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| Open AccessFibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs
A20 gene variants are linked with systemic sclerosis (SS), but the mechanisms are unclear. Here, the authors show that A20 expression is reduced in SS skin and lungs, that its ablation in mice induces SS, and that show that fibrosis can be ameliorated by induction of A20.
- Wenxia Wang
- , Swarna Bale
- & John Varga
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Article
| Open AccessThe E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS
The activity and stability of the cytosolic DNA sensor cGAS, a key mediator of innate antiviral immunity and autoimmunity, is fine-tuned by post-translational modifications. Here, the authors demonstrate that the ubiquitin E3 ligase ARIH1 catalyzes the mono-ISGylation of cGAS and promotes its oligomerization in response to viral and self DNA.
- Tian-Chen Xiong
- , Ming-Cong Wei
- & Dandan Lin
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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 AccessThe protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation
The anti-viral protein MAVS forms aggregates as part of the antiviral response and promoting type I IFN responses. Here the authors show that protein arginine methyltransferase 9 (PRMT9) methylates MAVS to keep the protein in a non-aggregated state and propose a regulatory mechanism for MAVS.
- Xuemei Bai
- , Chao Sui
- & Chengjiang Gao
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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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Article
| Open AccessTranscription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes
The transcription factor IRF8 has been shown to regulate monocyte differentiation via its DNA-binding activity. Here authors show that IRF8 is also involved in cytosolic DNA sensing via its phosphorylation-dependent association to the adaptor protein STING, thus representing an important checkpoint between immune response and autoimmunity in monocytes.
- Wei-Wei Luo
- , Zhen Tong
- & Yan-Yi Wang
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Article
| Open AccessSingle cell sequencing identifies clonally expanded synovial CD4+ TPH cells expressing GPR56 in rheumatoid arthritis
Antibodies against citrullinated proteins (ACPA) can divide rheumatoid arthritis patients but the difference in immune phenotype is not clear. Here the authors characterise T peripheral helper cells in arthritic joints comparing ACPA+ and ACPA- patients showing changes in immune cell phenotype and surface molecules.
- Alexandra Argyriou
- , Marc H. Wadsworth II
- & Karine Chemin
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Article
| Open AccessSelective activation and expansion of regulatory T cells using lipid encapsulated mRNA encoding a long-acting IL-2 mutein
IL-2 has been used to expand regulatory T (Treg) cells for treating inflammatory disorders. Here the authors test an engineered IL-2 mutein, delivered subcutaneously as mRNA, to show its increased specificity for activating and expanding Treg cells in both rodents and non-human primates, and to demonstrate its ability to suppress autoimmunity in mouse models.
- Seymour de Picciotto
- , Nicholas DeVita
- & Eric Huang
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Article
| Open AccessRe-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity
Invariant natural killer T (iNKT) cells are tissue-resident immune cells recognizing lipid antigens. Here the authors find that liver, but not lung nor spleen, iNKT cells alter their transcriptome upon systemic treatment of lipid nanoparticles for the induction of regulatory B cells and suppression of liver and pancreas autoimmunity in mouse models.
- Channakeshava Sokke Umeshappa
- , Patricia Solé
- & Pere Santamaria
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Article
| Open AccessThe Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness
Absence of regulatory T cells results in a severe inflammatory disease which leads to death in infancy in both human patients and in mouse models. Authors show here that in mice, conditional deletion of Rbx1, the RING component of Cullin-RING ligases in regulatory T cells causes a similar phenotype, due to the disrupted degradation of important regulatory proteins.
- Di Wu
- , Haomin Li
- & Yi Sun
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Article
| Open AccessPD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity
Phenotypic and functional states of dendritic cells critically influence the outcome of cancer and inflammation. Authors here show by single cell transcriptomics and in vitro validation assays that dichotomous PD-L1 and ICOSL expression assign dendritic cells to secretory and helper functions, with respective predominance of inflammatory cytokine expression or T helper cytokine induction.
- Caroline Hoffmann
- , Floriane Noel
- & Vassili Soumelis
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Article
| Open AccessDistinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy
Arthritis is the most common rheumatic immune-related adverse event (irAE) occurring in cancer patients receiving immune checkpoint inhibitors. Here the authors study the immune landscape of blood and synovial fluid samples from patients with arthritis-irAE, reporting immunological differences and similarities with classic autoimmune arthritis.
- Sang T. Kim
- , Yanshuo Chu
- & Roza Nurieva
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Article
| Open AccessCitrullination of glucokinase is linked to autoimmune diabetes
Post translational modifications are involved in the regulation of a number of proteins and can be themselves modified by the cellular environment. Here the authors implicate citrullination of glucokinase in autoimmune diabetes
- Mei-Ling Yang
- , Sheryl Horstman
- & Mark J. Mamula
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Article
| 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 AccessAutoantibodies targeting GPCRs and RAS-related molecules associate with COVID-19 severity
COVID-19, similarly to systemic autoimmune diseases, is characterised by the presence of autoantibodies. Authors show here that the abundance and network signature of autoantibodies targeting G protein-coupled receptors and RAS-related proteins are altered in COVID-19 patients, and the level of disruption marks clinical severity.
- Otavio Cabral-Marques
- , Gilad Halpert
- & Yehuda Shoenfeld
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Article
| Open AccessWhole exome sequencing in Alopecia Areata identifies rare variants in KRT82
Common variants have been discovered to be associated with Alopecia Areata; however, rare variants have been less well studied. Here, the authors use whole-exome sequencing to identify associated rare variants in the hair keratin gene KRT82. Further, they find that individuals with Alopecia Areata have reduced expression of KRT82 in the skin and hair follicle.
- Stephanie O. Erjavec
- , Sahar Gelfman
- & Angela M. Christiano
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Article
| Open AccessAdenosine receptor 2a agonists target mouse CD11c+T-bet+ B cells in infection and autoimmunity
CD11c+T-bet+ B cells have been linked with different autoimmune diseases, but targeting these cells has been challenging. Here the authors use an adenosine 2A receptor agonist to deplete these B cells and to inhibit or reverse autoimmune symptoms and pathology in mice.
- Russell C. Levack
- , Krista L. Newell
- & Gary M. Winslow
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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 AccessFollicular T cells are clonally and transcriptionally distinct in B cell-driven mouse autoimmune disease
Follicular T cells regulate germinal centre reactions, but their phenotypes in autoimmune disease are unclear. Using a mouse model of autoantibody disease, the authors show that autoimmune follicular T cells differ by TCR clonotype and transcriptional profile from non-autoimmune follicular T cells.
- Elliot H. Akama-Garren
- , Theo van den Broek
- & Michael C. Carroll
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Article
| Open AccessZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization
Macrophages employ epigenetic remodeling, especially the regulation of superenhancers (SEs), to promote classical polarization and function; whether liquid-liquid phase separation (LLPS) is involved is not known. Here, the authors show the epigenetic reader ZMYND8 forms condensates to deactivate latent SEs in a spatiotemporal manner and thereby restrict macrophage-mediated inflammation.
- Pan Jia
- , Xiang Li
- & Wei Lu
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Article
| Open AccessOptineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling
Optineurin (OPTN) has been implicated in various biological processes, but its function in dendritic cells (DC) maturation is still unclear. Here the authors show, by characterizing Optn-conditional knockout mice, that the loss of OPTN induces Jak2/Stat3 activation and IL-10 production to suppress DC maturation and function, thereby ameliorating autoimmune responses in mice.
- Jiajia Wang
- , Jiaying Wang
- & Qinjie Weng
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Article
| Open AccessInterleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis
Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.
- Ai Kuzumi
- , Ayumi Yoshizaki
- & Shinichi Sato
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Article
| Open AccessCD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression
Ectonucleotidases associated to regulatory T cells are known modulators in the inflammatory environment. Here the authors describe CD8 T cell-derived extracellular vesicles bearing CD73 and suggest they function as an additional intrinsic modulator of immune responses.
- Enja Schneider
- , Riekje Winzer
- & Eva Tolosa
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Article
| Open AccessPolymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases
The Cia21 locus on chromosome 3 has been associated with rheumatoid arthritis severity in females. Here the authors show this locus houses a non-coding polymorphic estrogen receptor binding site and how it regulates neighbouring gene expression of CD2, implicating CD2 signalling in the sexual dimorphism of a variety of T cell-dependent autoimmune diseases.
- Gonzalo Fernandez Lahore
- , Michael Förster
- & Rikard Holmdahl
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Article
| Open AccessNew-onset IgG autoantibodies in hospitalized patients with COVID-19
Infection with SARS-CoV2 and the development of Coronavirus disease 2019 (COVID-19) has been linked to induction of autoimmunity and autoantibody production. Here the authors characterise the new-onset IgG autoantibody response in hospitalised patients with COVID-19 which they correlate to the magnitude of the SARS-CoV2 response.
- Sarah Esther Chang
- , Allan Feng
- & Paul J. Utz
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Article
| Open AccessT cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8
Epitopes formed by fusion of more than one self peptide, such as proinsulin and other β cell proteins, can result in the formation of non-self hybrid peptides that can potentially trigger autoimmune responses. Here the authors show how TRBV5 + T cell receptors are geared towards recognition of HLA-DQ8 bound hybrid peptides in patients with type 1 diabetes.
- Mai T. Tran
- , Pouya Faridi
- & Hugh H. Reid
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Article
| Open AccessTet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
There are dynamic interactions between immune cells and β cells that lead to β cell destruction in the context of autoimmune diabetes. Here the authors show that TET2, a methylcytosine dioxygenase, can regulate this interaction and deletion of TET2 can prevent the autoimmune destruction of β cells in mice.
- Jinxiu Rui
- , Songyan Deng
- & Kevan C. Herold
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Article
| Open AccessSingle-cell sequencing of immune cells from anticitrullinated peptide antibody positive and negative rheumatoid arthritis
Patients with rheumatoid arthritis are commonly stratified by ACPA serology, with positivity being associated with more severe disease and joint destruction. Here the authors present a single cell RNA sequencing resource comparing peripheral blood and synovial tissue cells from patients with ACPA+ versus ACPA- rheumatoid arthritis.
- Xunyao Wu
- , Yi Liu
- & Xuan Zhang
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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 Access3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine
3-hydroxy-L-kynurenamine (3-HKA) is a metabolite deriving from a lateral pathway of tryptophan catabolism. Here the authors identify 3-HKA as a biogenic amine and show it has anti-inflammatory properties that can protect mice against psoriasis and nephrotoxic nephritis.
- Cristina C. Clement
- , Angelo D’Alessandro
- & Laura Santambrogio
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Article
| Open AccessGenetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease
IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.
- Tatsuma Ban
- , Masako Kikuchi
- & Tomohiko Tamura
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Article
| Open AccessIndispensable epigenetic control of thymic epithelial cell development and function by polycomb repressive complex 2
Development of the T cells requires functions from thymic epithelial cells, whose development and function are epigenetically regulated. Here the authors show that inactivation of the polycomb repressive complex 2 (PRC2) alters the H3K27me3 configuration, reduces TEC functions, reveals a specific TEC subset, and hampers T cell development.
- Thomas Barthlott
- , Adam E. Handel
- & Georg A. Holländer
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| Open AccessPhase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus
Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.
- Sarfaraz A. Hasni
- , Sarthak Gupta
- & Mariana J. Kaplan
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Article
| Open AccessDefective dystrophic thymus determines degenerative changes in skeletal muscle
Immune cells are known to aggravate the inflammatory impact of Duchene muscular dystrophy. Here, the authors describe impaired thymic development and suggest thymic involution in this model of disease is linked to disease acceleration due to impaired immunological tolerance.
- Andrea Farini
- , Clementina Sitzia
- & Yvan Torrente
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Article
| Open AccessType I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus
Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.
- Norzawani Buang
- , Lunnathaya Tapeng
- & Marina Botto
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Article
| Open AccessThe survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5
Regulatory B (Breg) cells suppress excessive inflammation primary via the production of interleukin 10 (IL-10). Here the authors show that the function and homeostasis of mouse and human IL-10+ Breg cells are negatively regulated by the cell surface receptor, SLAMF5, to impact experimental autoimmunity, thereby hinting SLAMF5 as a potential target for immunotherapy.
- Lihi Radomir
- , Matthias P. Kramer
- & Idit Shachar
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Article
| Open AccessSingle-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla
The thymus supports T cell immunity by providing the environment for thymocyte differentiation. Here the authors profile human thymic stroma at the single cell level, identifying ionocytes as a new medullary population and defining tissue specific antigen expression in multiple stromal cell types.
- Jhoanne L. Bautista
- , Nathan T. Cramer
- & Audrey V. Parent
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Article
| Open AccessPersistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling
The transcriptional adaptation processes of harmful self-reactive CD8+ T cells in the central nervous system are not well understood. Here the authors use a system in which self-reactive and virally generated CD8+ T cells are directly compared in vivo and demonstrate that TOX expression contributes to maintenance of auto-reactive CD8+ T cells through alteration of chromatin accessibility.
- Nicolas Page
- , Sylvain Lemeille
- & Doron Merkler
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Article
| 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 AccessEndophilin A2 deficiency protects rodents from autoimmune arthritis by modulating T cell activation
The autoimmune disorder, rheumatoid arthritis (RA), has been associated with multiple pathophysiological factors. Here the authors show that deficiency in endophilin A2 in rodents protects them from experimental arthritis by altering T cell activation threshold and effector functions, thereby hinting a potential target for RA therapy.
- Ulrika Norin
- , Carola Rintisch
- & Rikard Holmdahl
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Article
| Open AccessCTLA-4 expression by B-1a B cells is essential for immune tolerance
CTLA-4 is an important co-inhibitory receptor for T cells. Here, the authors show that CTLA-4 also has a function on B-1a cells, as conditional deletion results in activation of these cells and knockout mice develop an autoimmune profile.
- Yang Yang
- , Xiao Li
- & Leonore A. Herzenberg
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Article
| Open AccessSOX-5 activates a novel RORγt enhancer to facilitate experimental autoimmune encephalomyelitis by promoting Th17 cell differentiation
T helper 17 (Th17) cells are important mediators of inflammatory diseases and fungal infection protection, and are critically regulated by the transcription factor (TF), RORγt. Here the authors identify a new enhancer for RORγt, RORCE2, which synergizes with another TF, Sox5, for binding with RORγt promoter and thereby modulation of RORγt expression.
- Yi Tian
- , Chao Han
- & Yuzhang Wu
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Article
| Open AccessGranzyme B inhibition reduces disease severity in autoimmune blistering diseases
Pemphigoid diseases involve autoimmune mediated blistering and immunopathology of the upper dermis. Here, the authors implicate granzyme B in the immunopathology in multiple in vivo models of pemphigoid diseases and utilise a topical granzyme B inhibitor that attenuates disease phenotypes in vivo.
- Sho Hiroyasu
- , Matthew R. Zeglinski
- & David J. Granville
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Article
| Open AccessSLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression
Enhancers shape gene expression patterns and are involved in disease pathogenesis. Here the authors demonstrate a strategy to screen functional regulatory elements for non-coding RNAs ― illustrated with miR-146a ― and link autoimmune disease risk genetic variants to autoimmune disease etiology.
- Guojun Hou
- , Isaac T. W. Harley
- & Nan Shen
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Article
| Open AccessEarly-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling
Early life trauma has been associated with multiple sclerosis, but the causal link is unclear. Here the authors show in mice that early life trauma can result in IFN-β-resistant EAE as a result of β-adrenergic desensitization in immune cells and that a β1 adrenergic receptor agonist can reverse this susceptibility.
- Yee Ming Khaw
- , Danish Majid
- & Makoto Inoue
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Article
| Open AccessTARM1 contributes to development of arthritis by activating dendritic cells through recognition of collagens
TARM1 is a LILR family member that drives cell signalling via interactions with FcRγ. Here the authors show that TARM1 binds collagens to activate dendritic cells and thereby is an effector of inflammatory arthritis, plus provide a soluble TARM-Fc fusion protein that can limit collagen-induced arthritis in mice.
- Rikio Yabe
- , Soo-Hyun Chung
- & Yoichiro Iwakura
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Article
| Open AccessGenetic and pharmacological inhibition of the nuclear receptor RORα regulates TH17 driven inflammatory disorders
Unlike RORα, which has been thought to be somewhat redundant, RORγt has been well characterized in its function and contribution to the development of Th17 cells. Here the authors show that RORα is important in Th17 differentiation and that RORα deletion or a small molecule inhibitor of RORα can reduce disease in EAE and colitis mouse models.
- Ran Wang
- , Sean Campbell
- & Laura A. Solt
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Article
| Open AccessFunctionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity
Type I interferon drives autoimmune pathology in SLE and has been assumed to come predominantly from plasmacytoid dendritic cells (pDCs). Here, the authors show that prior to the onset of SLE, pDCs lose multiple immunogenic functions and, instead, non-hematopoietic cells such as keratinocytes are a major source of type I interferons.
- Antonios Psarras
- , Adewonuola Alase
- & Edward M. Vital
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Article
| Open AccessEndogenous antisense RNA curbs CD39 expression in Crohn’s disease
CD39 is an ectonucleotidase associated with immunoregulatory function. Here authors show regulation of CD39 expression by an endogenous antisense RNA moiety transcribed from the 3‘ end of CD39/ENTPD1 which when itself is silenced results in amelioration of pathology in an animal model of colitis.
- Rasika P. Harshe
- , Anyan Xie
- & Maria Serena Longhi