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JCI Insight

Karolina Pilipow, Eloise Scamardella, Simone Puccio, Sanjivan Gautam, Federica De Paoli, Emilia Mc Mazza, Gabriele De Simone, Sara Polletti, Marta Buccilli, Veronica Zanon, Pietro Di Lucia, Matteo Iannacone, Luca Gattinoni, Enrico Lugli
Adoptive T cell transfer (ACT) immunotherapy benefits from early differentiated stem cell memory T (Tscm) cells capable of persisting in the long term and generating potent antitumor effectors. Due to their paucity ex vivo, Tscm cells can be derived from naive precursors, but the molecular signals at the basis of Tscm cell generation are ill-defined. We found that less differentiated human circulating CD8+ T cells display substantial antioxidant capacity ex vivo compared with more differentiated central and effector memory T cells...
September 20, 2018: JCI Insight
Daniel Kelly, Michael Kotliar, Vivienne Woo, Sajjeev Jagannathan, Jordan Whitt, Jessica Moncivaiz, Bruce J Aronow, Marla C Dubinsky, Jeffrey S Hyams, James F Markowitz, Robert N Baldassano, Michael C Stephens, Thomas D Walters, Subra Kugathasan, Yael Haberman, Nambirajan Sundaram, Michael J Rosen, Michael Helmrath, Rebekah Karns, Artem Barski, Lee A Denson, Theresa Alenghat
Altered response to the intestinal microbiota strongly associates with inflammatory bowel disease (IBD); however, how commensal microbial cues are integrated by the host during the pathogenesis of IBD is not understood. Epigenetics represents a potential mechanism that could enable intestinal microbes to modulate transcriptional output during the development of IBD. Here, we reveal a histone methylation signature of intestinal epithelial cells isolated from the terminal ilea of newly diagnosed pediatric IBD patients...
September 20, 2018: JCI Insight
Stephanie T Chung, Amber B Courville, Anthony U Onuzuruike, Mirella Galvan-De La Cruz, Lilian S Mabundo, Christopher W DuBose, Kannan Kasturi, Hongyi Cai, Ahmed M Gharib, Peter J Walter, H Martin Garraffo, Shaji Chacko, Morey W Haymond, Anne E Sumner
Black women, compared with White women, have high rates of whole-body insulin resistance but a lower prevalence of fasting hyperglycemia and hepatic steatosis. This dissociation of whole-body insulin resistance from fasting hyperglycemia may be explained by racial differences in gluconeogenesis, hepatic fat, or tissue-specific insulin sensitivity. Two groups of premenopausal federally employed women, without diabetes were studied. Using stable isotope tracers, [2H2O] and [6,62-H2]glucose, basal glucose production was partitioned into its components (gluconeogenesis and glycogenolysis) and basal whole-body lipolysis ([2H5]glycerol) was measured...
September 20, 2018: JCI Insight
Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E Selsted, André J Ouellette
Paneth cells contribute to small intestinal homeostasis by secreting antimicrobial peptides and constituting the intestinal stem cell (ISC) niche. Certain T cell-mediated enteropathies are characterized by extensive Paneth cell depletion coincident with mucosal destruction and dysbiosis. In this study, mechanisms of intestinal crypt injury have been investigated by characterizing responses of mouse intestinal organoids (enteroids) in coculture with mouse T lymphocytes. Activated T cells induced enteroid damage, reduced Paneth cell and Lgr5+ ISC mRNA levels, and induced Paneth cell death through a caspase-3/7-dependent mechanism...
September 20, 2018: JCI Insight
Kenneth E Remy, Irene Cortés-Puch, Steven B Solomon, Junfeng Sun, Benjamin M Pockros, Jing Feng, Juan J Lertora, Roy R Hantgan, Xiaohua Liu, Andreas Perlegas, H Shaw Warren, Mark T Gladwin, Daniel B Kim-Shapiro, Harvey G Klein, Charles Natanson
During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity. CFH levels are elevated over approximately 24-48 hours in our antibiotic-treated canine model of S...
September 20, 2018: JCI Insight
Shelli F Farhadian, Sameet S Mehta, Chrysoula Zografou, Kevin Robertson, Richard W Price, Jenna Pappalardo, Jennifer Chiarella, David A Hafler, Serena S Spudich
Central nervous system (CNS) immune activation is an important driver of neuronal injury during several neurodegenerative and neuroinflammatory diseases. During HIV infection, CNS immune activation is associated with high rates of neurocognitive impairment, even during sustained long-term suppressive antiretroviral therapy (ART). However, the cellular subsets that drive immune activation and neuronal damage in the CNS during HIV infection and other neurological conditions remain unknown, in part because CNS cells are difficult to access in living humans...
September 20, 2018: JCI Insight
Mohammad Arifuzzaman, W X Gladys Ang, Hae Woong Choi, Matthew L Nilles, Ashley L St John, Soman N Abraham
When draining lymph nodes become infected by Yersinia pestis (Y. pestis), a massive influx of phagocytic cells occurs, resulting in distended and necrotic structures known as buboes. The bubonic stage of the Y. pestis life cycle precedes septicemia, which is facilitated by trafficking of infected mononuclear phagocytes through these buboes. However, how Y. pestis convert these immunocytes recruited by host to contain the pathogen into vehicles for bacterial dispersal and the role of immune cell death in this context are unknown...
September 20, 2018: JCI Insight
Federica Vecchio, Nicola Lo Buono, Angela Stabilini, Laura Nigi, Matthew J Dufort, Susan Geyer, Paola Maria Rancoita, Federica Cugnata, Alessandra Mandelli, Andrea Valle, Pia Leete, Francesca Mancarella, Peter S Linsley, Lars Krogvold, Kevan C Herold, Helena Elding Larsson, Sarah J Richardson, Noel G Morgan, Knut Dahl-Jørgensen, Guido Sebastiani, Francesco Dotta, Emanuele Bosi, Manuela Battaglia
BACKGROUND: Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported that the number of circulating neutrophils is reduced in patients with T1D and in presymptomatic at-risk subjects. The aim of the present work was to identify possible changes in circulating and pancreas-residing neutrophils throughout the disease course to better elucidate neutrophil involvement in human T1D...
September 20, 2018: JCI Insight
Richard M Jin, Jordan Warunek, Elizabeth A Wohlfert
The robust regenerative potential of skeletal muscle is imperative for the maintenance of tissue function across a host of potential insults including exercise, infection, and trauma. The highly coordinated action of multiple immune populations, especially macrophages, plays an indispensable role in guiding this reparative program. However, it remains unclear how skeletal muscle repair proceeds in a chronically inflamed setting, such as infection, where an active immune response is already engaged. To address this question, we used a cardiotoxin injury model to challenge the reparative potential of chronically infected muscle...
September 20, 2018: JCI Insight
Peter R Serafini, Michael J Feyder, Rylie M Hightower, Daniela Garcia-Perez, Natássia M Vieira, Angela Lek, Devin E Gibbs, Omar Moukha-Chafiq, Corinne E Augelli-Szafran, Genri Kawahara, Jeffrey J Widrick, Louis M Kunkel, Matthew S Alexander
Zebrafish are a powerful tool for studying muscle function owing to their high numbers of offspring, low maintenance costs, evolutionarily conserved muscle functions, and the ability to rapidly take up small molecular compounds during early larval stages. Fukutin-related protein (FKRP) is a putative protein glycosyltransferase that functions in the Golgi apparatus to modify sugar chain molecules of newly translated proteins. Patients with mutations in the FKRP gene can have a wide spectrum of clinical symptoms with varying muscle, eye, and brain pathologies depending on the location of the mutation in the FKRP protein...
September 20, 2018: JCI Insight
Gongbo Li, Justin C Boucher, Hiroshi Kotani, Kyungho Park, Yongliang Zhang, Bishwas Shrestha, Xuefeng Wang, Lawrence Guan, Nolan Beatty, Daniel Abate-Daga, Marco L Davila
Chimeric antigen receptors (CARs) have an antigen-binding domain fused to transmembrane, costimulatory, and CD3ζ domains. Two CARs with regulatory approval include a CD28 or 4-1BB costimulatory domain. While both CARs achieve similar clinical outcomes, biologic differences have become apparent but not completely understood. Therefore, in this study we aimed to identify mechanistic differences between 4-1BB and CD28 costimulation that contribute to the biologic differences between the 2 CARs and could be exploited to enhance CAR T cell function...
September 20, 2018: JCI Insight
Laura R Díaz, Elena Saavedra-López, Leire Romarate, Izaskun Mitxitorena, Paola V Casanova, George P Cribaro, José M Gallego, Ana Pérez-Vallés, Jerónimo Forteza-Vila, Clara Alfaro-Cervello, José M García-Verdugo, Carlos Barcia, Carlos Barcia
Since the proper activation of T cells requires the physical interaction with target cells through the formation of immunological synapses (IS), an alteration at this level could be a reason why tumors escape the immune response. As part of their life cycle, it is thought that T cells alternate between a static phase, the IS, and a dynamic phase, the immunological kinapse (IK), depending on high or low antigen sensing. Our investigation performed in tissue samples of human glioma shows that T cells are able to establish synapsing interactions not only with glioma tumorigenic cells, but also with stromal myeloid cells...
September 20, 2018: JCI Insight
Kandace Gollomp, Minna Kim, Ian Johnston, Vincent Hayes, John Welsh, Gowthami M Arepally, Mark Kahn, Michele P Lambert, Adam Cuker, Douglas B Cines, Lubica Rauova, M Anna Kowalska, Mortimer Poncz
Heparin-induced thrombocytopenia (HIT) is an immune-mediated thrombocytopenic disorder associated with a severe prothrombotic state. We investigated whether neutrophils and neutrophil extracellular traps (NETs) contribute to the development of thrombosis in HIT. Using an endothelialized microfluidic system and a murine passive immunization model, we show that HIT induction leads to increased neutrophil adherence to venous endothelium. In HIT mice, endothelial adherence is enhanced immediately downstream of nascent venous thrombi, after which neutrophils undergo retrograde migration via a CXCR2-dependent mechanism to accumulate into the thrombi...
September 20, 2018: JCI Insight
Rebecca T Veenhuis, Abena K Kwaa, Caroline C Garliss, Rachel Latanich, Maria Salgado, Christopher W Pohlmeyer, Christopher L Nobles, John Gregg, Eileen P Scully, Justin R Bailey, Frederic D Bushman, Joel N Blankson
Clonal expansion of T cells harboring replication-competent virus has recently been demonstrated in patients on suppressive antiretroviral therapy (ART) regimens. However, there has not been direct evidence of this phenomenon in settings of natural control, including in posttreatment controllers who maintain control of viral replication after treatment when ART is discontinued. We present a case of an individual who has had undetectable viral loads for more than 15 years following the cessation of ART. Using near-full-genome sequence analysis, we demonstrate that 9 of 12 replication-competent isolates cultured from this subject were identical and that this identity was maintained 6 months later...
September 20, 2018: JCI Insight
Geetha H Mylvaganam, Lynette S Chea, Gregory K Tharp, Sakeenah Hicks, Vijayakumar Velu, Smita S Iyer, Claire Deleage, Jacob D Estes, Steven E Bosinger, Gordon J Freeman, Rafi Ahmed, Rama R Amara
Therapeutic strategies that augment antiviral immunity and reduce the viral reservoir are critical to achieving durable remission of HIV. The coinhibitory receptor programmed death-1 (PD-1) regulates CD8+ T cell dysfunction during chronic HIV and SIV infections. We previously demonstrated that in vivo blockade of PD-1 during chronic SIV infection improves the function of antiviral CD8+ T cells and B cells. Here, we tested the immunological and virological effects of PD-1 blockade combined with antiretroviral therapy (ART) in rhesus macaques...
September 20, 2018: JCI Insight
Brendan Antiochos, Mariusz Matyszewski, Jungsan Sohn, Livia Casciola-Rosen, Antony Rosen
IFN-inducible protein 16 (IFI16) is an innate immune sensor that forms filamentous oligomers when activated by double-stranded DNA (dsDNA). Anti-IFI16 autoantibodies occur in patients with Sjögren's syndrome (SS) and associate with severe phenotypic features. We undertook this study to determine whether the structural and functional properties of IFI16 play a role in its status as an SS autoantigen. IFI16 immunostaining in labial salivary glands (LSGs) yielded striking evidence of filamentous IFI16 structures in the cytoplasm of ductal epithelial cells, representing the first microscopic description of IFI16 oligomerization in human tissues, to our knowledge...
September 20, 2018: JCI Insight
Clara Meana, Ginesa García-Rostán, Lucía Peña, Gema Lordén, África Cubero, Antonio Orduña, Balázs Győrffy, Jesús Balsinde, María A Balboa
Colon cancer is a devastating illness that is associated with gut inflammation. Here, we explored the possible role of lipin-1, a phosphatidic acid phosphatase, in the development of colitis-associated tumorigenesis. Azoxymethane and dextran sodium sulfate-treated (DSS-treated) animals deficient in lipin-1 harbored fewer tumors and carcinomas than WT animals due to decreased cellular proliferation, lower expression of antiapoptotic and protumorigenic factors, and a reduced infiltration of macrophages in colon tumors...
September 20, 2018: JCI Insight
Deshka S Foster, R Ellen Jones, Ryan C Ransom, Michael T Longaker, Jeffrey A Norton
The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries...
September 20, 2018: JCI Insight
Jasmine Samal, Samantha Kelly, Ali Na-Shatal, Abdallah Elhakiem, Antu Das, Ming Ding, Anwesha Sanyal, Phalguni Gupta, Kevin Melody, Brad Roland, Watfa Ahmed, Aala Zakir, Moses Bility
A major pathogenic feature associated with HIV infection is lymphoid fibrosis, which persists during antiretroviral therapy (ART). Lymphoid tissues play critical roles in the generation of antigen-specific immune response, and fibrosis disrupts the stromal network of lymphoid tissues, resulting in impaired immune cell trafficking and function, as well as immunodeficiency. Developing an animal model for investigating the impact of HIV infection-induced lymphoid tissue fibrosis on immunodeficiency and immune cell impairment is critical for therapeutics development and clinical translation...
September 20, 2018: JCI Insight
Shenpeng R Zhang, Marius Piepke, Hannah X Chu, Brad Rs Broughton, Raymond Shim, Connie Hy Wong, Seyoung Lee, Megan A Evans, Antony Vinh, Samy Sakkal, Thiruma V Arumugam, Tim Magnus, Samuel Huber, Mathias Gelderblom, Grant R Drummond, Christopher G Sobey, Hyun Ah Kim
Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain...
September 20, 2018: JCI Insight
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