Article
|
Open Access
Featured
-
-
Article
| Open AccessAirway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
The mechanisms driving lung inflammation and remodelling in chronic obstructive pulmonary disease (COPD) are incompletely understood. Here the authors show that lack of secretory IgA promotes bacterial invasion in small airways, resulting in leukocyte recruitment and a COPD-like phenotype.
- Bradley W. Richmond
- , Robert M. Brucker
- & Vasiliy V. Polosukhin
-
Article
| Open AccessSialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis
Post-translational modifications, such as glycosylation and sialylation, are thought to confer disease modifying effects on autoimmune-associated antibodies, including anti-citrullinated protein antibodies in rheumatoid arthritis. Here the authors show that sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis in mice.
- Yuhsuke Ohmi
- , Wataru Ise
- & Koichi Furukawa
-
Article
| Open AccessKappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination
Current treatments of multiple sclerosis are aimed at immunosuppression. Here the authors show that kappa opioid receptor is important for oligodendrocyte differentiation and myelination and the receptor agonists are protective in a mouse model of multiple sclerosis.
- Changsheng Du
- , Yanhui Duan
- & Xin Xie
-
Article
| Open AccessType 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice
Type 1 diabetes is associated with the loss of self-tolerance to the insulin-producing β-cells in the pancreas. Here the authors show that vaccination with insulin mimetopes can induce human insulin-specific regulatory T cells to mediate tolerance in a humanized mouse model.
- Isabelle Serr
- , Rainer W. Fürst
- & Carolin Daniel
-
Article
| Open AccessIL-15-dependent balance between Foxp3 and RORγt expression impacts inflammatory bowel disease
Transcription factors directing T cell fate are induced by instructive signals such as cytokines. Here the authors show that IL-15 promotes Foxp3 and inhibits RORγt expression in CD4 T cells, and that IL-15 is critical to suppress colitis by maintaining the Treg to Th1/Th17 ratio in a mouse model.
- Milena J. Tosiek
- , Laurence Fiette
- & Antonio A. Freitas
-
Article
| Open AccessElimination of HIV-1-infected cells by broadly neutralizing antibodies
Broadly neutralizing antibodies (bNAbs) are promising as potential therapies targeting HIV-1 but their overall antiviral activity remains to be fully elucidated. Here the authors evaluate the ability of a panel of bNAbs to trigger antibody-dependent cellular cytotoxicity and identify the most effective antibody combinations.
- Timothée Bruel
- , Florence Guivel-Benhassine
- & Olivier Schwartz
-
Article
| Open AccessIncreased generation of Foxp3+ regulatory T cells by manipulating antigen presentation in the thymus
The degree of Treg self-antigen reactivity varies across experimental systems. Here the authors develop a new model of skin autoimmunity and show that the size of tissue-specific Treg pool in the thymus depends on AIRE, the availability of the tissue antigen, and its presentation by dendritic cells.
- Jiqiang Lin
- , Lu Yang
- & Juan J. Lafaille
-
Article
| Open AccessLocal T/B cooperation in inflamed tissues is supported by T follicular helper-like cells
In secondary lymphoid organs T follicular helper (Tfh) cells help B cells to develop into memory B and plasma cells. Here, the authors show that inflamed lung becomes a reservoir of activated B cells with a germinal centre phenotype, and T cells that exhibit Tfh-like properties despite not expressing classical Tfh markers.
- Dana Vu Van
- , Katja C. Beier
- & Andreas Hutloff
-
Article
| Open Access1,25D3 prevents CD8+Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter
Type 2 CD8+ T cells (Tc2) play a role in the development of experimental asthma. Here the authors show that 1,25D3, the active form of vitamin D3, can prevent conversion of CD8+T cells to a Tc2 phenotype, reducing asthma susceptibility.
- Michaela Schedel
- , Yi Jia
- & Erwin W. Gelfand
-
Article
| Open AccessEndothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis
Atherosclerosis is an inflammatory disease with limited therapeutic options. Here, the authors show that protein kinase MAP4K4 regulates vascular inflammation underlying atherosclerotic plaque development and that its inhibition prevents the disease and promotes lesion regression in mice, proposing a new atherosclerosis treatment.
- Rachel J. Roth Flach
- , Athanasia Skoura
- & Michael P. Czech
-
Article
| Open AccessAKAP9 regulates activation-induced retention of T lymphocytes at sites of inflammation
A-kinase anchoring protein 9 (AKAP9) is a scaffold protein that binds signalling proteins and regulates microtubules. Here the authors show that during inflammation AKAP9 in T cells is required for their reactivation and retention at the inflammation site and that its deletion protects from inflammation-induced organ damage.
- Jan M. Herter
- , Nir Grabie
- & Tanya N. Mayadas
-
Article
| Open AccessCapture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci
There is evidence that a proportion of the polymorphisms identified by genome-wide association studies lie in enchancer regions. Here the authors use Capture Hi-C to investigate the interaction with targets in autoimmune disease, showing interactions can be long range and cell-type specific.
- Paul Martin
- , Amanda McGovern
- & Steve Eyre
-
Article
| Open AccessNADH oxidase-dependent CD39 expression by CD8+ T cells modulates interferon gamma responses via generation of adenosine
The ectonucleotidase CD39 ultimately generates extracellular adenosine, modulating paracrine purinergic signaling. Here the authors show that IFNγ induction in CD8+ T cells is accompanied by NADH oxidase-dependent CD39 expression, which then inhibits IFNγ production in CD39-CD8+ T cells.
- Aiping Bai
- , Alan Moss
- & Simon C. Robson
-
Article
| Open AccessMeta-analysis identifies seven susceptibility loci involved in the atopic march
The development of asthma following eczema is known as the atopic march. Here the authors conduct a GWAS on affected children and identify two novel loci associated with the disease phenotype.
- Ingo Marenholz
- , Jorge Esparza-Gordillo
- & Young Ae Lee
-
Article
| Open AccessHuman caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes
Human monocytes exhibit an unconventional one-step pathway of inflammasome activation and IL-1 release in response to LPS. Here the authors show that it is mediated by caspases 4 and 5, and characterize caspase 5 cleavage, Syk and calcium signalling as key mediators of this pathway.
- Elena Viganò
- , Catherine Emma Diamond
- & Alessandra Mortellaro
-
Article
| Open AccessGenetic sharing and heritability of paediatric age of onset autoimmune diseases
Autoimmune diseases are genetically complex disorders that affect up to 10% of the Western population. Here Li et al. quantify the heritability of a range of autoimmune diseases in the largest paediatric cohort examined to date, illustrating that genetic and non-genetic components variably contribute to the susceptibility of each disease.
- Yun R. Li
- , Sihai D. Zhao
- & Hakon Hakonarson
-
Article
| Open AccessImmunological biomarkers predict HIV-1 viral rebound after treatment interruption
In some HIV-1-infected individuals, viraemia remains undetectable after antiretroviral treatment, but which of these patients will experience viral rebound is difficult to predict. Here the authors show that T cell exhaustion markers before treatment are predictive of shorter time to viral rebound.
- Jacob Hurst
- , Matthias Hoffmann
- & John Frater
-
Article
| Open AccessEomesodermin-expressing T-helper cells are essential for chronic neuroinflammation
Eomesodermin is a master regulator of effector CD8+ T cells. Here the authors show that it also plays a critical role in pathogenic CD4+ cells in a mouse model of multiple sclerosis, and its inactivation ameliorates the chronic stage of the disease.
- Ben J. E. Raveney
- , Shinji Oki
- & Takashi Yamamura
-
Article
| Open AccessAntibiotics in neonatal life increase murine susceptibility to experimental psoriasis
Commensal microbes are necessary for proper development of the immune system. Here Zanvit et al. show that neonatal antibiotics treatment causes long-term changes in the gut and skin microbiomes, and exacerbates immune-mediated skin pathology at adult age in mouse experimental models of psoriasis.
- Peter Zanvit
- , Joanne E. Konkel
- & WanJun Chen
-
Article
| Open AccessCTRP6 is an endogenous complement regulator that can effectively treat induced arthritis
The complement system contributes to chronic inflammatory diseases. Here the authors show that CRTP6 suppresses the alternative complement pathway and reverses rheumatoid arthritis in a mouse model of the disease.
- Masanori A. Murayama
- , Shigeru Kakuta
- & Yoichiro Iwakura
-
Article
| Open AccessRegulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling
RIPK3-mediated signalling regulates the induction of necroptosis and inflammation. Here the authors show that RIPK3-PGAM5-Drp1 pathway is crucial for NKT cell activation independently of cell death in mouse models of melanoma and acute inflammatory liver injury.
- Young Jun Kang
- , Bo-Ram Bang
- & Motoyuki Otsuka
-
Article
| Open AccessAntagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway
The endothelial secreted protein Del-1 plays a role in limiting inflammation, and its deficiency is associated with pathology in periodontitis and multiple sclerosis. Here the authors show that the negative regulation of Del-1 by IL-17 involves targeting the transcription factor C/EBPß in a GSK-3ß- dependent manner.
- Tomoki Maekawa
- , Kavita Hosur
- & George Hajishengallis
-
Article
| Open AccessOxidation of the alarmin IL-33 regulates ST2-dependent inflammation
IL-33, released by epithelial cells in response to stress, is a potent activator of inflammation. Here Cohenet al. show that secreted IL-33 is rapidly inactivated by disulfide bond formation that prevents binding to its receptor, and that IL-33-related cytokines are susceptible to similar oxidation.
- E. Suzanne Cohen
- , Ian C. Scott
- & Tomas Mustelin
-
Article
| Open AccessNovel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis
Primary lymphoedema can lead to the swelling of the extremities and facial dysmorphism. Here the authors present evidence that compound heterozygous and homozygous mutations inPIEZO1result in an autosomal recessive form of generalised lymphatic dysplasia.
- Elisavet Fotiou
- , Silvia Martin-Almedina
- & Pia Ostergaard
-
Article
| Open AccessDiet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model
Environmental enteropathy is a disorder of the small intestine that contributes to the persistence of childhood malnutrition worldwide. Here, Brownet al. show in mice that early-life malnourishment, in combination with exposure to commensal bacteria, remodels the small intestine to resemble features of the disease.
- Eric M. Brown
- , Marta Wlodarska
- & B. Brett Finlay
-
Article
| Open AccessMutations in CDCA7 and HELLS cause immunodeficiency–centromeric instability–facial anomalies syndrome
Immunodeficiency-centromeric instability-facial anomalies syndrome is a life threatening autosomal recessive disorder caused by mutations in DNMT3B and ZBTB24. Here Thijssen et al. identify mutations in CDCA7 and HELLSin previously unexplained cases.
- Peter E. Thijssen
- , Yuya Ito
- & Hiroyuki Sasaki
-
Article
| Open AccessPhosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation
TGF-ß and IL-6 are the essential cytokines for mediating the differentiation of IL-17-producing CD4+ T helper cells (TH17). Here, Yoon et al. provide more insights into this process and describe the opposing roles of TGFß-signalling intermediates Smad2 and Smad3 as STAT3 cofactors in Th17 differentiation.
- Jeong-Hwan Yoon
- , Katsuko Sudo
- & Mizuko Mamura
-
Article
| Open AccessDesialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia
Immune thrombocytopenia (ITP) is caused by autoantibody-mediated platelet clearance, but refractoriness to current immunomodulatory therapies is common. Here the authors show that desialylated platelets can be cleared via hepatic Ashwell–Morell receptor, a process that can be attenuated by sialidase inhibitors, suggesting a new therapy for ITP.
- June Li
- , Dianne E. van der Wal
- & Heyu Ni
-
Article |
Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells
Adiponectin levels are decreased in metabolic syndrome and psoriasis patients. Here the authors show that adiponectin suppresses the pathogenic production of IL-17 of γδ T cells, and adiponectin administration improves psoriasis-like symptoms in a mouse model of the disease.
- Sayaka Shibata
- , Yayoi Tada
- & Shinichi Sato
-
Article |
Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation
Syndecan-4 is a surface protein implicated in the regulation of cytoskeleton, adhesion and migration. Here the authors show that blocking syndecan-4 prevents dendritic cell migration into the lung and inhibits the development of allergic airway inflammation in mice.
- Tobias Polte
- , Susanne Petzold
- & Marco Averbeck
-
Article
| Open AccessMicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3
Peripherally derived regulatory T cells (pTreg) exhibit immunosuppressive capacity. Here, the authors show that microRNA-31 acting through inhibiting its direct target Gprc5a negatively regulates pTreggeneration and promotes the development of experimental autoimmune encephalomyelitis.
- Lingyun Zhang
- , Fang Ke
- & Honglin Wang
-
Article |
PGD2 deficiency exacerbates food antigen-induced mast cell hyperplasia
Mast cells are major contributors to allergy. Here the authors show that prostaglandin D2-deficient mast cells produce more chemoattractants, promoting mast cell hyperplasia and exacerbating allergic responses in a mouse model of food allergy.
- Tatsuro Nakamura
- , Shingo Maeda
- & Takahisa Murata
-
Article
| Open AccessGenetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study
Graves’ disease is the leading cause of hyperthyroidism but treatment options can cause life-threatening complications. Chen et al. conduct two-stage direct HLA genotyping and genome-wide association studies to identify HLA-B*38:02 and HLA-DRB1*08:03 as major pharmacogenetic determinants.
- Pei-Lung Chen
- , Shyang-Rong Shih
- & Tien-Chun Chang
-
Article
| Open AccessNF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis
Psoriasis is accompanied by NF-κB activation and hyperplasia. Here the authors show that NF-κB transcriptionally activates miR-31, which downregulates a negative cell cycle regulator protein phosphatase 6, and that this is critical for NF-κB to drive keratinocyte hyperproliferation.
- Sha Yan
- , Zhenyao Xu
- & Honglin Wang
-
Article
| Open AccessIL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection
HIV-infected patients who maintain undetectable virus levels possess elevated plasma concentrations of IL-21. Here, Adoroet al. show that IL-21 inhibits early viral infection in humanized mice and suppresses HIV-1 replication in vitroby upregulating a microRNA via the regulatory protein STAT3.
- Stanley Adoro
- , Juan R. Cubillos-Ruiz
- & Laurie H. Glimcher
-
Article
| Open AccessIL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells
Control of γδ T-cell activation remains incompletely understood. Here the authors show that during autoimmune arthritis development αβ CD4+T cells recruit a subset of IL-17-producing γδ T cells to the joints, and that both components are essential to cause pathology in a mouse model of the disease.
- Aoi Akitsu
- , Harumichi Ishigame
- & Yoichiro Iwakura
-
Article |
Aquaporin-3-mediated hydrogen peroxide transport is required for NF-κB signalling in keratinocytes and development of psoriasis
Aquaporin-3 (AQP3) mediates cellular uptake of water and hydrogen peroxide (H2O2). Here, the authors show that TNF-induced H2O2enters keratinocytes via AQP3, eliciting NF-κB activation and the development of psoriasis, and identify AQP3 as a potential therapeutic target for this inflammatory immune-mediated disease.
- Mariko Hara-Chikuma
- , Hiroki Satooka
- & A. S. Verkman
-
Article |
Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites
Growing evidence suggests that environmental rather than genetic factors are major contributors to asthma development. Here the authors show that high intake of dietary fibre by pregnant mice increases resistance of their progeny to the development of allergic airways disease.
- Alison N. Thorburn
- , Craig I. McKenzie
- & Charles R. Mackay
-
Article
| Open AccessMonozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition
Epigenetic changes are thought to contribute to the aetiology of common variable immunodeficiency (CVID), a disease characterized by loss of B-cell function. Here, by comparing DNA methylation profile in B cells from monozygotic twins discordant for CVID, the authors show a gain of DNA methylation in CVID B cells.
- Virginia C. Rodríguez-Cortez
- , Lucia del Pino-Molina
- & Esteban Ballestar
-
Article
| Open AccessNeutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis
Autoimmune pulmonary alveolar proteinosis is caused by autoantibodies to GM-CSF. Here the authors show that the individual autoantibodies only partially neutralize GM-CSF and that antibodies to at least three different epitopes are required to block GM-CSF bioavailability.
- Luca Piccoli
- , Ilaria Campo
- & Antonio Lanzavecchia
-
Article
| Open Accessγ-secretase directly sheds the survival receptor BCMA from plasma cells
B-cell maturation antigen (BCMA) regulates the survival of B cells and is essential for the maintenance of long-lived plasma cells. Here, the authors show that γ-secretase directly sheds BCMA from the cell surface and therefore regulates the number of plasma cells.
- Sarah A. Laurent
- , Franziska S. Hoffmann
- & Edgar Meinl
-
Article |
HIV-1 Rev downregulates Tat expression and viral replication via modulation of NAD(P)H:quinine oxidoreductase 1 (NQO1)
Tat and Rev are HIV-1 proteins involved in feedback mechanisms that regulate the expression of viral genes. Here, the authors show that Rev reduces the intracellular Tat levels by inhibiting the expression of the cellular protein NQO1, which prevents Tat degradation.
- Sneh Lata
- , Amjad Ali
- & Akhil C. Banerjea
-
Article |
The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation
Multiple sclerosis is caused by autoreactive Th17 lymphocytes. Here the authors show that prostaglandin E2 promotes Th17 differentiation by activating transcription of IL-17 by CREB/CRTC2 complex, and that ablation of CRTC2 prevents Th17 differentiation and multiple sclerosis in a mouse model.
- Jeniffer B. Hernandez
- , Christina Chang
- & Marc Montminy
-
Article
| Open AccessCD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis
Dendritic cells are critical for initiation of immune responses and for induction of tolerance. Here the authors show that deletion of survival factor c-flip in CD11c-expressing cells subset perturbs CD8a+dendritic cell, NK and macrophage pools, and leads to development of autoimmune arthritis.
- Qi-Quan Huang
- , Harris Perlman
- & Richard M. Pope
-
Article |
MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis
Compromised function of regulatory T cells can lead to autoimmunity. Here the authors show that miR-125a stabilizes regulatory T-cell function and is downregulated in lupus and Crohn’s disease, as well as autoimmune mouse models, and that a chemical miR-125a analogue reverts established disease in a mouse model of multiple sclerosis.
- Wen Pan
- , Shu Zhu
- & Nan Shen
-
Article |
Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells
Self-reactive B cells producing autoantibodies are associated with autoimmune conditions. Here, the authors show that in mice lacking the surrogate light chain, which normally assembles with antibody heavy chain to form a pre-B-cell receptor, the autoantibody-producing cells derive from germinal centres.
- Ola Grimsholm
- , Weicheng Ren
- & Inga-Lill Mårtensson
-
Article |
Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci
About 2% of the population are affected by psoriasis, a chronic skin disease with complex genetics. Here Tsoi et al.conduct a meta-analysis of several genome-wide association studies and identify five novel loci, helping to further our understanding of the biology behind this condition.
- Lam C. Tsoi
- , Sarah L. Spain
- & James T. Elder
-
Article |
Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis
Autoantibodies targeting citrunillated proteins are common in rheumatoid arthritis patients. Here the authors show that vinculin (a human protein) and some microbial proteins are recognized by these antibodies and by CD4+T cells, and this response is absent in patients carrying a protective HLA allele.
- Jurgen van Heemst
- , Diahann T. S. L. Jansen
- & René E. Toes
-
Article
| Open AccessStructural basis for binding of human IgG1 to its high-affinity human receptor FcγRI
FcγRs are cell-surface receptors for IgGs that play key roles in the humoral and cellular immune response to infection. Here, the authors present a high-resolution crystal structure of the hFcγRI-Fc complex to reveal the molecular mechanisms underlying the high specificity of this important immunological interaction.
- Masato Kiyoshi
- , Jose M.M. Caaveiro
- & Kouhei Tsumoto