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| 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
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Article
| Open AccessMD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy
The mechanisms underlying cardiac inflammation in diabetic cardiomyopathy are incompletely understood. Here the authors show that advanced glycation end products bind to the TLR4 co-receptor MD2 initiating pro-inflammatory pathways.
- Yi Wang
- , Wu Luo
- & Guang Liang
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Article
| Open AccessTAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response
TAGAP gene variants are linked to human autoimmunity. Here the authors identify TAGAP as a Dectin-1 and EphB2-binding protein mediating antifungal innate immune signaling and cytokine production, and demonstrate TAGAP in non-T cells promotes Th17 response in mouse models of infection and autoimmunity.
- Jianwen Chen
- , Ruirui He
- & Chenhui Wang
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Article
| Open AccessGenome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma
Asthma is a common disease of the airways for which numerous genetic loci have been identified. Here, Han et al. carry out a genome-wide analysis for asthma to identify additional loci, report sex-stratified and genetic risk score analyses, and functionally follow-up one locus using a murine model of airway hyperreactivity.
- Yi Han
- , Qiong Jia
- & Hooman Allayee
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Article
| Open AccessDual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
The transcription factor Aire mediates tissue-specific antigen expression in the thymus for T cell central tolerance induction. Here the authors show that Aire, via its CARD domain, forms multimers that can misdirect Aire to PML bodies leading to the loss of Aire transcriptional activity and induction of autoimmunity.
- Yu-San Huoh
- , Bin Wu
- & Sun Hur
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Article
| Open AccessRapid expansion of Treg cells protects from collateral colitis following a viral trigger
Viral infection transiently depletes T regulatory cells (Treg). Here the authors identify a compensatory induced Treg population, which is required to rapidly replenish the Treg niche and suppress microbiota-driven, virus-induced colitis.
- Michelle Schorer
- , Katharina Lambert
- & Nicole Joller
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Article
| Open AccessMass cytometry reveals cellular fingerprint associated with IgE+ peanut tolerance and allergy in early life
Food allergy is triggered by IgE, but some individuals are not allergic to peanuts despite making peanut-specific IgE, and are considered peanut-tolerant. Here, the authors identify differences in blood immune cell composition of peanut-allergic and tolerant infants using mass cytometry, which may help uncover the mechanism of allergic tolerance.
- Melanie R. Neeland
- , Sandra Andorf
- & Kari C. Nadeau
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Article
| Open Accessc-FLIP is crucial for IL-7/IL-15-dependent NKp46+ ILC development and protection from intestinal inflammation in mice
Innate lymphoid cells (ILC) are important immune cells for maintaining the gut homeostasis. Here the authors show that c-FLIP, an anti-apoptotic molecule, is important for the development of NKP46+ ILC1, including conventional natural killer (cNK) cells, and ILC3, with cNK being more critical for ameliorating intestinal inflammation.
- Ute Bank
- , Katrin Deiser
- & Thomas Schüler
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Article
| Open AccessHuman FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells
FCH domain only 1 (FCHO1) is a key molecule involved in clathrin-mediated endocytosis (CME). Here, the authors report homozygous FCHO1 mutations in individuals with variable T and B cell lymphopenia, which are associated with loss-of-function of FCHO1 and impaired formation of clathrin-coated pits in T cells.
- Marcin Łyszkiewicz
- , Natalia Ziętara
- & Christoph Klein
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Article
| Open AccessSomatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.
- Eva Gonçalves Serra
- , Tobias Schwerd
- & Carl A. Anderson
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Article
| Open AccessPrenatal dietary supplements influence the infant airway microbiota in a randomized factorial clinical trial
Here, the authors present the results of a mother–child cohort randomized clinical trial of n-3 LCPUFA and vitamin D maternal supplementation, finding an association between supplement-induced microbiota changes in infant airways at age 1-month but not the infant fecal or maternal vaginal microbiome.
- Mathis H. Hjelmsø
- , Shiraz A. Shah
- & Hans Bisgaard
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Article
| Open AccessIntegrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis
Here the authors provide a single-cell characterization of cerebrospinal fluid and blood of newly diagnosed multiple sclerosis (MS) patients, revealing altered composition of lymphocyte and monocyte subsets, validated by other methods including the interrogation of the TFH subset in mouse models of MS.
- David Schafflick
- , Chenling A. Xu
- & Gerd Meyer zu Horste
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Article
| Open AccessCold-induced urticarial autoinflammatory syndrome related to factor XII activation
Systemic autoinflammatory syndromes such as cryopyrin-associated periodic syndrome (CAPS) are rare and often involve genes related to the inflammasome. Here, the authors report a syndrome characterised by systemic inflammation and cold-induced urticarial rash associated with a Factor XII-activating mutation.
- Jörg Scheffel
- , Niklas A. Mahnke
- & Karoline Krause
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Article
| Open AccessThe mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab
Immunoglobulin E (IgE) plays a central role in allergic responses, yet therapeutic targeting of IgE with antibodies such as omalizumab is met with various limitations. Here the authors characterize the molecular properties and crystal structure of a new anti-IgE antibody, ligelizumab, for mechanistic insights related to its enhanced suppression activity.
- Pascal Gasser
- , Svetlana S. Tarchevskaya
- & Alexander Eggel
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Article
| Open AccessmiRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
miRNA142-3p and Tet2 are separately known to regulate Treg. Here the authors show that miRNA142-3p targets Tet2 and by this opposes Treg differentiation in autoimmune diabetes.
- Martin G. Scherm
- , Isabelle Serr
- & Carolin Daniel
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Article
| Open AccessMissing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants
‘Missing self’ is a mode of natural killer (NK) cell activation aimed to detect the lack of HLA-I molecules on infected or neoplastic cells. Here, the authors show that mismatch between donor HLA-I and cognate receptors on recipient NK cells mediates microvascular inflammation-associated graft rejection, a pathology that is preventable by mTOR inhibition.
- Alice Koenig
- , Chien-Chia Chen
- & Olivier Thaunat
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Article
| Open AccessIn vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls
T cells from narcolepsy patients were recently reported to recognize hypocretin, a wakefulness-promoting neurohormone, suggesting autoimmune origin of the disease. Here the authors show that hypocretin-specific T cells expand both in healthy controls and in narcolepsy patients, and identify preliminary features that may distinguish them.
- Wei Jiang
- , James R. Birtley
- & Elizabeth D. Mellins
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Article
| Open AccessA human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation
Roquin-1 is a posttranscriptional regulator that controls the expression of many immune-related genes such as ICOS and TNFA. Here, the authors report a homozygous R688* loss of function mutation in Roquin-1 in a patient with syndromic uncontrolled hyperinflammation associated with immune cell activation and hypercytokinemia.
- S. J. Tavernier
- , V. Athanasopoulos
- & F. Haerynck
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Article
| Open AccessTrisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors
Down syndrome (DS) is caused by trisomy 21 (T21), but the underlying etiology of the related immune and neurological dysfunction is unclear. Here, the authors show that T21 activates the kynurenine pathway via increased interferon receptor copy number, which could contribute to DS pathophysiology.
- Rani K. Powers
- , Rachel Culp-Hill
- & Joaquin M. Espinosa
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Article
| Open AccessAbl family tyrosine kinases govern IgG extravasation in the skin in a murine pemphigus model
How antibody reaches tissues from circulation is critical for understanding antibody-mediated immunity. Here the authors show that IgG extravasation in the skin is mediated by endothelial caveolin transport independently of FcR, and is targetable by imatinib, which reduces IgG-dependent pathology in a mouse model of pemphigus.
- Sachiko Ono
- , Gyohei Egawa
- & Kenji Kabashima
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Article
| Open AccessDouble negative T cells mediate Lag3-dependent antigen-specific protection in allergic asthma
Allergic asthma symptoms may be controlled, but currently no effective therapy exist to address the underlying pathology. Here the authors show, using mouse model of adoptive cell transfer, that CD4-CD8- T cells can suppress the function of dendritic cells and T follicular helper cells via Lag3 to provide allergen-specific protection from asthma.
- Dan Tian
- , Lu Yang
- & Dong Zhang
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Article
| Open AccessMutations in topoisomerase IIβ result in a B cell immunodeficiency
Topoisomerases are required to release topological stress on DNA during replication and transcription. Here, Broderick et al. report genetic variants in TOP2B that cause a syndromic B cell immunodeficiency associated with reduced TOP2B function, defects in B cell development and B cell activation.
- Lori Broderick
- , Shawn Yost
- & Hal M. Hoffman
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Article
| Open AccessA plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity
Autoreactivity to myeloperoxidase (MPO) causes autoimmune vasculitis and severe glomerulonephritis. Here, Ooi et al. show that a Staphylococcus aureus plasmid encodes a peptide that is homologous to an immunodominant MPO epitope and induces anti-MPO autoimmunity and glomerulonephritis in mice.
- Joshua D. Ooi
- , Jhih-Hang Jiang
- & A. Richard Kitching
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Article
| Open AccessThe histone methyltransferase Setd2 is indispensable for V(D)J recombination
The repertoire of adaptive immune receptor is generated by V(D)J recombination, somatic rearrangements of V, D and J gene segments, in the respective loci. Here the authors show that the deficiency of Setd2, a histone methyl transfer, impairs V(D)J recombination and induces severe developmental blocks in both T and B lineages.
- Zhongzhong Ji
- , Yaru Sheng
- & Helen He Zhu
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Article
| Open AccessTherapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes
Dimethyl fumarate (DMF) is an established treatment for relapsing multiple sclerosis with unclear mechanism of action. Here the authors distinguish DMF responders by monocyte counts and redox gene signature in a prospective longitudinal cohort at 3 month of therapy, and associate NOX3 genetic variants with outcome.
- Karl E. Carlström
- , Ewoud Ewing
- & Fredrik Piehl
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Article
| Open AccessSerum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies
FHR1 is a serum protein implicated in complement regulation. Here the authors show that human FHR1 binds to necrotic cells, triggering inflammasome activation in monocytes in culture, localizes to necrotic tissue and correlates with inflammatory cytokine levels in vasculopathies.
- Sarah Irmscher
- , Silke R. Brix
- & Christine Skerka
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Article
| Open AccessA bioactive mammalian disaccharide associated with autoimmunity activates STING-TBK1-dependent immune response
Mammalian glycans have a role in host immunity but little is known about how they activate the host response in the context of autoimmune diseases. Here, the authors identify Manβ1-4GlcNAc as a novel innate immune modulator associated with chronic autoimmune diseases.
- Charles S. Fermaintt
- , Kanae Sano
- & Nan Yan
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Article
| Open AccessFunctional rare and low frequency variants in BLK and BANK1 contribute to human lupus
Function-altering variants of immune-related genes cause rare autoimmune syndromes, whereas their contribution to common autoimmune diseases remains uncharacterized. Here the authors show that rare variants of lupus-associated genes are present in the majority of lupus patients and healthy controls, but only the variants found in lupus patients alter gene function.
- Simon H. Jiang
- , Vicki Athanasopoulos
- & Carola G. Vinuesa
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Article
| Open AccessInterferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) shows a striking bias towards higher prevalence in females. Here, the authors perform fine-mapping of an SLE-associated locus at Xp21.2 and characterise a candidate gene, CXorf21, as IFN-responsive in immune cells that shows sexually dimorphic expression.
- Christopher A. Odhams
- , Amy L. Roberts
- & Timothy J. Vyse
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Article
| Open AccessLoss of TET2 and TET3 in regulatory T cells unleashes effector function
Loss of TET proteins in immune cell populations is known to result in immunopathology. Here the authors show that deficiency of Tet2 and Tet3 proteins, specifically in the CD4+ FoxP3+ Treg lineage, results in a dominant pathology in which ex-Treg cells and bystander T cells gain aberrant effector function.
- Xiaojing Yue
- , Chan-Wang J. Lio
- & Anjana Rao
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Article
| Open AccessImpaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats
Neonatal immune responses are known to differ to those of an adult immune response. Here Dreschers and colleagues, compare macrophage populations derived from cord blood or adult peripheral blood and show a metabolic impairment of glycolysis in macrophages derived from cord blood which may impair response to infective scenarios such as sepsis.
- Stephan Dreschers
- , Kim Ohl
- & Klaus Tenbrock
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Article
| Open AccessNeutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
The pathogenesis of heparin-induced thrombocytopenia and thrombosis (HIT) is mediated by heparin-reactive autoantibodies binding to platelets (thrombocytes). Here the authors show neutrophil activation and NETosis are elevated in patients with HIT, and are essential for thrombosis in HIT mouse models.
- José Perdomo
- , Halina H. L. Leung
- & Beng H. Chong
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Article
| Open AccessGenome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02
Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.
- Christos Tziotzios
- , Christos Petridis
- & John A. McGrath
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Article
| Open AccessSTAT1 signaling shields T cells from NK cell-mediated cytotoxicity
The JAK-STAT signaling pathway is important for cytokine responses and CD4 T-cell differentiation. Here the authors show that Stat1 also serves to protect CD4 T cells from natural killer cell-mediated killing, potentially by promoting the expression of Nlrc5 and MHC-I, to preserve the induction of experimental colitis via the adoptive transfer of CD4 T cells.
- Yu Hui Kang
- , Amlan Biswas
- & Scott B. Snapper
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Article
| Open AccessAdenosine deaminase-1 delineates human follicular helper T cell function and is altered with HIV
Follicular helper T cells are critical in the generation of the antibody response. Here the authors show that adenosine deaminase is involved in the Tfh program and ensuring the provision of B cell help.
- Virginie Tardif
- , Roshell Muir
- & Elias K. Haddad
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Article
| Open AccessEarly-onset autoimmune vitiligo associated with an enhancer variant haplotype that upregulates class II HLA expression
GWAS have led to the identification of 49 genetic loci associated with vitiligo. Here, the authors observe a bimodal distribution of age-of-onset and find a novel genetic locus specifically associated with early-onset vitiligo, located in a regulatory element in the MHC class II region.
- Ying Jin
- , Genevieve H. L. Roberts
- & Richard A. Spritz
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Article
| Open AccessDownregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity
Obesity is associated with low-grade chronic inflammation. Here the authors show that the activation of anti-inflammatory M2a-subtype macrophages requires the IL4/Irs2/Akt pathway. Due to decreased Irs2 expression this pathway is impaired in obese mice thus leading to a defect in M2a activation.
- Tetsuya Kubota
- , Mariko Inoue
- & Takashi Kadowaki
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Article
| Open AccessA homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease
Mutations in genes encoding NAPDH oxidase subunits are known to be causative for the primary immunodeficiency chronic granulomatous disease (CGD). Here, the authors identify CYBC1 mutations in patients with CGD and show that CYBC1 is important for formation of the NADPH complex and respiratory burst.
- Gudny A. Arnadottir
- , Gudmundur L. Norddahl
- & Kari Stefansson
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Article
| Open AccessCationic nanoparticle as an inhibitor of cell-free DNA-induced inflammation
Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here the authors use ~40 nm cationic nanoparticles to scavenge cfDNA, and demonstrate the potential for nanomedicine to relieve debilitating RA symptoms.
- Huiyi Liang
- , Bo Peng
- & Yongming Chen
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Article
| Open AccessTargeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
Activation of the NLRP3 inflammasome triggers the production of inflammatory cytokines. Here, the authors inactivate NLRP3 in macrophages using CRISPR/Cas9 encapsulated in nanoparticles, and show that administration in mice is effective in preventing septic shock and peritonitis, and in improving diabetes-associated inflammation and insulin resistance.
- Congfei Xu
- , Zidong Lu
- & Jun Wang
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Article
| Open AccessGenome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma
The driver mutations for the two main molecular subgroups of diffuse large B-cell lymphoma (DLBCL) are poorly defined. Here, an integrative genomics analysis identifies 3′ UTR NFKBIZ mutations within the activated B-cell DLBCL subgroup and small FCGR2B amplifications in the germinal centre B-cell DLBCL subgroup.
- Sarah E. Arthur
- , Aixiang Jiang
- & Ryan D. Morin
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Article
| Open AccessInnate and adaptive signals enhance differentiation and expansion of dual-antibody autoreactive B cells in lupus
Conventional B cells express clonally specific antigen receptors, but a small subset of B cells from patients and mice with systematic lupus erythematosus simultaneously expresses two distinct antigen receptors. Here the authors show that these dual-specificity B cells have higher levels of MHC-II, depend on IL-21 for expansion, and mount stronger memory response.
- Allison Sang
- , Thomas Danhorn
- & Roberta Pelanda
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Article
| Open AccessHuman Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments
At inflammatory sites, ectopic lymphoid-like structures (ELS) can be induced through the function of chemokine CXCL13 produced by CD4+ T cells. Here the authors show that a transcription factor, Sox4, induces the expression of CXCL13 in CD4 T cells in vitro, and is associated with ELS formation in patients with rheumatoid arthritis.
- Hiroyuki Yoshitomi
- , Shio Kobayashi
- & Junya Toguchida
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Article
| Open AccessMicrobial metabolite sensor GPR43 controls severity of experimental GVHD
The microbial metabolite sensor GPR43 has been previously shown to be a crucial modulator of immune responses. Here the authors show GPR43 is required for controlling disease pathology severity in the context of experimental models of GVHD.
- Hideaki Fujiwara
- , Melissa D. Docampo
- & Pavan Reddy
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Article
| Open AccessNrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming
Understanding how regulators of inflammation affect nucleic acid sensing is important for targeting research against inflammatory diseases and conditions. Here, the authors identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells.
- David Olagnier
- , Aske M. Brandtoft
- & Christian K. Holm
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Article
| Open AccessPI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner
Antibody mediated immune responses to Streptococcus pneumoniae are crucial for the immune response to infection. Here the authors show hyper-activation of PI3Kδ promotes development of a subset of B cells that exacerbate infection in an antibody-independent manner and can be reversed by therapeutic targeting in vivo.
- Anne-Katrien Stark
- , Anita Chandra
- & Klaus Okkenhaug
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Article
| Open AccessEnhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks
Disease risk variants can exert their influence on phenotypes by altering epigenome function. Here, Pelikan et al. show that variants inducing allelic imbalance in histone marks in lymphoblastoid cell lines from lupus patients are enriched in autoimmune disease haplotypes and influence gene expression.
- Richard C. Pelikan
- , Jennifer A. Kelly
- & Patrick M. Gaffney
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Article
| Open AccessAct1 is a negative regulator in T and B cells via direct inhibition of STAT3
Adaptor for IL-17 receptors (Act1) is known to be crucial for IL-17-mediated immune responses. Here the authors show that Act1 also functions as a negative regulator of T and B cells by direct inhibition of STAT3.
- Cun-Jin Zhang
- , Chenhui Wang
- & Xiaoxia Li