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| Open AccessEnhanced CD95 and interleukin 18 signalling accompany T cell receptor Vβ21.3+ activation in multi-inflammatory syndrome in children
Multi-Inflammatory Syndrome in Children (MIS-C) is a severe post-infectious presentation related to SARS-CoV-2 infection. Here authors used multi-omics approaches to characterise MIS-C cases and found increased CD95 and IL-18 signalling accompanying the expansion of TCR Vβ 21.3+ T cells.
- Zhenguang Zhang
- , Iain R. L. Kean
- & Nazima Pathan
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Article
| Open AccessHerpes simplex encephalitis due to a mutation in an E3 ubiquitin ligase
Encephalitis is a rare and severe complication of Herpes Simplex type 1 infection. Here, Bibert et al describe a genetic variant in a 2-year-old affected child that impairs interferon production in neuronal cells and enhances viral replication.
- Stéphanie Bibert
- , Mathieu Quinodoz
- & Pierre-Yves Bochud
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| Open AccessAn esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus with unclear immune cell involvement. Here the authors generate a single cell transcriptomic dataset with 400k cells from the esophageal mucosa of active EoE patients, remission EoE patients, and healthy individuals to characterise esophageal cellular composition, phenotype and interaction in this disease.
- Jiarui Ding
- , John J. Garber
- & Ramnik J. Xavier
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| Open AccessProfiling the colonic mucosal response to fecal microbiota transplantation identifies a role for GBP5 in colitis in humans and mice
Faecal microbiota transplantation (FMT) can be used to treat established colitis. Here the authors profile transcriptional changes in humans after FMT and how this relates to colitis remission identifying a role for GBP5, and this protein is validated in a loss-of-function mouse model.
- Laurence D. W. Luu
- , Abhimanu Pandey
- & Nadeem O. Kaakoush
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Article
| Open AccessExpression 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 AccessThe thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression
Regulation of thymocyte development by RNA-binding proteins is not fully characterized. Here the authors show the RBP ARPP21 interacting with the Rag1 3’-UTR to promote Rag1 expression, TCR rearrangement and an increased diversity of the TCR repertoire and that ARPP21 is down regulated by TCR stimulation.
- Meng Xu
- , Taku Ito-Kureha
- & Vigo Heissmeyer
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Article
| Open AccessSingle-cell profiling identifies IL1Bhi macrophages associated with inflammation in PD-1 inhibitor-induced inflammatory arthritis
Patients undergoing treatment with PD-1 blockade can experience inflammatory arthritis as an adverse event. Here, the authors use single-cell RNA sequencing to identify IL1Bhi macrophages in PD-1-inhibitor-induced arthritis, but not rheumatoid arthritis.
- Ziyue Zhou
- , Xiaoxiang Zhou
- & Xuan Zhang
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Article
| Open AccessCentrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells
People living with HIV-1 are at an increased risk of developing various cancers. Here, the authors suggest that HIV-1-encoded Vpr can promote oncogenesis by forming a ternary complex with VprBP and Plk4 and inducing Plk4-dependent centriole overduplication and aneuploidy.
- Jung-Eun Park
- , Tae-Sung Kim
- & Kyung S. Lee
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Article
| Open AccessInactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice
Cytidine nucleotide triphosphate (CTP) is a key precursor involved in the metabolism of DNA, RNA and phospholipids. In this study, the authors examine the physiological consequences of CTP synthase (Ctps) 1 and 2 deletion in vivo and demonstrate that Ctps1 protects mice from fatal autoimmunity.
- Claire Soudais
- , Romane Schaus
- & Sylvain Latour
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Article
| Open AccessSingle-cell transcriptomics identifies the differentiation trajectory from inflammatory monocytes to pro-resolving macrophages in a mouse skin allergy model
Classical monocytes can differentiate into pro-inflammatory or pro-resolving macrophages. Here the authors characterise mouse macrophage differentiation and show that Ly6Chi classical monocytes can differentiate into Ly6Clo pro-resolving macrophages which are involved in the resolution of skin allergic inflammation.
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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Article
| Open AccessPathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
Gain-of-function mutations in NLRP3 result in Cryopyrin-Associated Periodic Syndrome in human patients. Here authors show that although these NLRP3 variants are constitutively active, they preserve their responsiveness to external pro-inflammatory stimuli, and they interfere with the immune-metabolic inflammatory pathways in monocytes.
- Cristina Molina-López
- , Laura Hurtado-Navarro
- & Pablo Pelegrin
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Article
| Open AccessEtrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells
The clinical success of anti- αEβ7 antibody Etrolizumab for Crohn’s disease is less than what is expected based on proof-of-concept studies. Here authors show, by characterization of T cells from Etrolizumab-treated patients, in vitro functional assays and reanalysis of public single cell datasets on Etrolizumab-treated patients, that at high level of T cell activation, which characterises T cells in Crohn’s disease, E-Cadherin-αEβ7 interactions become resistant to Etrolizumab inhibition.
- Maximilian Wiendl
- , Mark Dedden
- & Sebastian Zundler
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Article
| Open AccessVEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation
Acquired mutations of the gene UBA1 occurring in myeloid cells that result in the expression of impaired isoforms of the enzyme E1 have been described in patients with a severe adult onset auto-inflammatory syndrome called VEXAS. Here the authors profile patients with UBA1 mutations presenting with or without VEXAS disease and show VEXAS disease is characterized by inflammasome activation and monocyte dysregulation.
- Olivier Kosmider
- , Céline Possémé
- & Benjamin Terrier
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Article
| Open AccessWNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease
Fibroblast heterogeneity is a recognized feature in chronic kidney disease, and although fibrosis is integrant to the pathology, it is lesser known which of the fibroblast populations contribute. Here authors describe a population of proinflammatory fibroblasts, which are found in close proximity to macrophages and may facilitate their recruitment and acquisition of a FOLR2+, pathogenic phenotype.
- Camille Cohen
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
Steroid-refractory acute graft-versus-host disease (aGVHD) is associated with a low one-year survival rate. Here, the authors show that ROCK1 is upregulated in leukocytes from patients with steroid-refractory aGVHD and that ROCK1/2 inhibition reduces the severity of aGVHD in mice by interfering with activation of multiple immune cell types.
- Kristina Maas-Bauer
- , Anna-Verena Stell
- & Robert Zeiser
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Article
| Open AccessGasdermin E dictates inflammatory responses by controlling the mode of neutrophil death
Apoptotic and lytic cell death pathways are both utilised in the removal of damaged cells; however, the downstream inflammatory outcomes widely vary according to the chosen pathway. Here authors show that in mice with genetic deletion of Gasdermin E specifically in neutrophils, these cells undergo apoptosis rather than pyroptotic cell death upon senescence, with consequential attenuation of reactive inflammatory responses.
- Fengxia Ma
- , Laxman Ghimire
- & Hongbo R. Luo
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Article
| Open AccessSynovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis
Mast cells have been shown to be involved with rheumatoid arthritis, but the mechanisms are not clear. Here using mouse models and making association with human patients, the authors show mast cells have an important function in the pathogenesis of rheumatoid arthritis, involving regulation of T cell responses and release of mast cell mediators.
- Yunxuan Lei
- , Xin Guo
- & Guangjie Chen
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Article
| Open AccessIgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency
IgA protects mucosal barriers by coating microorganisms, yet infection related complications are rare in human IgA deficiency. Authors here show that in humans lacking IgA, IgG assists IgM in coating of most bacterial families, thus contributing to gut mucosal defence.
- Carsten Eriksen
- , Janne Marie Moll
- & Susanne Brix
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| Open AccessData-driven grading of acute graft-versus-host disease
Acute GVHD severity grading is based on target organ assessments. Here, the authors show that data-driven grading can identify 12 distinct grades with specific aGVHD phenotypes, which are associated with clinical outcomes, and that their method outperformed conventional gradings.
- Evren Bayraktar
- , Theresa Graf
- & Amin T. Turki
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Article
| Open AccessMutual modulation of gut microbiota and the immune system in type 1 diabetes models
Type-1 diabetes pathogenesis has been strongly linked with changes in the intestinal microbiota. Here, the authors demonstrate that mice susceptible to type-1 diabetes become resistant when co-housed with resistant mice, an effect that was associated with changes in gut microbiota, gut permeability, and the immune system.
- Estela Rosell-Mases
- , Alba Santiago
- & Chaysavanh Manichanh
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Article
| Open AccessThe 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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| Open AccessDistinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection
Although type-1 diabetes has a clear genetic component, not all children who are at risk eventually develop autoimmunity, suggesting the existence of environmental triggers. In this longitudinal transcriptomic study, the authors find that children who later develop autoimmunity have a distinct profile before the appearance of autoantibodies and may have impaired responses to enterovirus infection.
- Jake Lin
- , Elaheh Moradi
- & Matti Nykter
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer
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Article
| Open AccessContinually recruited naïve T cells contribute to the follicular helper and regulatory T cell pools in germinal centers
B cell clonal expansion and affinity maturation takes place in germinal centers (GC) and is orchestrated by follicular T cells. Here authors show that naïve conventional T cells are continuously recruited to the GCs during the GC reaction and develop into follicular helper and regulatory T cells, thus quantitatively contribute to remodelling the GC overtime.
- Julia Merkenschlager
- , Riza-Maria Berz
- & Michel C. Nussenzweig
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Article
| Open AccessSingle-atom catalysts-based catalytic ROS clearance for efficient psoriasis treatment and relapse prevention via restoring ESR1
Psoriasis is a common inflammatory disease, and the overproduction of reactive oxygen species (ROS) in skin lesions plays a critical role in the progress of psoriasis. Here, the authors report the use of multienzyme-inspired biomimetic iron single-atom catalysts (FeN4O2-SACs) with broad-spectrum ROS-scavenging capability for psoriasis treatment and relapse prevention via related gene restoration.
- Xiangyu Lu
- , Le Kuai
- & Jianlin Shi
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Article
| Open AccessSingle-cell multi-omics analysis identifies two distinct phenotypes of newly-onset microscopic polyangiitis
Autoimmune vasculitis can be heterogeneous in terms of immune cell involvement. Here the authors use a single cell transcriptomics approach to characterise a group of microscopic polyangiitis patients that could be split into two groups typified by monocyte or Interferon associated gene expression.
- Masayuki Nishide
- , Kei Nishimura
- & Atsushi Kumanogoh
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Article
| Open AccessImmunosuppression causes dynamic changes in expression QTLs in psoriatic skin
Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. Here, the authors investigate the genetic basis of gene expression in skin biopsies from psoriasis patients and interactions with inflammation to better understand mechanisms of the disease.
- Qian Xiao
- , Joseph Mears
- & Soumya Raychaudhuri
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Article
| Open AccessMultifaceted analysis of cross-tissue transcriptomes reveals phenotype–endotype associations in atopic dermatitis
Atopic dermatitis is an inflammatory skin disease featuring systemic involvement. Here authors show that the two major clinical manifestations of the disease, erythema and papulation, are distinguished by differential interplay between local skin and systemic immunity, uncovered by integrated transcriptomics.
- Aiko Sekita
- , Hiroshi Kawasaki
- & Haruhiko Koseki
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Article
| Open AccessA common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.
- Sarah E. Garnish
- , Katherine R. Martin
- & Joanne M. Hildebrand
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Article
| Open AccessOrai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models
The regulation and intracellular transport of Ca2+ in immune cells involves Ca2+ release-activated Ca2+ (CRAC) channels. Here the authors show targeting CRAC components Orai1 and Orai2 modulates pulmonary ILC2 cells altering their metabolism, function and is linked to alleviation of immunopathology in a murine model of allergic airway disease.
- Emily Howard
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open AccessCREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients
The mechanistic functions of neutrophils in skin inflammation are not fully understood. Here the authors use human psoriasis samples and a mouse model of skin inflammation to study neutrophils and find a CXCR4hi population of NET-forming, phagocytic neutrophils whose induction depends on the transcription factor CREB1.
- Jiaoling Chen
- , Yaxing Bai
- & Shuai Shao
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Article
| Open AccessGerminal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells
Loss-of-function mutations in the chromatin remodelling protein HELLS result in humoral immune deficiency. Authors here show in a conditional knockout mouse model that HELLS controls the kinetics of a typical germinal center response by DNA methylation, its absence leading to either the appearance of memory-B cell markers or a metabolic state change typical of plasma cells.
- Clara Cousu
- , Eléonore Mulot
- & Sébastien Storck
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| Open AccessSolar ultraviolet B radiation promotes α-MSH secretion to attenuate the function of ILC2s via the pituitary–lung axis
Allergic asthma is episodic and associated with seasonal changes which may have links with UV exposure levels. Here the authors propose a link between UVB exposure and ILC2 function through α-MSH released from the pituitary gland which accumulates in the serum and alters ILC2 function through the MC5R receptor.
- Yuying Huang
- , Lin Zhu
- & Bing Sun
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Article
| Open AccessAntibody-mediated neutralization of galectin-3 as a strategy for the treatment of systemic sclerosis
Galectin-3 (Gal-3) has been proposed to have a pathogenic role in systemic sclerosis (SSc). Here, the authors identify a Gal-3-based transcriptomic signature associated with SSc severity in patients and demonstrate that Gal-3 blockade reduces the severity of SSc skin and lung lesions in murine models.
- Céline Ortega-Ferreira
- , Perrine Soret
- & Frédéric De Ceuninck
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Article
| Open AccessType-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations
The most appreciated producers of pathogenic type-2 cytokines in asthma are T helper 2 cells and group 2 innate lymphoid cells, however, CD8+ cytotoxic T cells are also capable of secreting these mediators. Authors here show that IL-33, a cytokine that is produced by the inflammatory microenvironment, promotes type-2 cytotoxic T cell development, which is linked to asthma exacerbations.
- Esmee K. van der Ploeg
- , Lisette Krabbendam
- & Ralph Stadhouders
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Article
| Open AccessAge-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis
The incidence of rheumatoid arthritis (RA) and accumulation of circulating free (cf) DNA increase with age but it is unknown whether DNA fragments cause joint inflammation. Here authors show that cf DNA levels are higher in RA patients and that in a rat adjuvant-induced arthritis model, the exonuclease TREX1 suppresses synovial inflammation via promoting the degradation of cf DNA and inhibiting a senescence-like cellular state.
- Wei-Dan Luo
- , Yu-Ping Wang
- & Vincent Kam Wai Wong
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Article
| Open AccessIL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation
Interleukin 9 (IL-9) is a cytokine that plays causative role in airway inflammation of both infectious and allergic origin. Here authors show in a mouse model of SARS-CoV-2 infection that IL-9, predominantly produced by helper T cells, plays a critical pathogenic role in COVID-19 via an inflammatory pathway involving the transcription factor Foxo1.
- Srikanth Sadhu
- , Rajdeep Dalal
- & Amit Awasthi
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Article
| Open AccessSUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways
Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.
- Dan Tan
- , Meiping Lu
- & Ximei Wu
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Article
| Open AccessInherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling
Mutations that impact the function of the Arp2/3 complex are known to cause inborn errors of immunity. Here the authors describe biallelic null mutations in the ARPC5 subunit of Arp2/3 that disrupt actin function and cytokine signaling, causing infections, autoimmunity, inflammation and dysmorphisms.
- Cristiane J. Nunes-Santos
- , HyeSun Kuehn
- & Sergio D. Rosenzweig
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Article
| Open AccessStructural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84
The orphan GPR84 plays important roles in inflammation, fibrosis, and metabolism. Here, authors report cryo-EM structures of the receptor bound to two ligands, with insights into ligand binding and entry from the extracellular milieu.
- Heng Liu
- , Qing Zhang
- & Wanchao Yin
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Article
| Open AccessImpaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis
Inflammatory skin diseases are frequently associated with dysregulation of cutaneous immunity. Here the authors perform human challenge with house dust mite allergen in patients with atopic dermatitis and explore the molecular network determining tolerance versus inflammation and identify a role for metallothioneins in the modulation of allergen induced inflammation.
- Sofia Sirvent
- , Andres F. Vallejo
- & Marta E. Polak
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Article
| Open AccessLung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation
Mast cells are activated and proliferate during allergic reactions which can involve mast cell specific proteins. Here the authors show that mast cell-expressed membrane protein1 (MCEMP1) is an adaptor for KIT to promote SCF mediated mast cell proliferation and lack of MCEMP1 reduces inflammation in mouse asthma models.
- Youn Jung Choi
- , Ji-Seung Yoo
- & Jae U. Jung
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Article
| Open AccessTenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis
Local cues for hyperinnervation in chronic skin diseases are not fully understood. Here, the authors show that a distinct subset of dermal papillary fibroblasts promote neurite outgrowth and facilitate neuron-immune interactions through extracellular matrix remodeling in a mouse model of psoriasis
- Xiaojie Cai
- , Maoying Han
- & Honglin Wang
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Article
| Open AccessConstitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases. Here the authors report a case series of three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation, and identify de novo truncating and missense variants in the Src-family tyrosine kinase LYN.
- Adriana A. de Jesus
- , Guibin Chen
- & Raphaela Goldbach-Mansky
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Article
| Open AccessItaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming
Dysregulation of T cell homeostasis is known to contribute to the immunopathology of autoimmune diseases. Here the authors show that itaconate impacts autoimmune pathology by altering T cells via modulation of metabolic and epigenetic programs.
- Kuniyuki Aso
- , Michihito Kono
- & Tatsuya Atsumi
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Article
| Open AccessCitrullination modulates antigen processing and presentation by revealing cryptic epitopes in rheumatoid arthritis
Antibodies directed against citrullinated proteins are commonly found in patients with rheumatoid arthritis. Here, the authors show that citrullination alters the peptide repertoire presented to T cells by altering protease cleavage and inducing protein destabilization, thereby exposing cryptic epitopes.
- Ashley M. Curran
- , Alexander A. Girgis
- & Erika Darrah
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Article
| Open AccessUnique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis
The aetiology of primary biliary cholangitis (PBC) remains unclear. Here, the authors find that the numbers of DUOX2 + ACE2 + small cholangiocytes in human and mouse livers are inversely associated with disease severity, and present data indicating that they may be the target of polymeric immunoglobulin receptor (pIgR) -mediated humoral responses, suggesting that preservation of these cells and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.
- Xi Li
- , Yan Li
- & Jin Chai
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Article
| Open AccessSpatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases
Inflammatory skin diseases involve various different immune cells in a localised area. Here the authors use spatial transcriptomics to show that disease relevant cytokine transcripts are sparsely expressed in lesional skin, yet are associated with local amplification cascades that promote skin inflammation.
- A. Schäbitz
- , C. Hillig
- & S. Eyerich
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Article
| Open AccessCD1a promotes systemic manifestations of skin inflammation
Skin inflammation is often accompanied by systemic disease, yet the pathways that regulate this escalation are little known. Here authors show that transgenic expression of human CD1a in mice leads to the escalation of experimental skin inflammation and systemic inflammatory disease, and the generalized symptoms could be alleviated by blocking antibodies developed against CD1a.
- Clare S. Hardman
- , Yi-Ling Chen
- & Graham S. Ogg