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Journal of Clinical Investigation

Yongjun Sui, George K Lewis, Yichuan Wang, Kurt Berckmueller, Blake Frey, Amiran Dzutsev, Diego Vargas-Inchaustegui, Venkatramanan Mohanram, Thomas Musich, Xiaoying Shen, Anthony DeVico, Timothy Fouts, David Venzon, James Kirk, Robert C Waters, James Talton, Dennis Klinman, John Clements, Georgia D Tomaras, Genoveffa Franchini, Marjorie Robert-Guroff, Giorgio Trinchieri, Robert C Gallo, Jay A Berzofsky
It is widely believed that protection against acquisition of HIV or SIV infection requires anti-envelope (anti-Env) antibodies, and that cellular immunity may affect viral loads but not acquisition, except in special cases. Here we provide evidence to the contrary. Mucosal immunization may enhance HIV vaccine efficacy by eliciting protective responses at portals of exposure. Accordingly, we vaccinated macaques mucosally with HIV/SIV peptides, modified vaccinia Ankara-SIV (MVA-SIV), and HIV-gp120-CD4 fusion protein plus adjuvants, which consistently reduced infection risk against heterologous intrarectal SHIVSF162P4 challenge, both high dose and repeated low dose...
February 18, 2019: Journal of Clinical Investigation
Elena Goleva, Evgeny Berdyshev, Donald Ym Leung
Allergic diseases have in common a dysfunctional epithelial barrier, which allows the penetration of allergens and microbes, leading to the release of type 2 cytokines that drive allergic inflammation. The accessibility of skin, compared with lung or gastrointestinal tissue, has facilitated detailed investigations into mechanisms underlying epithelial barrier dysfunction in atopic dermatitis (AD). This Review describes the formation of the skin barrier and analyzes the link between altered skin barrier formation and the pathogenesis of AD...
February 18, 2019: Journal of Clinical Investigation
Kazunori Inoue, Geliang Gan, Maria Ciarleglio, Yan Zhang, Xuefei Tian, Christopher E Pedigo, Corey Cavanaugh, Janet Tate, Ying Wang, Elizabeth Cross, Marwin Groener, Nathan Chai, Zhen Wang, Amy Justice, Zhenhai Zhang, Chirag R Parikh, Francis P Wilson, Shuta Ishibe
We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival...
February 18, 2019: Journal of Clinical Investigation
Yashaar Chaichian, Daniel J Wallace, Michael H Weisman
Despite advances in understanding systemic lupus erythematosus (SLE) pathogenesis, most clinical trials of new targeted therapies have been met with disappointment. The type I IFN pathway is believed to play an important role in SLE, and the proposed involvement of this pathway helps explain the frustration behind the failure at targeting either IFN-α or the type 1 IFN receptor itself. In this issue of the JCI, Furie et al. report on an intriguing phase 1b study that demonstrates an approach for inhibiting this pathway in the skin using an mAB (BIIB059) that targets the blood DC antigen 2 (BDCA-2) receptor on plasmacytoid DCs (pDCs)...
February 18, 2019: Journal of Clinical Investigation
Stephen J Galli
IgE-mediated activation of mast cells is a hallmark of an anaphylactic reaction to allergen. In this issue of the JCI, Duan et al. describe an approach for suppressing IgE-dependent mast cell activation, thereby suppressing anaphylaxis. Specifically, the authors show that delivery of liposomes containing both the specific antigen recognized by the mast cell-bound IgE and a high-affinity glycan ligand of the inhibitory receptor CD33 (CD33L) to targeted mast cells inhibits antigen-induced, FcεRI-dependent spleen tyrosine kinase (Syk) phosphorylation and downstream protein tyrosine kinase (PTK) phosphorylation, Ca++ flux, and β-hexosaminidase release (i...
February 18, 2019: Journal of Clinical Investigation
Shiteng Duan, Cynthia J Koziol-White, William F Jester, Corwin M Nycholat, Matthew S Macauley, Reynold A Panettieri, James C Paulson
Allergen immunotherapy for patients with allergies begins with weekly escalating doses of allergen under medical supervision to monitor and treat IgE mast cell-mediated anaphylaxis. There is currently no treatment to safely desensitize mast cells to enable robust allergen immunotherapy with therapeutic levels of allergen. Here, we demonstrated that liposomal nanoparticles bearing an allergen and a high-affinity glycan ligand of the inhibitory receptor CD33 profoundly suppressed IgE-mediated activation of mast cells, prevented anaphylaxis in Tg mice with mast cells expressing human CD33, and desensitized mice to subsequent allergen challenge for several days...
February 18, 2019: Journal of Clinical Investigation
Gerardo A Vitiello, Timothy G Bowler, Mengyuan Liu, Benjamin D Medina, Jennifer Q Zhang, Nesteene J Param, Jennifer K Loo, Rachel L Goldfeder, Frederic Chibon, Ferdinand Rossi, Shan Zeng, Ronald P DeMatteo
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs...
February 14, 2019: Journal of Clinical Investigation
Kwi Hye Koh, Yanxia Cao, Steve Mangos, Nicholas J Tardi, Ranadheer R Dande, Ha Won Lee, Beata Samelko, Mehmet M Altintas, Vincent P Schmitz, Hyun Lee, Kamalika Mukherjee, Vasil Peev, David J Cimbaluk, Jochen Reiser, Eunsil Hahm
Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvβ3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven't been discovered yet. Here we report a novel, renoprotective role for inducible costimulator (ICOS) ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvβ3 integrin. Contrary to ICOSL's immune-regulatory role, ICOSL in non-hematopoietic cells limited the activation of αvβ3 integrin...
February 12, 2019: Journal of Clinical Investigation
Michael R Strickland, David M Holtzman
Alzheimer's disease (AD) is the leading cause of dementia, and its pathogenesis is initiated by the accumulation of amyloid-β (Aβ) into extracellular plaques. Apolipoprotein E4 (ApoE4) is the largest genetic risk factor for sporadic AD and contributes to AD pathogenesis by influencing clearance and seeding of the initial aggregation of Aβ. In this issue of the JCI, Tachibana et al. investigated the relationship between neuronal LRP1 expression and ApoE4-mediated seeding of Aβ and showed that knockout of neuronal LRP1 prevents the increase in Aβ pathology caused by ApoE4 expression...
February 11, 2019: Journal of Clinical Investigation
Yajuan Li, Qingsong Hu, Chunlai Li, Ke Liang, Yu Xiang, Heidi Hsiao, Tina K Nguyen, Peter K Park, Sergey D Egranov, Chandrashekar R Ambati, Nagireddy Putluri, David H Hawke, Leng Han, Mien-Chie Hung, Farhad R Danesh, Liuqing Yang, Chunru Lin
Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-β), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTENK27-polyUb)...
February 11, 2019: Journal of Clinical Investigation
Nelomi Anandagoda, Joanna Cd Willis, Arnulf Hertweck, Luke B Roberts, Ian Jackson, M Refik Gökmen, Richard G Jenner, Jane K Howard, Graham M Lord
Tregs play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). This function is dependent on maintenance of a high intracellular cAMP concentration. A number of microRNAs are implicated in the maintenance of Tregs. In this study, we demonstrate that peripheral immune tolerance is critically dependent on posttranscriptional repression of the cAMP-hydrolyzing enzyme phosphodiesterase-3b (Pde3b) by microRNA-142-5p (miR-142-5p). In this manner, miR-142-5p acts as an immunometabolic regulator of intracellular cAMP, controlling Treg suppressive function...
February 11, 2019: Journal of Clinical Investigation
Liza Bronner Murrison, Eric B Brandt, Jocelyn Biagini Myers, Gurjit K Khurana Hershey
Environmental exposures interplay with human host factors to promote the development and progression of allergic diseases. The worldwide prevalence of allergic disease is rising as a result of complex gene-environment interactions that shape the immune system and host response. Research shows an association between the rise of allergic diseases and increasingly modern Westernized lifestyles, which are characterized by increased urbanization, time spent indoors, and antibiotic usage. These environmental changes result in increased exposure to air and traffic pollution, fungi, infectious agents, tobacco smoke, and other early-life and lifelong risk factors for the development and exacerbation of asthma and allergic diseases...
February 11, 2019: Journal of Clinical Investigation
Masaya Tachibana, Marie-Louise Holm, Chia-Chen Liu, Mitsuru Shinohara, Tomonori Aikawa, Hiroshi Oue, Yu Yamazaki, Yuka A Martens, Melissa E Murray, Patrick M Sullivan, Kathrin Weyer, Simon Glerup, Dennis W Dickson, Guojun Bu, Takahisa Kanekiyo
Carrying the ε4 allele of the APOE gene encoding apolipoprotein E (APOE4) markedly increases the risk for late-onset Alzheimer's disease (AD), in which APOE4 exacerbates the brain accumulation and subsequent deposition of amyloid-β (Aβ) peptides. While the LDL receptor-related protein 1 (LRP1) is a major apoE receptor in the brain, we found that its levels are associated with those of insoluble Aβ depending on APOE genotype status in postmortem AD brains. Thus, to determine the functional interaction of apoE4 and LRP1 in brain Aβ metabolism, we crossed neuronal LRP1-knockout mice with amyloid model APP/PS1 mice and APOE3-targeted replacement (APO3-TR) or APOE4-TR mice...
February 11, 2019: Journal of Clinical Investigation
Kelly A Mills
A variety of neurological procedures, including deep brain stimulation and craniotomies that require tissue removal near elegant cortices, require patients to remain awake and responsive in order to monitor function. Such procedures can produce anxiety and are poorly tolerated in some subjects. In this issue of the JCI, Bijanki and colleagues demonstrate that electrical stimulation of the left dorsal anterior cingulum bundle promoted a positive (mirthful) effect and reduced anxiety, without sedation, in three patients with epilepsy undergoing intracranial electrode monitoring...
February 11, 2019: Journal of Clinical Investigation
Kelly R Bijanki, Joseph R Manns, Cory S Inman, Ki Sueng Choi, Sahar Harati, Nigel P Pedersen, Daniel L Drane, Allison C Waters, Rebecca E Fasano, Helen S Mayberg, Jon T Willie
BACKGROUND: Awake neurosurgery requires patients to converse and respond to visual or verbal prompts to identify and protect brain tissue supporting essential functions such as language, primary sensory modalities, and motor function. These procedures can be poorly tolerated because of patient anxiety, yet acute anxiolytic medications typically cause sedation and impair cortical function. METHODS: In this study, direct electrical stimulation of the left dorsal anterior cingulum bundle was discovered to reliably evoke positive affect and anxiolysis without sedation in a patient with epilepsy undergoing research testing during standard inpatient intracranial electrode monitoring...
February 11, 2019: Journal of Clinical Investigation
Simona Stivala, Tamara Codilupi, Sime Brkic, Anne Baerenwaldt, Nilabh Ghosh, Hui Hao-Shen, Stephan Dirnhofer, Matthias S Dettmer, Cedric Simillion, Beat A Kaufmann, Sophia Chiu, Matthew D Keller, Maria Kleppe, Morgane Hilpert, Andreas S Buser, Jakob R Passweg, Thomas Radimerski, Radek C Skoda, Ross L Levine, Sara C Meyer
Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT and MEK/ERK signaling. However, the therapeutic efficacy of current JAK2 inhibitors is limited. We investigated the role of MEK/ERK signaling in MPN cell survival in the setting of JAK kinase inhibition. Type I and II JAK2 inhibition suppressed MEK/ERK activation in MPN cell lines in vitro, but not in Jak2V617F and MPLW515L mouse models in vivo. JAK2 inhibition ex vivo inhibited MEK/ERK signaling suggesting cell extrinsic factors maintain ERK activation in vivo...
February 7, 2019: Journal of Clinical Investigation
Changli Wei, Jing Li, Brian D Adair, Ke Zhu, Jian Cai, Michael Merchant, Beata Samelko, Zhongji Liao, Kwi Hye Koh, Nicholas J Tardi, Ranadheer R Dande, Shuangxin Liu, Jianchao Ma, Salvatore DiBartolo, Stefan Hägele, Vasil Peev, Salim S Hayek, David J Cimbaluk, Melissa Tracy, Jon B Klein, Sanja Sever, Sanford J Shattil, M Amin Arnaout, Jochen Reiser
Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived circulating signaling molecule that has been implicated in chronic kidney disease such as focal segmental glomerulosclerosis (FSGS). Typically, native uPAR (isoform 1) translates to a three-domain protein capable of binding and activating integrins, yet the function of additional isoforms generated by alternative splicing is unknown. Here, we characterized mouse uPAR isoform 2 (msuPAR2), encoding domain I and nearly one-half of domain II, as a dimer in solution, as revealed by 3D electron microscopy structural analysis...
February 7, 2019: Journal of Clinical Investigation
Fangyang Wang, Damián Gatica, Zhang Xiao Ying, Luke F Peterson, Peter K Kim, Denzil Bernard, Kamlai Saiya-Cork, Shaomeng Wang, Mark S Kaminski, Alfred E Chang, Tycel Phillips, Daniel J Klionsky, Sami N Malek
The discovery of recurrent mutations in subunits of the vacuolar-type H+-translocating ATPase (v-ATPase) in follicular lymphoma (FL) highlights a role for the amino acid- and energy-sensing pathway to MTOR in the pathogenesis of this disease. Here, through the use of complementary experimental approaches involving mammalian cells and Saccharomyces cerevisiae, we have demonstrated that mutations in the v-ATPase subunit ATP6V1B2/Vma2 activate autophagic flux and maintain MTOR/Tor in an active state. Engineered lymphoma cell lines and primary follicular lymphoma B cells (FL B cells) carrying mutated ATP6V1B2 demonstrated a remarkable ability to survive low leucine concentrations...
February 5, 2019: Journal of Clinical Investigation
Divij Mathew, Kimberly N Kremer, Raul M Torres
Primary antibody deficiencies are the most common immunodeficiencies in humans; however, identification of the underlying genetic and biochemical basis for these diseases is often difficult, given that these deficiencies typically involve complex genetic etiologies. In this issue of the JCI, Bouafia et al. performed whole-exome sequencing on a pair of siblings with primary antibody deficiencies and identified genetic mutations that result in a deficiency of ARHGEF1, a hematopoietic intracellular signaling molecule that transmits signals from GPCRs...
February 4, 2019: Journal of Clinical Investigation
Austin K Mattox, Justin Lowenthal
No abstract text is available yet for this article.
February 4, 2019: Journal of Clinical Investigation
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