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Abstract

BACKGROUND T cell responses to the common cold coronaviruses have not been well characterized. Preexisting T cell immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported, and a recent study suggested that this immunity was due to cross-recognition of the novel coronavirus by T cells specific for the common cold coronaviruses.METHODS We used the enzyme-linked immunospot (ELISPOT) assay to characterize the T cell responses against peptide pools derived from the spike protein of 3 common cold coronaviruses (HCoV-229E, HCoV-NL63, and HCoV-OC43) and SARS-CoV-2 in 21 healthy donors (HDs) who were seronegative for SARS-CoV-2 and had no known exposure to the virus. An in vitro expansion culture assay was also used to analyze memory T cell responses.RESULTS We found responses to the spike protein of the 3 common cold coronaviruses in many of the donors. We then focused on HCoV-NL63 and detected broad T cell responses to the spike protein and identified 22 targeted peptides. Interestingly, only 1 study participant had a significant response to SARS-CoV-2 spike or nucleocapsid protein in the ELISPOT assay. In vitro expansion studies suggested that T cells specific for the HCoV-NL63 spike protein in this individual could also recognize SARS-CoV-2 spike protein peptide pools.CONCLUSION HDs have circulating T cells specific for the spike proteins of HCoV-NL63, HCoV-229E, and HCoV-OC43. T cell responses to SARS-CoV-2 spike and nucleocapsid proteins were present in only 1 participant and were potentially the result of cross-recognition by T cells specific for the common cold coronaviruses. Further studies are needed to determine whether this cross-recognition influences coronavirus disease 2019 (COVID-19) outcomes.

Authors

Bezawit A. Woldemeskel, Abena K. Kwaa, Caroline C. Garliss, Oliver Laeyendecker, Stuart C. Ray, Joel N. Blankson

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Abstract

Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggest a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date, however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals have not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of 15 patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced p53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor that gives rise to the parallel evolution of GCTs and blood cancers in these patients.

Authors

Justin Taylor, Mark T.A. Donoghue, Caleb Ho, Kseniya Petrova-Drus, Hikmat A. Al-Ahmadie, Samuel A. Funt, Yanming Zhang, Umut Aypar, Pavitra Rao, Shweta S. Chavan, Michael Haddadin, Roni Tamari, Sergio Giralt, Martin S. Tallman, Raajit K. Rampal, Priscilla Baez, Rajya Kappagantula, Satyajit Kosuri, Ahmet Dogan, Satish K. Tickoo, Victor E. Reuter, George J. Bosl, Christine A. Iacobuzio-Donahue, David B. Solit, Barry S. Taylor, Darren R. Feldman, Omar Abdel-Wahab

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Abstract

BACKGROUND Understanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations.METHODS We retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available.RESULTS We identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354–1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients.CONCLUSION In this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution.FUNDING NIH grant P01 CA23766 and NIH/National Cancer Institute grant P30 CA008748.

Authors

Gunjan L. Shah, Susan DeWolf, Yeon Joo Lee, Roni Tamari, Parastoo B. Dahi, Jessica A. Lavery, Josel Ruiz, Sean M. Devlin, Christina Cho, Jonathan U. Peled, Ioannis Politikos, Michael Scordo, N. Esther Babady, Tania Jain, Santosha Vardhana, Anthony Daniyan, Craig S. Sauter, Juliet N. Barker, Sergio A. Giralt, Cheryl Goss, Peter Maslak, Tobias M. Hohl, Mini Kamboj, Lakshmi Ramanathan, Marcel R.M. van den Brink, Esperanza Papadopoulos, Genovefa Papanicolaou, Miguel-Angel Perales

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Abstract

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the urgent need for assays that detect protective levels of neutralizing antibodies. We studied the relationship among anti-spike ectodomain (anti-ECD), anti–receptor-binding domain (anti-RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by 2 in vitro assays using convalescent plasma samples from 68 patients with COVID-19. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers and in vitro VN titers. The probability of a VN titer of ≥160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment, was ≥80% when anti-RBD or anti-ECD titers were ≥1:1350. Of all donors, 37% lacked VN titers of ≥160. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease VN or IgG titers. Analysis of 2814 asymptomatic adults found 73 individuals with anti-ECD IgG titers of ≥1:50 and strong positive correlation with anti-RBD and VN titers. Fourteen of these individuals had VN titers of ≥1:160, and all of them had anti-RBD titers of ≥1:1350. We conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titers of ≥1:1350 may provide critical information about protection against COVID-19 disease.

Authors

Eric Salazar, Suresh V. Kuchipudi, Paul A. Christensen, Todd Eagar, Xin Yi, Picheng Zhao, Zhicheng Jin, S. Wesley Long, Randall J. Olsen, Jian Chen, Brian Castillo, Christopher Leveque, Dalton Towers, Jason Lavinder, Jimmy Gollihar, Jose Cardona, Gregory Ippolito, Ruth Nissly, Ian Bird, Denver Greenawalt, Randall M. Rossi, Abhinay Gontu, Sreenidhi Srinivasan, Indira Poojary, Isabella M. Cattadori, Peter J. Hudson, Nicole M. Josleyn, Laura Prugar, Kathleen Huie, Andrew Herbert, David W. Bernard, John M. Dye, Vivek Kapur, James M. Musser

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Abstract

Authors

Jill E. Weatherhead, Eva Clark, Tiphanie P. Vogel, Robert L. Atmar, Prathit A. Kulkarni

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Abstract

The transcription factor IFN regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 are associated with a risk of systemic lupus erythematosus (SLE), and mice lacking Irf5 are protected from lupus onset and severity, but how IRF5 functions in the context of SLE disease progression remains unclear. Using the NZB/W F1 model of murine lupus, we show that murine IRF5 becomes hyperactivated before clinical onset. In patients with SLE, IRF5 hyperactivation correlated with dsDNA titers. To test whether IRF5 hyperactivation is a targetable function, we developed inhibitors that are cell permeable, nontoxic, and selectively bind to the inactive IRF5 monomer. Preclinical treatment of NZB/W F1 mice with an inhibitor attenuated lupus pathology by reducing serum antinuclear autoantibodies, dsDNA titers, and the number of circulating plasma cells, which alleviated kidney pathology and improved survival. Clinical treatment of MRL/lpr and pristane-induced lupus mice with an inhibitor led to significant reductions in dsDNA levels and improved survival. In ex vivo human studies, the inhibitor blocked SLE serum–induced IRF5 activation and reversed basal IRF5 hyperactivation in SLE immune cells. We believe this study provides the first in vivo clinical support for treating patients with SLE with an IRF5 inhibitor.

Authors

Su Song, Saurav De, Victoria Nelson, Samin Chopra, Margaret LaPan, Kyle Kampta, Shan Sun, Mingzhu He, Cherrie D. Thompson, Dan Li, Tiffany Shih, Natalie Tan, Yousef Al-Abed, Eugenio Capitle, Cynthia Aranow, Meggan Mackay, William L. Clapp, Betsy J. Barnes

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Abstract

Human coronaviruses (hCoVs) cause severe respiratory illness in the elderly. Age-related impairments in innate immunity and suboptimal virus-specific T cell and antibody responses are believed to cause severe disease upon respiratory virus infections. This phenomenon has recently received increased attention, as elderly patients are at substantially elevated risk for severe COVID-19 disease and experience increased rates of mortality following SARS-CoV-2 infection compared with younger populations. However, the basis for age-related fatal pneumonia following pathogenic hCoVs is not well understood. In this Review, we provide an overview of our current understanding of hCoV-induced fatal pneumonia in the elderly. We describe host immune response to hCoV infections derived from studies of young and aged animal models and discuss the potential role of age-associated increases in sterile inflammation (inflammaging) and virus-induced dysregulated inflammation in causing age-related severe disease. We also highlight the existing gaps in our knowledge about virus replication and host immune responses to hCoV infection in young and aged individuals.

Authors

Rudragouda Channappanavar, Stanley Perlman

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Abstract

Patients with type 2 diabetes (T2D) fail to secrete insulin in response to increased glucose levels that occur with eating. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two incretins secreted from gastrointestinal cells that amplify insulin secretion when glucose is high. In this issue of the JCI, Oduori et al. explore the role of ATP-sensitive K+ (KATP) channels in maintaining glucose homeostasis. In persistently depolarized β cells from KATP channel knockout (KO) mice, the researchers revealed a shift in G protein signaling from the Gs family to the Gq family. This shift explains why GLP-1, which signals via Gq, but not GIP, which signals preferentially via Gs, can effectively potentiate secretion in islets from the KATP channel–deficient mice and in other models of KATP deficiency, including diabetic KK-Ay mice. Their results provide one explanation for differential insulinotropic potential of incretins in human T2D and point to a potentially unifying model for T2D progression itself.

Authors

Colin G. Nichols, Nathaniel W. York, Maria S. Remedi

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Abstract

Tertiary lymphoid organs are aggregates of immune and stromal cells including high endothelial venules and lymphatic vessels that resemble secondary lymphoid organs and can be induced at nonlymphoid sites during inflammation. The function of lymphatic vessels within tertiary lymphoid organs remains poorly understood. During lung transplant tolerance, Foxp3+ cells accumulate in tertiary lymphoid organs that are induced within the pulmonary grafts and are critical for the local downregulation of alloimmune responses. Here, we showed that tolerant lung allografts could induce and maintain tolerance of heterotopic donor-matched hearts through pathways that were dependent on the continued presence of the transplanted lung. Using lung retransplantation, we showed that Foxp3+ cells egressed from tolerant lung allografts via lymphatics and were recruited into donor-matched heart allografts. Indeed, survival of the heart allografts was dependent on lymphatic drainage from the tolerant lung allograft to the periphery. Thus, our work indicates that cellular trafficking from tertiary lymphoid organs regulates immune responses in the periphery. We propose that these findings have important implications for a variety of disease processes that are associated with the induction of tertiary lymphoid organs.

Authors

Wenjun Li, Jason M. Gauthier, Alice Y. Tong, Yuriko Terada, Ryuji Higashikubo, Christian C. Frye, Margaret S. Harrison, Kohei Hashimoto, Amit I. Bery, Jon H. Ritter, Ruben G. Nava, Varun Puri, Brian W. Wong, Kory J. Lavine, Ankit Bharat, Alexander S. Krupnick, Andrew E. Gelman, Daniel Kreisel

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Abstract

By restoring glucose-regulated insulin secretion, glucagon-like peptide-1–based (GLP-1–based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic β cells. However, the reason why only GLP-1–based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K+ (KATP) channels play a crucial role in coupling the systemic metabolic status to β cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of β cells due to genetic (β cell–specific Kcnj11–/– mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the KATP channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse β cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in β cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.

Authors

Okechi S. Oduori, Naoya Murao, Kenju Shimomura, Harumi Takahashi, Quan Zhang, Haiqiang Dou, Shihomi Sakai, Kohtaro Minami, Belen Chanclon, Claudia Guida, Lakshmi Kothegala, Johan Tolö, Yuko Maejima, Norihide Yokoi, Yasuhiro Minami, Takashi Miki, Patrik Rorsman, Susumu Seino

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Abstract

Some germ cell tumors (GCTs) in men develop into hematologic malignancies; however, the clonal origins of such malignancies remain unknown. In this issue of the JCI, Taylor, Donoghue, et al. unravel the clonal relationship between primary mediastinal nonseminomas (PMNs) and hematologic somatic-type malignancies (HSTMs). Whole-exome sequencing was used to construct phylogenetic trees of the PMNs and the ensuing HSTM clones. HSTMs were derived from multiple distinct clones not detected within the PMNs. Clones from PMNs and HSTMs shared a common precursor, arguably an embryonal carcinoma cell resulting from a reprogrammed primordial germ cell from the thymus. Mutational and copy number variation analysis of a large cohort of patients with PMNs also demonstrated a high prevalence of TP53 mutations not found in testicular nonseminomas. These data likely explain why patients with PMNs are frequently resistant to platinum-based chemotherapy and provide TP53 mutations as potential targets.

Authors

J. Wolter Oosterhuis, Leendert H.J. Looijenga

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Abstract

BACKGROUND Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODS We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTS In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSION Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATION International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDING National Institute for Health Research and NIH.

Authors

Ali Abbara, Pei Chia Eng, Maria Phylactou, Sophie A. Clarke, Rachel Richardson, Charlene M. Sykes, Chayarndorn Phumsatitpong, Edouard Mills, Manish Modi, Chioma Izzi-Engbeaya, Debbie Papadopoulou, Kate Purugganan, Channa N. Jayasena, Lisa Webber, Rehan Salim, Bryn Owen, Paul Bech, Alexander N. Comninos, Craig A. McArdle, Margaritis Voliotis, Krasimira Tsaneva-Atanasova, Suzanne Moenter, Aylin Hanyaloglu, Waljit S. Dhillo

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Abstract

Human antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hold intense interest, with research efforts directed at optimizing antibody-based interventions and monitoring immune status. By relating individual variations in antibody response to coronavirus disease 2019 (COVID-19) severity, beneficial antiviral immune responses may be identified in detail. In this issue of the JCI, Secchi and collaborators describe antibody response profiles in 509 patients with COVID-19 from Italy during the 2020 pandemic. The research team found that multiple antibody types to multiple SARS-CoV-2 antigens developed over four weeks. Notably, IgG against the spike receptor binding domain (RBD) was predictive of survival and IgA against the viral spike protein (S protein) associated with rapid virologic clearance. These results may help guide selection of convalescent plasma, hyperimmune products, monoclonal antibodies, and vaccine strategies for COVID-19.

Authors

Jeffrey P. Henderson

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Abstract

Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from patients with sickle cell disease (SCD) induces fetal hemoglobin (HbF) without detectable toxicity, as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer–edited HSPCs in 4 nonhuman primates. We used a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits persisted in peripheral blood (PB) and bone marrow (BM) for up to 101 weeks similarly for BCL11A enhancer– or control locus–targeted (AAVS1-targeted) cells. Biallelic BCL11A enhancer editing resulted in robust γ-globin induction, with the highest levels observed during stress erythropoiesis. Indels were evenly distributed across PB and BM lineages. Off-target edits were not observed. Nonhomologous end-joining repair alleles were enriched in engrafting HSCs. In summary, we found that edited HSCs can persist for at least 101 weeks after transplant and biallelic-edited HSCs provide substantial HbF levels in PB red blood cells, together supporting further clinical translation of this approach.

Authors

Selami Demirci, Jing Zeng, Yuxuan Wu, Naoya Uchida, Anne H. Shen, Danilo Pellin, Jackson Gamer, Morgan Yapundich, Claire Drysdale, Jasmine Bonanno, Aylin C. Bonifacino, Allen E. Krouse, Nathaniel S. Linde, Theresa Engels, Robert E. Donahue, Juan J. Haro-Mora, Alexis Leonard, Tina Nassehi, Kevin Luk, Shaina N. Porter, Cicera R. Lazzarotto, Shengdar Q. Tsai, Mitchell J. Weiss, Shondra M. Pruett-Miller, Scot A. Wolfe, Daniel E. Bauer, John F. Tisdale

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Abstract

The sodium-phosphate cotransporter NPT2a plays a key role in the reabsorption of filtered phosphate in proximal renal tubules, thereby critically contributing to phosphate homeostasis. Inadequate urinary phosphate excretion can lead to severe hyperphosphatemia as in tumoral calcinosis and chronic kidney disease (CKD). Pharmacological inhibition of NPT2a may therefore represent an attractive approach for treating hyperphosphatemic conditions. The NPT2a-selective small-molecule inhibitor PF-06869206 was previously shown to reduce phosphate uptake in human proximal tubular cells in vitro. Here, we investigated the acute and chronic effects of the inhibitor in rodents and report that administration of PF-06869206 was well tolerated and elicited a dose-dependent increase in fractional phosphate excretion. This phosphaturic effect lowered plasma phosphate levels in WT mice and in rats with CKD due to subtotal nephrectomy. PF-06869206 had no effect on Npt2a-null mice, but promoted phosphate excretion and reduced phosphate levels in normophophatemic mice lacking Npt2c and in hyperphosphatemic mice lacking Fgf23 or Galnt3. In CKD rats, once-daily administration of PF-06869206 for 8 weeks induced an unabated acute phosphaturic and hypophosphatemic effect, but had no statistically significant effect on FGF23 or PTH levels. Selective pharmacological inhibition of NPT2a thus holds promise as a therapeutic option for genetic and acquired hyperphosphatemic disorders.

Authors

Valerie Clerin, Hiroshi Saito, Kevin J. Filipski, An Hai Nguyen, Jeonifer Garren, Janka Kisucka, Monica Reyes, Harald Jüppner

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Abstract

Tregs require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Tregs persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator ubiquitin-like with plant homeodomain and RING finger domains 1 (Uhrf1) is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet nonuniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg lineage, and spontaneous inflammation. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg genome for both lineage establishment and stability of identity and suppressive function.

Authors

Kathryn A. Helmin, Luisa Morales-Nebreda, Manuel A. Torres Acosta, Kishore R. Anekalla, Shang-Yang Chen, Hiam Abdala-Valencia, Yuliya Politanska, Paul Cheresh, Mahzad Akbarpour, Elizabeth M. Steinert, Samuel E. Weinberg, Benjamin D. Singer

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Abstract

Chronic viral infections are often established by the exploitation of immune-regulatory mechanisms that result in nonfunctional T cell responses. Viruses that establish persistent infections remain a serious threat to human health. Sphingosine kinase 2 (SphK2) generates sphingosine 1-phosphate, which is a molecule known to regulate multiple cellular processes. However, little is known about SphK2’s role during the host immune responses to viral infection. Here, we demonstrate that SphK2 functions during lymphocytic choriomeningitis virus Cl 13 (LCMV Cl 13) infection to limit T cell immune pathology, which subsequently aids in the establishment of virus-induced immunosuppression and the resultant viral persistence. The infection of Sphk2-deficient (Sphk2–/–) mice with LCMV Cl 13 led to the development of nephropathy and mortality via T cell–mediated immunopathology. Following LCMV infection, Sphk2–/– CD4+ T cells displayed increased activity and proliferation, and these cells promoted overactive LCMV Cl 13–specific CD8+ T cell responses. Notably, oral instillation of an SphK2-selective inhibitor promoted protective T cell responses and accelerated the termination of LCMV Cl 13 persistence in mice. Thus, SphK2 is indicated as an immunotherapeutic target for the control of persistent viral infections.

Authors

Caleb J. Studstill, Curtis J. Pritzl, Young-Jin Seo, Dae Young Kim, Chuan Xia, Jennifer J. Wolf, Ravi Nistala, Madhuvanthi Vijayan, Yong-Bin Cho, Kyung Won Kang, Sang-Myeong Lee, Bumsuk Hahm

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Abstract

Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress–induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress–induced mood disorders, such as anxiety, influence bone metabolism.

Authors

Fan Yang, Yunhui Liu, Shanping Chen, Zhongquan Dai, Dazhi Yang, Dashuang Gao, Jie Shao, Yuyao Wang, Ting Wang, Zhijian Zhang, Lu Zhang, William W. Lu, Yinghui Li, Liping Wang

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Abstract

BACKGROUND Serological assays are of critical importance to investigate correlates of response and protection in coronavirus disease 2019 (COVID-19), to define previous exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in populations, and to verify the development of an adaptive immune response in infected individuals.METHODS We studied 509 patients confirmed to have COVID-19 from the San Raffaele Hospital of Milan and 480 samples of prepandemic organ donor sera collected in 2010–2012. Using fluid-phase luciferase immune precipitation (LIPS) assays, we characterized IgG, IgM, and IgA antibodies to the spike receptor binding domain (RBD), S1+S2, nucleocapsid, and ORF6 to ORF10 of SARS-CoV-2, to the HCoV-OC43 and HCoV-HKU1 betacoronaviruses spike S2, and the H1N1Ca2009 flu virus hemagglutinin. Sequential samples at 1 and 3 months after hospital discharge were also tested for SARS-CoV-2 RBD antibodies in 95 patients.RESULTS Antibodies developed rapidly against multiple SARS-CoV-2 antigens in 95% of patients by 4 weeks after symptom onset and IgG to the RBD increased until the third month of follow-up. We observed a major synchronous expansion of antibodies to the HCoV-OC43 and HCoV-HKU1 spike S2. A likely coinfection with influenza was neither linked to a more severe presentation of the disease nor to a worse outcome. Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival.CONCLUSION The measurement of antibodies to selected epitopes of SARS-CoV-2 antigens can offer a more accurate assessment of the humoral response in patients and its impact on survival. The presence of partially cross-reactive antibodies with other betacoronaviruses is likely to impact on serological assay specificity and interpretation.TRIAL REGISTRATION COVID-19 Patients Characterization, Biobank, Treatment Response and Outcome Predictor (COVID-BioB). ClinicalTrials.gov identifier: NCT04318366.FUNDING IRCCS Ospedale San Raffaele and Università Vita Salute San Raffaele.

Authors

Massimiliano Secchi, Elena Bazzigaluppi, Cristina Brigatti, Ilaria Marzinotto, Cristina Tresoldi, Patrizia Rovere-Querini, Andrea Poli, Antonella Castagna, Gabriella Scarlatti, Alberto Zangrillo, Fabio Ciceri, Lorenzo Piemonti, Vito Lampasona

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Abstract

BACKGROUND Interpatient differences in the accumulation of methotrexate’s active polyglutamylated metabolites (MTXPGs) in leukemia cells influence its antileukemic effects.METHODS To identify genomic and epigenomic and patient variables determining the intracellular accumulation of MTXPGs, we measured intracellular MTXPG levels in acute lymphoblastic leukemia (ALL) cells from 388 newly diagnosed patients after in vivo high-dose methotrexate (HDMTX) (1 g/m2) treatment, defined ALL subtypes, and assessed genomic and epigenomic variants influencing folate pathway genes (mRNA, miRNA, copy number alterations [CNAs], SNPs, single nucleotide variants [SNVs], CpG methylation).RESULTS We documented greater than 100-fold differences in MTXPG levels, which influenced its antileukemic effects (P = 4 × 10–5). Three ALL subtypes had lower MTXPG levels (T cell ALL [T-ALL] and B cell ALL [B-ALL] with the TCF3-PBX1 or ETV6-RUNX1 fusions), and 2 subtypes had higher MTXPG levels (hyperdiploid and BCR-ABL like). The folate pathway genes SLC19A1, ABCC1, ABCC4, FPGS, and MTHFD1 significantly influenced intracellular MTXPG levels (P = 2.9 × 10–3 to 3.7 × 10–8). A multivariable model including the ALL subtype (P = 1.1 × 10–14), the SLC19A1/(ABCC1 + ABCC4) transporter ratio (P = 3.6 × 10–4), the MTX infusion time (P = 1.5 × 10–3), FPGS mRNA expression (P = 2.1 × 10–3), and MTX systemic clearance (P = 4.4 × 10–2) explained 42% of the variation in MTXPG accumulation (P = 1.1 × 10–38). Model simulations indicated that a longer infusion time (24 h vs. 4 h) was superior in achieving higher intracellular MTXPG levels across all subtypes if ALL.CONCLUSIONS These findings provide insights into mechanisms underlying interpatient differences in intracellular accumulation of MTXPG in leukemia cells and its antileukemic effectsFUNDING THE National Cancer Institute (NCI) and the Institute of General Medical Sciences of the NIH, the Basque Government Programa Posdoctoral de Perfeccionamiento de Personal Investigador doctor, and the American Lebanese Syrian Associated Charities (ALSAC).

Authors

Elixabet Lopez-Lopez, Robert J. Autry, Colton Smith, Wenjian Yang, Steven W. Paugh, John C. Panetta, Kristine R. Crews, Erik J. Bonten, Brandon Smart, Deqing Pei, J. Robert McCorkle, Barthelemy Diouf, Kathryn G. Roberts, Lei Shi, Stanley Pounds, Cheng Cheng, Charles G. Mullighan, Ching-Hon Pui, Mary V. Relling, William E. Evans

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Abstract

Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no cure. Using conditional knockout mice, we found that ablation of the genomic organizer Special AT-rich sequence-binding protein-1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T-cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T-cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T-cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition), restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with Mycosis fungoides/Sézary syndrome, a set of incurable diseases.

Authors

Carly M. Harro, Jairo Perez-Sanz, Tara Lee Costich, Kyle K. Payne, Carmen M. Anadon Galindo, Ricardo A. Chaurio, Subir Biswas, Gunjan Mandal, Kristen E. Rigolizzo, Kimberly B. Sprenger, Jessica A. Mine, Louise Showe, Xiaoqing Yu, Kebin Liu, Paulo C. Rodriguez, Javier Pinilla-Ibarz, Lubomir Sokol, Jose R. Conejo-Garcia

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Abstract

In this viewpoint, Robert Califf, former commissioner of the U.S. Food and Drug Administration, and colleagues reflect on how to approach questions about which patient treatments and strategies work, particularly in light of the tremendous pressure on the government and biomedical research enterprise to quickly develop safe, effective therapies during the SARS-CoV-2 pandemic.

Authors

Robert M. Califf, Lesley H. Curtis, Robert A. Harrington, Adrian F. Hernandez, Eric D. Peterson

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Abstract

Randomized controlled trials are the preferred design for the analysis of health-related interventions. In this Viewpoint, Nigel Paneth and Michael Joyner discuss circumstances when randomized controlled trials might not be feasible and the criteria that should be used when considering applying observational data medicine.

Authors

Nigel Paneth, Michael Joyner

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Abstract

The triggering receptor expressed on myeloid cells-1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of Angiotensin (Ang) II-induced AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalizes with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2 and Mmp9 mRNA expression, and led to a decreased macrophage content, due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L up-regulation and promoted pro-inflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII Receptor Type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared to patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in human.

Authors

Marie Vandestienne, Yujiao Zhang, Icia Santos-Zas, Rida Al-Rifai, Jeremie Joffre, Andreas Giraud, Ludivine Laurans, Bruno Esposito, Florence Pinet, Patrick Bruneval, Juliette Raffort, Fabien Lareyre, Jose Vilar, Amir Boufenzer, Lea Guyonnet, Coralie L. Guerin, Eric Clauser, Jean-Sébastien Silvestre, Sylvie Lang, Laurie Soulat-Dufour, Alain Tedgui, Ziad Mallat, Soraya Taleb, Alexandre Boissonnas, Marc Derive, Giulia Chinetti, Hafid Ait-Oufella

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Abstract

Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anti-cancer target. However, only a fraction of cancer patients benefits from angiogenesis inhibitors. Whether anti-angiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric – the Endothelial Index (EI) – to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypo-vascular tumors, enabling the classification of human tumors into six vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular hub genes. EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Our studies thus provide an unbiased picture of human tumor vasculature which may enable more precise deployment of anti-angiogenesis therapy.

Authors

Benjamin M. Kahn, Alfredo Lucas, Rohan Alur, Maximilian D. Wengyn, Gregory W. Schwartz, Jinyang Li, Kathryn Sun, H. Carlo Maurer, Kenneth P. Olive, Robert B. Faryabi, Ben Stanger

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Latest issue: December 1, 2020

December 1, 2020, issue

On the cover:
<i>YIPF5</i> mutations linked to neonatal diabetes and ER stress

Neonatal diabetes (NDM) results from single-gene mutations that impair β cell function or negatively impact β cell populations. In this issue of the JCI, De Franco et al. investigate homozygous mutations in YIPF5 identified in 6 patients with NDM and microcephaly from 5 families. YIPF5-mutant β cells differentiated from genetically engineered human embryonic stem cells (hESCs) displayed proinsulin accumulation, increased ER stress, and impaired C-peptide secretion in the implanted mice, providing a mechanistic explanation for insulin deficiency in affected patients. In addition to characterizing a novel gene underlying NDM with neurological features, the work provides novel insights into biological pathways essential for β cell function. The cover image depicts an hESC-derived islet implanted under the kidney capsule of immunocompromised mice, showing β cells in yellow, α cells in cyan, and nuclei in red. Image credit: Hazem Ibrahim, Jonna Saarimäki-Vire, and Hossam Montaser.

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December 2020 JCI This Month

JCI This Month is a digest of the research, reviews, and other features published each month.

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Review Series - More

Hypoxia-inducible factors in disease pathophysiology and therapeutics

Series edited by Gregg L. Semenza

Maintaining adequate oxygen levels in the organs and tissues of multicellular organisms is essential to preserving cellular metabolism and bioenergetics. When oxygen levels fall below normal physiological levels, hypoxia signaling pathways trigger physiological changes meant to evoke adaptive responses at organismal, tissue, and cellular levels. Hypoxia-inducible factors (HIFs) are positioned at the crux of these oxygen-sensing mechanisms, regulating a multitude of transcriptional programs that control angiogenesis, metabolism, immune function, erythropoiesis, and more. In this issue, a review series created by JCI’s deputy editor Gregg Semenza highlights how HIFs contribute to the pathogenesis and treatment of human disease. The reviews describe the hypoxic conditions that drive or exacerbate pathophysiology in diseases ranging from pulmonary hypertension to cancer. Moreover, they highlight HIF-targeting strategies in preclinical and clinical development, discussing their potential to improve the therapeutic outcomes in these diseases.

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