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| 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 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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Article
| 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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| 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 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 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 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 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 AccessFluorinated polyamidoamine dendrimer-mediated miR-23b delivery for the treatment of experimental rheumatoid arthritis in rats
Delivery of anti-inflammatory microRNA (miRNA) could be beneficial for inflammatory diseases such as rheumatoid arthritis (RA). Here the authors show that a fluorinated polyamidoamine dendrimer nanoparticle delivers miR-23b to affected RA joints and reduces inflammation, joint damage and synovial cell influx.
- Haobo Han
- , Jiakai Xing
- & Quanshun Li
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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 AccessImmunosuppressive biomaterial-based therapeutic vaccine to treat multiple sclerosis via re-establishing immune tolerance
Multiple sclerosis is a debilitating autoimmune disease, for which therapy is not curative, only slowing down progression at the expense of general immune suppression. Here authors show that in a mouse model of multiple sclerosis, disease progression could be halted or even reversed by a nanovaccine, composed of reactive oxygen species scavenging cerium oxide nanoparticles, which establishes immune tolerance against the relevant autoantigen.
- Thanh Loc Nguyen
- , Youngjin Choi
- & Jaeyun Kim
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Article
| Open AccessLow-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes
Low-dose interleukin-2 is showing promise in the treatment of several autoimmune inflammatory diseases. Here authors map the trajectory of cellular and transcriptional changes in type 1 diabetes patients receiving an interval dosing interleukin-2 regimen, which shows an anti-inflammatory gene expression signature shared by all immune cell types analysed, persisting for at least a month after ending treatment.
- Jia-Yuan Zhang
- , Fiona Hamey
- & Ricardo C. Ferreira
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Article
| Open AccessPrioritizing autoimmunity risk variants for functional analyses by fine-mapping mutations under natural selection
Immune genes under selection can shed light on phenotypes contributing to survival and modern inflammatory conditions. Here, the authors prioritize adaptive disease variants in 535 risk loci for 21 inflammatory conditions and report promising SNPs for functional studies with predictions of cell context and function.
- Vasili Pankratov
- , Milyausha Yunusbaeva
- & Bayazit Yunusbayev
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| Open AccessUse of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes
Type I diabetes is characterized by autoantibodies directed against protein or non-protein self-antigens. Here the authors profile glycan reactive anti-carbohydrate antibodies (ACA) in a longitudinal and cross-sectional childhood diabetes cohort and associate clusters of ACA with disease progression.
- Paul M. H. Tran
- , Fran Dong
- & Sharad Purohit
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Article
| Open AccessSingle-cell profiling reveals distinct adaptive immune hallmarks in MDA5+ dermatomyositis with therapeutic implications
Anti-melanoma differentiation-associated gene 5-positive dermatomyositis is a severe autoimmune disease with largely unknown aetiology. Here authors identify the key immune cell types that contribute to the disease phenotype and implicate type I interferons signalling in the patho-mechanism.
- Yan Ye
- , Zechuan Chen
- & Xiaoming Zhang
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| Open AccessSystems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function
Fibroblast-like synoviocytes (FLS) are used as a model of rheumatoid arthritis synoviocytes, although cell lines derived from individual patients can have heterogeneous biology. Here the authors use a Taiji computational approach to analyze gene expression, chromatin accessibility and functional differences between individual patient-derived RA FLS lines.
- Richard I. Ainsworth
- , Deepa Hammaker
- & Wei Wang
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Article
| Open AccessThe Fab region of IgG impairs the internalization pathway of FcRn upon Fc engagement
Disrupting the association between the Immunoglobulin G constant fragment (Fc) and the neonatal Fc receptor (FcRn) by engineered antibodies is a promising strategy to reduce autoantibody levels in autoimmune diseases. Here authors show that the variable fragment (Fab) of immunoglobulins could disturb the Fc-FcRn interaction, therefore the therapeutic effect of Fc-only fragments might surpass that of Fc-engineered antibodies with enhanced binding to FcRn.
- Maximilian Brinkhaus
- , Erwin Pannecoucke
- & Gestur Vidarsson
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Article
| Open AccessMulticellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis
Uveitis is a complex autoimmune inflammatory disease of the eye and defining molecules involved is a priority. Here the authors use scRNA sequencing in mouse experimental autoimmune uveitis (EAU) and show PIM1 promotes the imbalance of Th17 and Treg cells, and find elevated PIM-1 in human uveitis disease.
- He Li
- , Lihui Xie
- & Wenru Su
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Article
| Open AccessSingle cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease
Celiac disease is linked to responsiveness to dietary gluten, which manifests itself as immune cell activation and the immunopathology including destruction of the epithelium of the small intestine. Here the authors apply single cell transcriptomics to characterise the immune cell compartment of the human small intestine during active Celiac disease.
- Nader Atlasy
- , Anna Bujko
- & Hendrik G. Stunnenberg
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| Open AccessMyasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma
Myasthenia Gravis and thymoma are frequently associated with patients suffering from both diseases. Here the authors perform single cell sequencing of thymoma and find that there are autoimmune antigens such as neuromuscular proteins expressed aberrantly in neuromuscular mTECs in patients with both diseases.
- Yoshiaki Yasumizu
- , Naganari Ohkura
- & Hideki Mochizuki
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| Open AccessTemporal changes in gastrointestinal fungi and the risk of autoimmunity during early childhood: the TEDDY study
Here, via metagenomics and ITS2 sequencing analysis of children's stool samples from three months to four years, the authors show that the fungal composition changes and relative abundance increases at weaning, but unlike bacteria, the overall levels of fungal diversity do not change substantially over time.
- Thomas A. Auchtung
- , Christopher J. Stewart
- & Joseph F. Petrosino
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Article
| Open AccessInhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis
Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.
- William Damsky
- , Alice Wang
- & Brett King
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Article
| Open AccessChildhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach
The rise in type 1 diabetes is thought to be related to increased childhood obesity, but this relationship is not well understood. In this study, the authors utilize Mendelian randomization to separate the direct and indirect effects of childhood body size on risk of type 1 diabetes and 7 other immune-associated disease outcomes.
- Tom G. Richardson
- , Daniel J. M. Crouch
- & George Davey Smith
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Article
| Open AccessTNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease
Reduction of systemic autoimmunity using TNF blockers may also reduce inflammatory diseases in other organs. Here, the authors use a patient database and scRNA-seq to link autoimmune diseases to benign prostatic hyperplasia (BPH), and demonstrate that prostatic hyperplasia is reduced by TNF blockers in humans and mice.
- Renee E. Vickman
- , LaTayia Aaron-Brooks
- & Simon W. Hayward
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| Open AccessProgression of type 1 diabetes from latency to symptomatic disease is predicted by distinct autoimmune trajectories
Presence of islet autoantibodies precedes the onset of type 1 diabetes but it does not predict whether and how fast symptomatic disease appears. Here authors present a model to predict and visualize progression to diabetes by using a large longitudinal data set on autoantibodies and clinical parameters as input.
- Bum Chul Kwon
- , Vibha Anand
- & Brigitte I. Frohnert
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Article
| Open AccessLymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto’s thyroiditis
Hashimoto’s Thyroiditis is an autoimmune disease with a complex pathomechanism. Authors here show by single cell RNA sequencing that the thyroidal microenvironment in the disease is characterised by three stromal cell subtypes that are potentially responsible for the recruitment of infiltrating inflammatory immune cells, such as macrophages and dendritic cells.
- Qian-Yue Zhang
- , Xiao-Ping Ye
- & Huai-Dong Song
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Article
| Open AccessDNA/RNA heteroduplex oligonucleotide technology for regulating lymphocytes in vivo
Using gene silencing to regulate lymphocyte function is a promising therapeutic approach for autommunity, inflammation and cancer. Here the authors use a heteroduplex oligonucleotide for improved potency, efficacy and longer retention times.
- Masaki Ohyagi
- , Tetsuya Nagata
- & Takanori Yokota
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Article
| Open AccessG-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through autocrine/paracrine mediators
P2Y10 is a G-protein-coupled receptor that is expressed in CD4 T cells. Here authors show that its ligands, lysophosphatidylserine and ATP, are induced in T cells upon chemokine stimulation and regulate RhoA activation and migration through an autocrine/paracrine loop.
- Malarvizhi Gurusamy
- , Denise Tischner
- & Nina Wettschureck
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Article
| Open AccessAltered function and differentiation of age-associated B cells contribute to the female bias in lupus mice
Autoimmunity mediated by age-associated B cells (ABC) can affect males and females differently. Here, using a lupus-like mouse model that affects females more severely, the authors observe an ABC mediated and guanine nucleotide exchange factor (GEF) restrained pathogenic process involving TLR7.
- Edd Ricker
- , Michela Manni
- & Alessandra B. Pernis
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Article
| Open AccessThe RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response
Zinc finger proteins are involved in the resolution of immune responses and function by degrading mRNA of inflammatory cytokines. Here the authors show MCPIP3 promotes skin inflammation via modification of cytokine profiles in pDCs and macrophages.
- Bo Liu
- , Jiancheng Huang
- & Cliff Y. Yang
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Article
| Open AccessGenome-wide association study identifies five risk loci for pernicious anemia
Pernicious anemia shows co-incidence with autoimmune disorders, yet the genetic basis for this condition is understudied. Here, the authors perform a genome-wide association study meta-analysis on pernicious anemia, identifying five susceptibility loci that map to genes with known roles in autoimmune disease.
- Triin Laisk
- , Maarja Lepamets
- & Reedik Mägi
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| Open AccessIdentification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups
The presentation of systemic lupus erythematosus has been known to differ by ancestry, but the underlying genetic factors remain unclear. Here, the authors report ancestry-specific susceptibility loci and better risk prediction when using data from matched ancestral groups.
- Yong-Fei Wang
- , Yan Zhang
- & Wanling Yang
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Article
| Open AccessEvaluating the informativeness of deep learning annotations for human complex diseases
Deep learning models have shown great promise in predicting regulatory effects from DNA sequence. Here the authors evaluate sequence-based epigenomic deep learning models and conclude that these models are not yet ready to inform our knowledge of human disease.
- Kushal K. Dey
- , Bryce van de Geijn
- & Alkes L. Price
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Article
| Open 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 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 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 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 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 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 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 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 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 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 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