Featured
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| Open AccessSingle-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications
Anti-melanoma differentiation-associated gene 5-positive dermatomyositis is a severe autoimmune disease with largely unknown aetiology. Here authors identify the key immune cell types that contribute to the disease phenotype and implicate type I interferons signalling in the patho-mechanism.
- Yan Ye
- , Zechuan Chen
- & Xiaoming Zhang
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Article
| Open AccessDNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.
- Antonella Fazio
- , Dora Bordoni
- & Philip Rosenstiel
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Article
| Open AccessSystems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function
Fibroblast-like synoviocytes (FLS) are used as a model of rheumatoid arthritis synoviocytes, although cell lines derived from individual patients can have heterogeneous biology. Here the authors use a Taiji computational approach to analyze gene expression, chromatin accessibility and functional differences between individual patient-derived RA FLS lines.
- Richard I. Ainsworth
- , Deepa Hammaker
- & Wei Wang
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Article
| Open AccessThe Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement
Disrupting the association between the Immunoglobulin G constant fragment (Fc) and the neonatal Fc receptor (FcRn) by engineered antibodies is a promising strategy to reduce autoantibody levels in autoimmune diseases. Here authors show that the variable fragment (Fab) of immunoglobulins could disturb the Fc-FcRn interaction, therefore the therapeutic effect of Fc-only fragments might surpass that of Fc-engineered antibodies with enhanced binding to FcRn.
- Maximilian Brinkhaus
- , Erwin Pannecoucke
- & Gestur Vidarsson
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Article
| Open AccessMulticellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis
Uveitis is a complex autoimmune inflammatory disease of the eye and defining molecules involved is a priority. Here the authors use scRNA sequencing in mouse experimental autoimmune uveitis (EAU) and show PIM1 promotes the imbalance of Th17 and Treg cells, and find elevated PIM-1 in human uveitis disease.
- He Li
- , Lihui Xie
- & Wenru Su
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Article
| Open AccessHeterologous vector versus homologous mRNA COVID-19 booster vaccination in non-seroconverted immunosuppressed patients: a randomized controlled trial
Optimizing COVID-19 vaccination strategies for patients under immunosuppressive medication is of high importance. In this clinical trial including non-seroconverted immunosuppressed patients, a homologous mRNA booster vaccination resulted in higher seroconversion rate than a switch to a vector-based vaccine.
- Daniel Mrak
- , Daniela Sieghart
- & Michael Bonelli
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Article
| Open AccessPD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability
Regulatory T (Treg) cells have been implicated in the induction of airway tolerance and amelioration of respiratory duct inflammation. Here the authors show, using PD-L2 deficient mice, that the immune suppression signal from PD-L2 is important for modulating Treg cell metabolism and function for proper induction of respiratory tolerance in mice.
- Benjamin P. Hurrell
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessSingle cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease
Celiac disease is linked to responsiveness to dietary gluten, which manifests itself as immune cell activation and the immunopathology including destruction of the epithelium of the small intestine. Here the authors apply single cell transcriptomics to characterise the immune cell compartment of the human small intestine during active Celiac disease.
- Nader Atlasy
- , Anna Bujko
- & Hendrik G. Stunnenberg
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Article
| Open AccessSynthesis of bioactive (1→6)-β-glucose branched poly-amido-saccharides that stimulate and induce M1 polarization in macrophages
Difficulty with purification, structural heterogenicity, and limited water solubility of β-glucans has significantly limited their therapeutic applications. Here, the authors report the synthesis of (1→6)-β-glucose-branched poly-amido-saccharides as glycan-mimetics and demonstrate macrophage stimulation and polarization.
- Ruiqing Xiao
- , Jialiu Zeng
- & Mark W. Grinstaff
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Article
| Open AccessMyasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma
Myasthenia Gravis and thymoma are frequently associated with patients suffering from both diseases. Here the authors perform single cell sequencing of thymoma and find that there are autoimmune antigens such as neuromuscular proteins expressed aberrantly in neuromuscular mTECs in patients with both diseases.
- Yoshiaki Yasumizu
- , Naganari Ohkura
- & Hideki Mochizuki
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Article
| Open AccessCigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells
Cigarette smoking may exacerbate asthma, but the underlying mechanisms have not been studied extensively in human patients. Here authors show that type 3 innate lymphoid cells with activated phenotypes are found in the sputum and blood of smokers in higher frequencies, which might result in the aggravation of asthma.
- Jongho Ham
- , Jihyun Kim
- & Hye Young Kim
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Poster
| Open AccessImmune monitoring and treatment in immune-mediated inflammatory diseases
Immune monitoring assists in the diagnosis and clinical management of immune-mediated inflammatory diseases.
- Femke van Wijk
- , Marjolein de Bruin
- & Stefan Nierkens
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Article
| Open AccessTemporal changes in gastrointestinal fungi and the risk of autoimmunity during early childhood: the TEDDY study
Here, via metagenomics and ITS2 sequencing analysis of children's stool samples from three months to four years, the authors show that the fungal composition changes and relative abundance increases at weaning, but unlike bacteria, the overall levels of fungal diversity do not change substantially over time.
- Thomas A. Auchtung
- , Christopher J. Stewart
- & Joseph F. Petrosino
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Article
| Open AccessInhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis
Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.
- William Damsky
- , Alice Wang
- & Brett King
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Article
| Open AccessThe phosphatase PTEN links platelets with immune regulatory functions of mouse T follicular helper cells
Platelets have been shown to alter immune cell function but it is not clear if this includes autoimmunity. Here the authors show that phosphatase and tensin homolog (PTEN) deficient platelets promote autoimmunity in mouse models through excessive activation of TFH cells and systemic autoimmune pathology.
- Xue Chen
- , Yanyan Xu
- & Junling Liu
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Article
| Open AccessCumulative SARS-CoV-2 mutations and corresponding changes in immunity in an immunocompromised patient indicate viral evolution within the host
Variants of concerns arise from SARS-CoV-2 mutations poise as severe public health threats. Here the authors chronicle SARS-CoV-2 mutations onset and immune parameters in an immunocompromised patient with continuous virus-shedding, thereby hinting potential intra-host viral evolution and escape facilitated by ineffective T cell immunity.
- Sissy Therese Sonnleitner
- , Martina Prelog
- & Gernot Walder
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Article
| Open AccessDeficiency in coatomer complex I causes aberrant activation of STING signalling
Mutations in the coatomer complex I can result in endoplasmic reticulum stress and inflammatory consequences. Here authors define aberrant activation of the STING immunosensing pathway in a disturbed coatmer complex context and the therapeutic modulation of this axis to counter the associated immunopathology.
- Annemarie Steiner
- , Katja Hrovat-Schaale
- & Seth L. Masters
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Article
| Open AccessChildhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach
The rise in type 1 diabetes is thought to be related to increased childhood obesity, but this relationship is not well understood. In this study, the authors utilize Mendelian randomization to separate the direct and indirect effects of childhood body size on risk of type 1 diabetes and 7 other immune-associated disease outcomes.
- Tom G. Richardson
- , Daniel J. M. Crouch
- & George Davey Smith
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Article
| Open AccessTNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease
Reduction of systemic autoimmunity using TNF blockers may also reduce inflammatory diseases in other organs. Here, the authors use a patient database and scRNA-seq to link autoimmune diseases to benign prostatic hyperplasia (BPH), and demonstrate that prostatic hyperplasia is reduced by TNF blockers in humans and mice.
- Renee E. Vickman
- , LaTayia Aaron-Brooks
- & Simon W. Hayward
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Article
| Open AccessConstruction of a two-dimensional artificial antioxidase for nanocatalytic rheumatoid arthritis treatment
Inflammatory diseases such as rheumatoid arthritis are associated with high reactive oxygen species levels. Here, the authors report on 2D metal-organic frameworks as an artificial antioxidase with the same manganese coordination centre as two natural enzymes, and demonstrate their anti-inflammatory effects and anti-arthritic effects in vivo.
- Bowen Yang
- , Heliang Yao
- & Jianlin Shi
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Article
| Open AccessSingle-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses
Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency. Here the authors perform single-cell omics analyses in CVID-discordant monozygotic twins and show epigenetic and transcriptional alterations associated with activation in memory B cells.
- Javier Rodríguez-Ubreva
- , Anna Arutyunyan
- & Esteban Ballestar
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Article
| Open AccessProgression of type 1 diabetes from latency to symptomatic disease is predicted by distinct autoimmune trajectories
Presence of islet autoantibodies precedes the onset of type 1 diabetes but it does not predict whether and how fast symptomatic disease appears. Here authors present a model to predict and visualize progression to diabetes by using a large longitudinal data set on autoantibodies and clinical parameters as input.
- Bum Chul Kwon
- , Vibha Anand
- & Brigitte I. Frohnert
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Article
| Open AccessHomeostatic serum IgE is secreted by plasma cells in the thymus and enhances mast cell survival
Elevated levels of IgE is associated with a range of allergic pathology but the source of such IgE producing B cells during the steady state is poorly understood. Here, Kwon et al. show that homeostatic IgE is secreted by plasma cells in the thymus and link this to mast cell survival.
- Dong-il Kwon
- , Eun Seo Park
- & You Jeong Lee
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Article
| Open AccessLymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto’s thyroiditis
Hashimoto’s Thyroiditis is an autoimmune disease with a complex pathomechanism. Authors here show by single cell RNA sequencing that the thyroidal microenvironment in the disease is characterised by three stromal cell subtypes that are potentially responsible for the recruitment of infiltrating inflammatory immune cells, such as macrophages and dendritic cells.
- Qian-Yue Zhang
- , Xiao-Ping Ye
- & Huai-Dong Song
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Article
| Open AccessDefective humoral immunity disrupts bile acid homeostasis which promotes inflammatory disease of the small bowel
Mucosal antibodies maintain gut homeostasis, and may influence gut health through modulation of microbiota composition. Here the authors use a CD19-deficient mouse model with deficient B-cell immune responses to uncover an association between humoral immunodeficiency, dysbiosis, and perturbations to bile acid homeostasis in the gut in the context of glute-sensitive enteropathy.
- Ahmed Dawood Mohammed
- , Zahraa Mohammed
- & Jason L. Kubinak
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Article
| Open AccessDNA/RNA heteroduplex oligonucleotide technology for regulating lymphocytes in vivo
Using gene silencing to regulate lymphocyte function is a promising therapeutic approach for autommunity, inflammation and cancer. Here the authors use a heteroduplex oligonucleotide for improved potency, efficacy and longer retention times.
- Masaki Ohyagi
- , Tetsuya Nagata
- & Takanori Yokota
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Article
| Open AccessHeterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency
Genetic variants of proteasome subunit genes have been shown to associate with perturbed immune function. Here authors show that a heterozygous missense variant of the immunoproteasome subunit β-type 9 causes an autoinflammatory/immune deficiency syndrome in humans and in a mouse model.
- Nobuo Kanazawa
- , Hiroaki Hemmi
- & Tsuneyasu Kaisho
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Article
| Open AccessG-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through autocrine/paracrine mediators
P2Y10 is a G-protein-coupled receptor that is expressed in CD4 T cells. Here authors show that its ligands, lysophosphatidylserine and ATP, are induced in T cells upon chemokine stimulation and regulate RhoA activation and migration through an autocrine/paracrine loop.
- Malarvizhi Gurusamy
- , Denise Tischner
- & Nina Wettschureck
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Article
| Open AccessRare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.
- Sarah Grosche
- , Ingo Marenholz
- & Young-Ae Lee
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Article
| Open AccessClonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils
Pulmonary hypertension is characterized by increased pulmonary arterial pressure, driven in part by inflammatory infiltrates. Here, the authors show that in mice, transgenic expression of mutant JAK2 leads to clonal hematopoiesis and lung accumulation of elastase- and cytokine-expressing neutrophils, and that the phenotype can be reversed by ALK1 inhibition.
- Yusuke Kimishima
- , Tomofumi Misaka
- & Yasuchika Takeishi
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Article
| Open AccessInvestigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases
An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well-established, but a genetic link is unclear. Here, the authors investigate the shared genetic architecture between MS and IBD to shed light on the biological basis of comorbidity.
- Yuanhao Yang
- , Hannah Musco
- & Yuan Zhou
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Article
| Open AccessAltered function and differentiation of age-associated B cells contribute to the female bias in lupus mice
Autoimmunity mediated by age-associated B cells (ABC) can affect males and females differently. Here, using a lupus-like mouse model that affects females more severely, the authors observe an ABC mediated and guanine nucleotide exchange factor (GEF) restrained pathogenic process involving TLR7.
- Edd Ricker
- , Michela Manni
- & Alessandra B. Pernis
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Article
| Open AccessThe RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response
Zinc finger proteins are involved in the resolution of immune responses and function by degrading mRNA of inflammatory cytokines. Here the authors show MCPIP3 promotes skin inflammation via modification of cytokine profiles in pDCs and macrophages.
- Bo Liu
- , Jiancheng Huang
- & Cliff Y. Yang
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Article
| Open AccessSingle-cell transcriptomic analysis reveals disparate effector differentiation pathways in human Treg compartment
Human Treg cells are central to immune tolerance, yet their heterogeneity and differentiation remain incompletely understood. Here the authors perform single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease revealing Treg complexity in health and disease.
- Yuechen Luo
- , Changlu Xu
- & Xiaoming Feng
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Article
| Open AccessGenome-wide association study identifies five risk loci for pernicious anemia
Pernicious anemia shows co-incidence with autoimmune disorders, yet the genetic basis for this condition is understudied. Here, the authors perform a genome-wide association study meta-analysis on pernicious anemia, identifying five susceptibility loci that map to genes with known roles in autoimmune disease.
- Triin Laisk
- , Maarja Lepamets
- & Reedik Mägi
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Article
| Open AccessDual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice
Asthma is caused by hyperreactivity to benign antigens, with humoral immunity orchestrated by interleukin-4 (IL-4) and IL-13 being the key etiological factor. Here the authors show, in humanized mouse models, that dual vaccination against IL-4 and IL-13 induces their durable suppression ameliorate experimental asthma, and to hint clinical translation.
- Eva Conde
- , Romain Bertrand
- & Laurent L. Reber
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Article
| Open AccessPancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation
Glycoprotein-2 (GP-2) can protect the intestinal epithelial barrier from bacteria and is associated with protection against Crohn’s disease. Here, the authors show pancreatic GP-2 is the source of the intestine’s luminal GP-2 that binds bacteria and prevents them from attaching to the epithelium, also limiting pathology in a DSS colitis mouse model.
- Yosuke Kurashima
- , Takaaki Kigoshi
- & Hiroshi Kiyono
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Article
| Open AccessIdentification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups
The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups.
- Yong-Fei Wang
- , Yan Zhang
- & Wanling Yang
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Article
| Open AccessLongitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease
Fecal microbiota transplant (FMT) is emerging as a potential treatment for graft-versus-host disease (GvHD). Here, the authors examine temporal dynamics of the bacteriome, mycobiome, and virome of a patient with GvHD who received multiple FMTs.
- Fen Zhang
- , Tao Zuo
- & Siew C. Ng
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Article
| Open AccessEarly-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling
Early life trauma has been associated with multiple sclerosis, but the causal link is unclear. Here the authors show in mice that early life trauma can result in IFN-β-resistant EAE as a result of β-adrenergic desensitization in immune cells and that a β1 adrenergic receptor agonist can reverse this susceptibility.
- Yee Ming Khaw
- , Danish Majid
- & Makoto Inoue
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Article
| Open AccessTreatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report
Remdesivir is under evaluation for treatment of COVID-19 in clinical trials. Here, the authors report results of remdesivir treatment in a patient with COVID-19 and the genetic antibody deficiency XLA. They show a temporally correlated clinical and virological response, suggesting that remdesivir can reduce SARS-CoV-2 replication in patients.
- Matthew S. Buckland
- , James B. Galloway
- & James E. D. Thaventhiran
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Article
| Open AccessUbiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
RIPK1 is a critical kinase which mediates necroptosis, apoptosis and inflammation. Regulation of RIPK1 by ubiquitination is being intensively investigated. Here, the authors made knock-in RIPK1-K612R mice and demonstrate that this mutation alters the RIPK1 ubiquitinylation pattern and inhibits its prodeath kinase activity in response to TNFα but sensitizes cell death to TLRs signals.
- Xingyan Li
- , Mengmeng Zhang
- & Junying Yuan
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Article
| Open AccessDisease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a progressing disease, with lung but not gut microbiota implicated in its etiology. Here the authors compare the stool from patients with COPD and healthy controls to find specific gut bacteria and metabolites associated with active disease, thereby hinting at a potential role for the gut microbiome in COPD.
- Kate L. Bowerman
- , Saima Firdous Rehman
- & Philip M. Hansbro
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Article
| Open AccessEvaluating the informativeness of deep learning annotations for human complex diseases
Deep learning models have shown great promise in predicting regulatory effects from DNA sequence. Here the authors evaluate sequence-based epigenomic deep learning models and conclude that these models are not yet ready to inform our knowledge of human disease.
- Kushal K. Dey
- , Bryce van de Geijn
- & Alkes L. Price
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Article
| Open AccessTargeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome
In recent years, hematopoietic stem cells gene editing has emerged as a promising tool to treat blood disorders. Here the authors develop a CRISPR/Cas9-based genome editing strategy that allows the precise correction of Wiskott-Aldrich Syndrome in vitro and in vivo with high efficiency.
- Rajeev Rai
- , Marianna Romito
- & Alessia Cavazza
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Matters Arising
| Open AccessReply to “Acid inhibitors and allergy: comorbidity, causation and confusion”
- Erika Jensen-Jarolim
- , Michael Kundi
- & Galateja Jordakieva
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Article
| Open AccessLong-lasting severe immune dysfunction in Ebola virus disease survivors
Patients who have recovered from Ebola virus can have ongoing health problems. Here, the authors show that 35 Guinean survivors of the last West African Ebola epidemic have a chronic disease with high inflammatory cytokine expression and other markers of immune activation as well as evidence of intestinal tissue damage nearly two years after their release from hospital.
- Aurélie Wiedemann
- , Emile Foucat
- & Abdoulaye Touré
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Article
| Open AccessA missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.
- Joanne M. Hildebrand
- , Maria Kauppi
- & John Silke
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Article
| Open AccessContrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes
Infiltration of immune cells to the pancreatic islets precedes clinical symptoms of type 1 diabetes, and lack of methods to detect this insulitis impedes early interventions. Here the authors report a contrast enhanced ultrasound method that can detect early insulitis in mouse models of type 1 diabetes, based on increased microvascular permeability.
- David G. Ramirez
- , Eric Abenojar
- & Richard K. P. Benninger