting Tregs, and by suppressing expression of programmed cell death protein 1 (PD-1) by T cells. These properties of C3d appear specific for the tumor and dependent on complement receptor 2, and they incur no obvious systemic toxicity. The heretofore unrecognized properties of free C3d suggest that protein might determine the effectiveness of immune surveillance and that increasing availability of the protein might prove advantageous in the treatment or prevention of cancer and premalignant conditions.

Authors

Jeffrey L. Platt, Inês Silva, Samuel J. Balin, Adam R. Lefferts, Evan Farkash, Ted M. Ross, Michael C. Carroll, Marilia Cascalho

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Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes
Xuming Mao, … , Eric M. Mukherjee, Aimee S. Payne
Xuming Mao, … , Eric M. Mukherjee, Aimee S. Payne
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e92253. https://doi.org/10.1172/jci.insight.92253.
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Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes

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Abstract

Pemphigus vulgaris (PV) is an epithelial blistering disease caused by autoantibodies to the desmosomal cadherin desmoglein 3 (DSG3). Glucocorticoids improve disease within days by increasing DSG3 gene transcription, although the mechanism for this observation remains unknown. Here, we show that DSG3 transcription in keratinocytes is regulated by Stat3. Treatment of primary human keratinocytes (PHKs) with hydrocortisone or rapamycin, but not the p38 MAPK inhibitor SB202190, significantly increases DSG3 mRNA and protein expression and correspondingly reduces phospho-S727 Stat3. Stat3 inhibition or shRNA-knockdown also significantly increases DSG3 mRNA and protein levels. Hydrocortisone- or rapamycin-treated PHKs demonstrate increased number and length of desmosomes by electron microscopy and are resistant to PV IgG–induced loss of cell adhesion, whereas constitutive activation of Stat3 in PHKs abrogates DSG3 upregulation and inhibits hydrocortisone and rapamycin’s therapeutic effects. Topical hydrocortisone, rapamycin, or Stat3 inhibitor XVIII prevents autoantibody-induced blistering in the PV passive transfer mouse model, correlating with increased epidermal DSG3 expression and decreased phospho-S727 Stat3. Our data indicate that glucocorticoids and rapamycin upregulate DSG3 transcription through inhibition of Stat3. These studies explain how glucocorticoids rapidly improve pemphigus and may also offer novel insights into the physiologic and pathophysiologic regulation of desmosomal cadherin expression in normal epidermis and epithelial carcinomas.

Authors

Xuming Mao, Michael Jeffrey T. Cho, Christoph T. Ellebrecht, Eric M. Mukherjee, Aimee S. Payne

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Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia
Maria Karamita, … , Hans Lassmann, Lesley Probert
Maria Karamita, … , Hans Lassmann, Lesley Probert
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e87455. https://doi.org/10.1172/jci.insight.87455.
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Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia

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Abstract

Multiple sclerosis (MS) is an inflammatory CNS demyelinating disease in which remyelination largely fails. Transmembrane TNF (tmTNF) and TNF receptor 2 are important for remyelination in experimental MS models, but it is unknown whether soluble TNF (solTNF), a major proinflammatory factor, is involved in regeneration processes. Here, we investigated the specific contribution of solTNF to demyelination and remyelination in the cuprizone model. Treatment with XPro1595, a selective inhibitor of solTNF that crosses the intact blood-brain barrier (BBB), in cuprizone-fed mice did not prevent toxin-induced oligodendrocyte loss and demyelination, but it permitted profound early remyelination due to improved phagocytosis of myelin debris by CNS macrophages and prevented disease-associated decline in motor performance. The beneficial effects of XPro1595 were absent in TNF-deficient mice and replicated in tmTNF-knockin mice, showing that tmTNF is sufficient for the maintenance of myelin and neuroprotection. These findings demonstrate that solTNF inhibits remyelination and repair in a cuprizone demyelination model and suggest that local production of solTNF in the CNS might be one reason why remyelination fails in MS. These findings also suggest that disinhibition of remyelination by selective inhibitors of solTNF that cross the BBB might represent a promising approach for treatment in progressive MS.

Authors

Maria Karamita, Christopher Barnum, Wiebke Möbius, Malú G. Tansey, David E. Szymkowski, Hans Lassmann, Lesley Probert

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