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Article
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Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease
IgG4-related disease is a fibro-inflammatory disorder, characterized by infiltration of IgG4 producing plasma cells in the target organs. Here authors show that the affected B cells express less ubiquitin-specific protease 25 (USP25), and this results in activation of multiple pathways involved in cytoskeleton reorganization, inflammation and energy metabolism, which might govern disease pathogenesis.
- Panpan Jiang
- , Yukai Jing
- & Chaohong Liu
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Article
| Open Access
Parechovirus infection in human brain organoids: host innate inflammatory response and not neuro-infectivity correlates to neurologic disease
In comparison to PeV-A1, infection with PeV-A3 is associated with neurological illness in infants. Here, using brain organoids, the authors suggest that the innate inflammatory response as the underlying reason, and not replication kinetics.
- Pamela E. Capendale
- , Inés García-Rodríguez
- & Katja C. Wolthers
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Article
| Open Access
BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion
Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function in patients with chronic liver disease. Here, the authors show that BTLA expression in CD4+ T cells is associated with disease severity and inflammation in hepatitis B virus-related ACLF.
- Xueping Yu
- , Feifei Yang
- & Jiming Zhang
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Article
| Open Access
Inhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide
The mode of action of the tuberculosis antibiotic pyrazinamide is poorly understood. Here, Krug et al show that pyrazinamide inhibits the immune regulator PARP1 and demonstrate PARP1 inhibition as a host-directed therapy.
- Stefanie Krug
- , Manish Gupta
- & William R. Bishai
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Article
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Dermis resident macrophages orchestrate localized ILC2 eosinophil circuitries to promote non-healing cutaneous leishmaniasis
Tissue resident macrophages are intricately involved in homeostatic processes but also in tissue repair. Here Lee and colleagues show dermis-resident macrophages are a source of thymic stromal lymphopoietin and CCL24, which act on type 2 innate lymphoid cells and eosinophils respectively, to maintain their M2 properties and promote non-healing cutaneous leishmaniasis.
- Sang Hun Lee
- , Byunghyun Kang
- & David L. Sacks
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Article
| Open Access
The extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome
Although B cell-targeting therapies can provide clinical benefits to children with idiopathic nephrotic syndrome (INS), B lymphocyte subsets have not been extensively studied in this disease. Here, using single-cell RNA sequencing, the authors identify an extrafollicular B cell signature in children with INS.
- Tho-Alfakar Al-Aubodah
- , Lamine Aoudjit
- & Tomoko Takano
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Article
| Open Access
NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid cells in tuberculosis
Mycobacterium tuberculosis disrupts glycolysis in infected myeloid cells. Here, Pacl et al. show that maximal glycolytic capacity in myeloid cells is essential for host protection from tuberculosis and that NAD(H) homeostasis underlies glycolysis-mediated protection of the host.
- Hayden T. Pacl
- , Krishna C. Chinta
- & Adrie J. C. Steyn
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Article
| Open Access
Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype
Acquired resistance to immune checkpoint inhibitors limits therapeutic success in non-small-cell lung cancer, however, the underpinning immune parameters are largely unknown. Here authors distinguish resistance types based on immune cell infiltration, immune checkpoint molecule and cytokine expression level, using paired samples from patients in the sensitive and in the resistant disease phase.
- Stefanie Hiltbrunner
- , Lena Cords
- & Alessandra Curioni-Fontecedro
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Article
| Open Access
Differentiation of IL-26+ TH17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis
Interleukin 26 (IL-26) has been shown to have antimicrobial and pro-inflammatory effects. Here the authors establish a role for IL-26 in the generation of IL-17A producing Th17 CD4+ T cells and suggest it involves epithelial cross talk in skin lesions of psoriasis patients.
- Anissa Fries
- , Fanny Saidoune
- & Michel Gilliet
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Article
| Open Access
Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19
Infection with SARS-CoV-2 has been linked with substantive inflammation, lung pathology and development of COVID-19. Here the authors spatially associate CCL18 and CCL21 in distinct tissue niches with lung pathology of severe COVID-19.
- Ronja Mothes
- , Anna Pascual-Reguant
- & Anja E. Hauser
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Article
| Open Access
Integrated relationship of nasopharyngeal airway host response and microbiome associates with bronchiolitis severity
Bronchiolitis is major cause of infection, morbidity and hospitalisation. Here the authors apply transcriptomic based assessment of the host response, microbiome composition and function, and associate this to bronchiolitis severity.
- Michimasa Fujiogi
- , Yoshihiko Raita
- & Kohei Hasegawa
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Article
| Open Access
EGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance
In obesity, adipose tissue is chronically inflamed, leading to insulin resistance, and adipose tissue macrophages (ATMs) are a major source of cytokines that aggravate adipocyte dysfunction. Here, the authors show that selective deletion of the epidermal growth factor receptor in ATMs decreased obesity and development of insulin resistance.
- Shirong Cao
- , Yu Pan
- & Ming-Zhi Zhang
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Article
| Open Access
A CRISPR-based ultrasensitive assay detects attomolar concentrations of SARS-CoV-2 antibodies in clinical samples
CRISPR diagnostics are routinely used for the detecting nucleic acids, but rarely for clinically important proteins. Here, by translating a CRISPR-based DNA test into an ultrasensitive assay for antibodies, the authors achieve antibody detection from serum samples at attomolar concentrations.
- Yanan Tang
- , Turun Song
- & Feng Li
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Article
| Open Access
WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage
Cancer develops in Wiskott-Aldrich syndrome (WAS). Here the authors identify a role for WAS-protein (WASp) in the DNA stress-resolution pathway by promoting the function of Replication Protein A at replication forks after DNA damage.
- Seong-Su Han
- , Kuo-Kuang Wen
- & Yatin M. Vyas
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Poster
| Open Access
Immune 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 Access
Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade
Immune checkpoint blockade is a promising approach to treat lung cancer, however, immune related adverse events hold back success in some patients. Here authors show that regulatory B cells fail to limit self-reactive T cells in these patients, and B cell phenotyping prior treatment may identify those at risk for these unfavourable outcomes.
- Akshay J. Patel
- , Zena N. Willsmore
- & Gary W. Middleton
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Article
| Open Access
Lymphocyte 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 Access
Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation
TGFβ is secreted in an inactive form in the tumor microenvironment. Authors here show that although TGFβ is produced mainly by cancer cells, regulatory T cells are necessary for its activation via expression of the b8 chain of avb8 integrin. Thus, both cell types contribute to TGFβ dependent tumor growth.
- Alexandra Lainé
- , Ossama Labiad
- & Julien C. Marie
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Article
| Open Access
The GPR171 pathway suppresses T cell activation and limits antitumor immunity
Proliferative and effector functions of T cells are determined by T cell receptor signalling and modulated by activator and inhibitory co-receptors. Authors report here that the G-protein-coupled receptor GPR171 functions as a co-inhibitor of T cell signalling and might serve as a target for cancer immunotherapy.
- Yuki Fujiwara
- , Robert J. Torphy
- & Yuwen Zhu
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Article
| Open Access
IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro
IFITM proteins can inhibit several viruses, but effects on SARS-CoV-2 infection are not well understood. Here, the authors show that endogenous IFITMs support SARS-CoV-2 infection in different in vitro models by binding spike and enhancing virus entry.
- Caterina Prelli Bozzo
- , Rayhane Nchioua
- & Frank Kirchhoff
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Article
| Open Access
Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity
Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 and poor outcomes. Here the authors compare the transcriptomes of single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in these patients.
- Linh T. Bui
- , Nichelle I. Winters
- & Laure Emmanuelle Zaragosi
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Article
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Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1
Narcolepsy type 1 (NT1) is a severe sleep disorder with strong association to the HLA type DQB1*0602 and increased incidence among children vaccinated with the Influenza A vaccine Pandemrix. Here the authors show that these children develop T and B cell autoimmunity against protein-O-mannosyltransferase 1 via cross-reactivity.
- A. Vuorela
- , T. L. Freitag
- & O. Vaarala
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Article
| Open Access
Red blood cell mannoses as phagocytic ligands mediating both sickle cell anaemia and malaria resistance
Red blood cells (RBCs) are phagocytosed in the spleen in sickle cell disease and malaria. Here, Cao et al. show that high mannose N-glycans, exposed on diseased or oxidized RBC surfaces, bind mannose receptor CD206 on host cells, mediating phagocytosis.
- Huan Cao
- , Aristotelis Antonopoulos
- & Mark A. Vickers
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Article
| Open Access
Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities
Necrotizing Enterocolitis (NEC) is an untreatable intestinal disease in infants. Here the authors show that human and experimental mouse NEC is associated with altered toll-like receptor expression in the intestine, enhanced Th17/type 3 polarization in adaptive immune and innate lymphoid cells, dysregulated microbiota, and reduced interleukin-37 signaling.
- Steven X. Cho
- , Ina Rudloff
- & Marcel F. Nold
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Article
| Open Access
Two distinct immunopathological profiles in autopsy lungs of COVID-19
The immunopathological features of SARS-CoV-2 infection in the lungs remain unclear. Here, the authors provide a comprehensive characterization of post mortem lung tissues of COVID-19 patients and find two distinct patterns characterized by differential expression of interferon stimulated genes (ISGs), which correlate to viral loads, cytokines, lung damage and time of hospitalization, suggesting ISG profiles to mark disease progression
- Ronny Nienhold
- , Yari Ciani
- & Kirsten D. Mertz
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Article
| Open Access
Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia
COVID-19 is a serious pandemic threat to public health, but insights on the pathophysiological and immunological conditions are only emerging. Here the authors use multi-color flow cytometry to characterize CD4+ and CD8+ T cells in peripheral blood from 39 COVID-19 patients in Italy to report altered T cell activation, function and polarization.
- Sara De Biasi
- , Marianna Meschiari
- & Andrea Cossarizza
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Article
| Open Access
Metabolic reprogramming by Zika virus provokes inflammation in human placenta
Zika virus (ZIKV) infection of pregnant women is associated with pregnancy loss and birth defects, but molecular insights for the aetiology are scarce. Here the authors show that ZIKV reprograms the host lipidome to facilitate viral replication, induce mitochondria dysfunction, and cause immune imbalance, thereby identifying a potential target for ZIKV therapy.
- Qian Chen
- , Jordi Gouilly
- & Nabila Jabrane-Ferrat
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Article
| Open Access
Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity
Fibroblast contributions to lung fibrosis and in particular their crosstalk with immune cells in the lung are incompletely understood. Here, the authors show an overall immune suppressive environment transcriptionally controlled and maintained by fibroblasts in lung fibrosis with possible therapeutic implications.
- Lu Cui
- , Shih-Yu Chen
- & Gerlinde Wernig
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Article
| Open Access
Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection
Here, the authors report that exhausted HCV-specific CD8+ T cells are marked by upregulation of p53 signaling already detectable in an early phase of chronic HCV infection and by a later development of a repressive chromatin state, and show that chemical targeting of these pathways improves CD8+ T cell metabolism and antiviral function.
- Valeria Barili
- , Paola Fisicaro
- & Carlo Ferrari
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Article
| Open Access
Neutrophils-related host factors associated with severe disease and fatality in patients with influenza infection
Identification of host factors associated with severe influenza infection could provide insights into treatment options. Here, the authors provide transcriptomic analyses of blood from >100 influenza infected patients and show that changes in circulating neutrophils are associated with severe influenza infection.
- Benjamin M. Tang
- , Maryam Shojaei
- & Klaus Schughart
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Article
| Open Access
CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens
Autoreactive T cells are suspected to destroy hypocretin-producing neurons in narcolepsy. Here the authors detect CD8 T cells recognizing narcolepsy-related proteins in healthy individuals and in patients with narcolepsy, and show that the frequency of self-reactive CD8 T cells differs between patients and controls sharing the same HLA-II risk allele.
- Natasja Wulff Pedersen
- , Anja Holm
- & Birgitte Rahbek Kornum
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Article
| Open Access
Factor H binding proteins protect division septa on encapsulated Streptococcus pneumoniae against complement C3b deposition and amplification
Streptococcus pneumoniae evades the action of the complement system by expressing an immuno-protective polysaccharide capsule as well as Factor H-binding proteins. Here, Pathak et al. show that these two defence mechanisms are functionally and spatially coordinated on the bacterial cell surface.
- Anuj Pathak
- , Jan Bergstrand
- & Birgitta Henriques-Normark
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Article
| Open Access
Genetic deficiency of NOD2 confers resistance to invasive aspergillosis
NOD2 has been shown to be crucial for immune recognition of Aspergillus infection. Here the authors show that a common NOD2 genetic variant associated with Crohn’s disease is associated with reduced risk of disease due to enhanced antifungal activates of monocytes and macrophages.
- Mark S. Gresnigt
- , Cristina Cunha
- & Frank L. van de Veerdonk
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Article
| Open Access
Activated NK cells cause placental dysfunction and miscarriages in fetal alloimmune thrombocytopenia
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a gestational disease caused by maternal immune responses against fetal platelets. Using a FNAIT mouse model and human trophoblast cell lines, here the authors show that uterine natural killer cell-mediated trophoblast apoptosis contributes to FNAIT pathogenesis.
- Issaka Yougbaré
- , Wei-She Tai
- & Heyu Ni
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Article
| Open Access
Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy
Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.
- Eunice E. To
- , Ross Vlahos
- & Stavros Selemidis
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Article
| Open Access
Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression
Osteoarthritis (OA) is a debilitating and destructive joint disease for which disease modifying drugs are not available. Here the authors show that extracellular adenosine signalling via the A2AR receptor on chondrocytes is needed to prevent OA and that liposome-bound adenosine injection can treat the pathology in rats.
- Carmen Corciulo
- , Matin Lendhey
- & Bruce N. Cronstein
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Article
| Open Access
The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model
Alzheimer’s disease (AD) is pathologically characterized by the accumulation of neuritic plaques and neurofibrillary tangles but it is not known whether the neuritic plaque is necessary to drive the conversion of wild-type tau. Here the authors developed a mouse model in which wild-type tau is converted into pathological tau in a neuritic plaque-dependent manner.
- Tong Li
- , Kerstin E. Braunstein
- & Philip C. Wong
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Article
| Open Access
Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes
Rheumatoid arthritis is an inflammatory disease that selectively affects different joints. Here the authors show that gene expression and DNA methylation patterns of fibroblast-like synoviocytes differ between hip and knee joints in patients with RA, thus providing epigenetic and transcriptomic evidence for this anatomic selectivity of inflammation.
- Rizi Ai
- , Deepa Hammaker
- & Wei Wang
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Article
| Open Access
Sialylation 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
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Article
| Open Access
CD8+ T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing
Rasmussen Encephalitis is a rare neurological disease accompanied by inflammation and T cell infiltration in the brain. Here the authors show that the severity of this disease correlates with clonal CD8 T cell expansion.
- Tilman Schneider-Hohendorf
- , Hema Mohan
- & Nicholas Schwab
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Article
| Open Access
HIV–tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling
Some patients with HIV-associated tuberculosis develop an immune reconstitution inflammatory syndrome (TB-IRIS) in response to antiretroviral therapy. Here the authors identify genes differentially expressed in patients likely to progress to TB-IRIS and find activation of Toll-like receptor and inflammasome pathways.
- Rachel P. J. Lai
- , Graeme Meintjes
- & Robert J. Wilkinson
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Article
| Open Access
Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology
Immunosuppression has been unsuccessful in treatment of Alzheimer’s disease. Here the authors show in a mouse model of the disease that transient inhibition of regulatory T cells mitigates amyloid plaque pathology and reverses cognitive decline, whereas augmenting these cells worsens the pathology.
- Kuti Baruch
- , Neta Rosenzweig
- & Michal Schwartz
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Article
| Open Access
Genome-wide analysis of the genetic regulation of gene expression in human neutrophils
Neutrophils are abundant immune cells important for antimicrobial defence and in autoimmunity. Here, by mapping expression quantitative trait loci (eQTL) in neutrophils of Chinese ethnicity from Singapore, Andiappan et al.provide a resource for understanding immune-related trait associated genetic variants.
- Anand Kumar Andiappan
- , Rossella Melchiotti
- & Olaf Rotzschke
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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
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Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons
Abnormal accumulation of TDP-43 and FUS proteins is found in a neurodegenerative disease amyotrophic lateral sclerosis. Here the authors show by modelling the disease in worms that these proteins activate local and distal immune responses, and blocking this pathway in neurons ameliorates the disease.
- Julie Vérièpe
- , Lucresse Fossouo
- & J Alex Parker
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Article
| Open Access
CD11c-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
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IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis
Innate immune responses are regulated in the intestine to prevent excessive inflammation. Here the authors demonstrate a pivotal role for intestinal macrophages that constitutively produce IL-10 in controlling excessive innate immune activation and preventing tissue damage after an acute bacterial infection.
- Petra Krause
- , Venetia Morris
- & Masako Murai
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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
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Article
| Open Access
Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes
Diabetes can be caused by viral infections in humans and some inbred mice, suggesting genetic predisposition. Here the authors show that mutations in Tyk2 gene underlie susceptibility to virus-induced diabetes in mice, due to Tyk2requirement for antiviral response in insulin-producing cells.
- Kenichi Izumi
- , Keiichiro Mine
- & Seiho Nagafuchi
The IL-33/ST2 axis is protective against acute inflammation during the course of periodontitis