Featured
-
-
Article
| Open AccessApplying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.
- Pavel Loginovic
- , Feiyi Wang
- & Tasanee Braithwaite
-
Article
| Open AccessProfiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Microglia nodules are associated with brain pathology. Here, the authors show demyelination in microglia nodules in multiple sclerosis (MS), likely due to oxidized phospholipid phagocytosis and immune activation, suggesting that nodules could be involved in MS lesion formation.
- Aletta M. R. van den Bosch
- , Marlijn van der Poel
- & Jörg Hamann
-
Article
| Open AccessRegulation of stress granule formation in human oligodendrocytes
Oligodendrocyte (OL) injury and loss is a pathologic hallmark of multiple sclerosis. Here, the authors show the presence of stress granules in OLs in multiple sclerosis lesions, and their in vitro studies in human OLs indicate that stress granules formation is a response to a combination of metabolic stress and pro-inflammatory conditions.
- Florian Pernin
- , Qiao-Ling Cui
- & Jack P. Antel
-
Article
| Open AccessThe aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34
Microglia could have health-promoting capacities in age-associated neuroinflammation. Here, the authors describe an autophagy and IL-34 dependent neuroprotective microglia population in the aging brain as a potential therapeutic target.
- Rasmus Berglund
- , Yufei Cheng
- & Maja Jagodic
-
Article
| Open AccesshnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)
HnRNP A1 dysfunction is associated with neurodegeneration in multiple sclerosis (MS). Herein, advanced RNA sequencing and CLIPseq of MS brains and relevant models demonstrated that hnRNP A1 binding of target RNAs and RNA splicing were altered, precipitating neurodegeneration.
- Hannah E. Salapa
- , Patricia A. Thibault
- & Michael C. Levin
-
Article
| Open AccessAssociations of myeloid cells with cellular and humoral responses following vaccinations in patients with neuroimmunological diseases
Patients with autoimmune diseases require immunosuppressive treatments that affect their responses to infection and vaccination. Here, using mass cytometry, the authors to identify a role for myeloid cells in cellular and humoral responses following vaccination against SARS-CoV-2 in patients with neuroimmunological diseases.
- Meng Wang
- , Adeline Dehlinger
- & Chotima Böttcher
-
Article
| Open AccessProteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
Precise biomarkers for multiple sclerosis prognosis are vital for treatment decisions. Here, the authors identify specific proteins in cerebrospinal fluid that can predict short-term disease activity and long-term disability outcomes in persons with multiple sclerosis.
- Julia Åkesson
- , Sara Hojjati
- & Mika Gustafsson
-
Article
| Open AccessAstrocyte-oligodendrocyte interaction regulates central nervous system regeneration
The mechanisms regulating central nervous system remyelination efficiency are poorly understood. Here, the authors show that remyelination is driven by astrocytes supporting oligodendrocyte survival, regulated by the Nrf2 and cholesterol pathways.
- Irene Molina-Gonzalez
- , Rebecca K. Holloway
- & Veronique E. Miron
-
Article
| Open AccessAndrogens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination
Androgen effects have been poorly studied in demyelinating diseases in females. Here, authors show androgen requirement for proper myelin regeneration in females and the critical need to consider male-female differences in multiple sclerosis patients.
- Amina Zahaf
- , Abdelmoumen Kassoussi
- & Elisabeth Traiffort
-
Article
| Open AccessMolecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms
Multiple sclerosis (MS) changes the composition of the CSF. Here the authors use patient samples and aggregate CSF biomarkers into models that predict disability across all MS phenotypes, and identify potentially causal mechanisms and molecular disease heterogeneity.
- Peter Kosa
- , Christopher Barbour
- & Bibiana Bielekova
-
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
-
Article
| Open AccessEstimating individual treatment effect on disability progression in multiple sclerosis using deep learning
There are limited predictive biomarkers for drug treatment responses in individuals with multiple sclerosis. Here using existing clinical trials data, the authors propose a deep-learning predictive enrichment strategy to identify which participants are most likely to respond to a treatment.
- Jean-Pierre R. Falet
- , Joshua Durso-Finley
- & Douglas Lorne Arnold
-
Article
| Open AccessRestoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing
Age-dependent decline in remyelination in the CNS is associated with declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). Here, the authors show nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing in mouse OPCs. β-nicotinamide mononucleotide (β-NMN) supplement delays myelin aging and enhances remyelination in the aged mice.
- Xiao-Ru Ma
- , Xudong Zhu
- & Jing-Wei Zhao
-
Article
| Open AccessProximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome
Integrating functional data with GWAS loci can help interpret the function of genetic variants associated with disease. Here the authors map cis and trans methylation QTL in CD4 + T cells from patients and colocalize with GWAS loci in order to interpret genetic variants associated with multiple sclerosis.
- Tina Roostaei
- , Hans-Ulrich Klein
- & Philip L. De Jager
-
Article
| Open AccessPericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
Fibrotic scar tissue limits central nervous system regeneration. Here, Dias et al. show that fibrotic scarring is common in mice and humans, following distinct lesions to the adult brain and spinal cord, and derives from a discrete population of GLAST-expressing perivascular cells.
- David O. Dias
- , Jannis Kalkitsas
- & Christian Göritz
-
Article
| Open AccessMicroglia-neuron interaction at nodes of Ranvier depends on neuronal activity through potassium release and contributes to remyelination
Microglia are important for brain homeostasis and plasticity. The mechanisms underlying microglia-neuron interactions are still unclear. Here, the authors show that microglia preferentially interact with the nodes of Ranvier along axons. This interaction is modulated by neuronal activity and contributes to remyelination in mice.
- R. Ronzano
- , T. Roux
- & A. Desmazières
-
Article
| Open AccessIdentifying multiple sclerosis subtypes using unsupervised machine learning and MRI data
Multiple sclerosis is a heterogeneous progressive disease. Here, the authors use an unsupervised machine learning algorithm to determine multiple sclerosis subtypes, progression, and response to potential therapeutic treatments based on neuroimaging data.
- Arman Eshaghi
- , Alexandra L. Young
- & Olga Ciccarelli
-
Article
| Open AccessA CD8+ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis
A better understanding of how multiple sclerosis (MS) can relapse and remit is needed for the identification of biomarkers and better therapeutics. Here the authors identify a CD8 + NK cell population in patients with relapsing remitting MS and validate its association with clinical outcome.
- Eoin F. McKinney
- , Iona Cuthbertson
- & Kenneth G. C. Smith
-
Article
| Open AccessMyelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits
Myelination optimizes conduction speed of excitatory neurons. However, whether myelination of interneurons (INs) refines cortical networks is unclear. Here, the authors show that INs myelination shapes feedforward inhibition of mouse cortical sensory circuits and impacts whisker-mediated behaviour.
- Najate Benamer
- , Marie Vidal
- & María Cecilia Angulo
-
Article
| Open AccessGsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis
Impaired oligodendrocyte (OL) differentiation and remyelination after myelin damage in multiple sclerosis is associated with neurodegeneration. The authors show that Gsta4 is expressed during adult OL differentiation and identify it as a regulator of OL differentiation, survival, and remyelination.
- Karl E. Carlström
- , Keying Zhu
- & Fredrik Piehl
-
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
-
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
-
Article
| Open AccessDietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology
Food intake shapes intestinal microbiome composition, which in turn shapes adaptive immune responses. Here the authors show that dietary tryptophan restriction (DTR) protects mice from subsequent autoimmune neuropathology challenge by altering intestinal microbiota, highlighting the potential of diet-regulated microbiota to prevent immune pathology.
- Jana K. Sonner
- , Melanie Keil
- & Michael Platten
-
Article
| Open AccessOligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination
In multiple sclerosis (MS), antigen-presenting cells inducing cytotoxic T cell response against mature oligodendrocytes remain to be identified. Here the authors show that oligodendrocyte precursors cross-present antigen taken up from mature oligodendrocytes, and are targeted by cytotoxic T cells in cell culture and in an animal model of MS.
- Leslie Kirby
- , Jing Jin
- & Peter A. Calabresi
-
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
-
Article
| Open AccessA systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis
Genome-wide association studies (GWAS) have so far uncovered more than 200 loci for multiple sclerosis (MS). Here, the authors integrate data from various sources for a cell type-specific pathway analysis of MS GWAS results that specifically highlights the involvement of the immune system in disease pathogenesis.
- Lohith Madireddy
- , Nikolaos A. Patsopoulos
- & Sergio E. Baranzini
-
Article
| Open AccessDNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis
Monozygotic (MZ) twins are ideal to study the influence of non-genetic factors on complex phenotypes. Here, Souren et al. perform an EWAS in peripheral blood mononuclear cells from 45 MZ twins discordant for multiple sclerosis and identify disease and treatment-associated epigenetic markers.
- Nicole Y. Souren
- , Lisa A. Gerdes
- & Jörn Walter
-
Article
| Open AccessTranscriptional profiling of human microglia reveals grey–white matter heterogeneity and multiple sclerosis-associated changes
It is unclear if early pathological changes in normal-appearing multiple sclerosis (MS) tissue are reflected by molecular changes in microglia, which might contribute to lesion initiation. Here, authors demonstrate significant intrinsic differences in the human microglial transcriptome between grey and white matter regions, isolated from MS and non-neurological control donors, and show early microglial changes related to MS pathology.
- Marlijn van der Poel
- , Thomas Ulas
- & Inge Huitinga
-
Article
| Open AccessModulation of proteoglycan receptor PTPσ enhances MMP-2 activity to promote recovery from multiple sclerosis
Demyelination failure in multiple sclerosis (MS) may contribute to the disease progression. This study shows that chondroitin sulfate proteoglycans (CSPGs) can inhibit remyelination in an animal model of MS via CSPG binding with the receptor PTPσ on oligodendrocyte progenitor cells, and disruption of this interaction can promote recovery in the animal models of MS.
- Fucheng Luo
- , Amanda Phuong Tran
- & Yan Yang
-
Article
| Open AccessA scalable online tool for quantitative social network assessment reveals potentially modifiable social environmental risks
An individual’s social network—their friends, family, and acquaintances—is important for their health, but existing tools for assessing social networks have limitations. Here, the authors introduce a quantitative social network assessment tool on a secure open-source web platform and show its utility in a nation-wide study.
- Amar Dhand
- , Charles C. White
- & Philip L. De Jager
-
Article
| Open AccessDNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here the authors find that DNA methylation at HLA-DRB1 gene mediates the effect of DRB1*15:01 and of a protective HLA variant on HLA-DRB1 expression and the risk of MS.
- Lara Kular
- , Yun Liu
- & Maja Jagodic
-
Article
| Open AccessA20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation
As resident macrophages of the brain, microglia are important for neuroinflammatory responses. This work shows that nuclear factor kappa B regulatory protein A20 is important for microglia activation and regulation during inflammation of the central nervous system.
- Sofie Voet
- , Conor Mc Guire
- & Geert van Loo
-
Article
| Open AccessEGFL7 reduces CNS inflammation in mouse
Endothelial cells release extracellular matrix components that regulate inflammation. Here the authors demonstrate that the extracellular matrix component epidermal growth factor-like protein 7 regulates inflammation in experimental autoimmune encephalomyelitis in the mouse.
- Catherine Larochelle
- , Timo Uphaus
- & Frauke Zipp
-
Article
| Open AccessNon-canonical Wnt signaling regulates neural stem cell quiescence during homeostasis and after demyelination
Following demyelination injury, neural stem cells (NSCs) in the subventricular zone switch to an activated state. Here, the authors show that a transient shift from non-canonical to canonical Wnt signaling is necessary for activation of quiescent NSCs to achieve tissue homeostasis and brain repair.
- Manideep Chavali
- , Michael Klingener
- & Adan Aguirre
-
Article
| Open AccessCirculating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis
MiRNAs are small RNA molecules that can regulate gene expression. Here the authors show that expression of several exosomal miRNAs are altered in patients with multiple sclerosis, and that let-7i modulates regulatory T cell homeostasis to contribute to pathogenesis.
- Kimitoshi Kimura
- , Hirohiko Hohjoh
- & Takashi Yamamura
-
Article
| Open AccessSystematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic
Progressive multiple sclerosis is an inflammatory and degenerative disease of the central nervous system, for which effective treatment is lacking. The authors carry out a screen to identify orally available generic medications, and show that the antidepressant clomipramine reduces pathology in mouse models.
- Simon Faissner
- , Manoj Mishra
- & V. Wee Yong
-
Article
| Open AccessTranscriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis
CD4+ T cells secreting interleukin-17 (TH17) have diverse functions in modulating autoimmune diseases. Here the authors show via transcriptome analyses that a subset of human TH 17 co-expressing interferon-γ (TH1/17) has a molecular signature similar to “pathogenic” mouse TH 17 but distinct from “non-pathogenic” mouse TH 17.
- Dan Hu
- , Samuele Notarbartolo
- & Howard L. Weiner
-
Article
| Open AccessDietary cholesterol promotes repair of demyelinated lesions in the adult brain
Cholesterol is important for axonal myelination during development. Here the authors show that cholesterol levels are reduced in a cuprizone mouse model of multiple sclerosis and that dietary cholesterol supplementation enhances remyelination and recovery.
- Stefan A. Berghoff
- , Nina Gerndt
- & Gesine Saher
-
Article
| Open AccessMyelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model
Oligodendrocyte damage is a key component of demyelinating diseases. Here, the authors use in vivolight and correlated electron microscopy in EAE mouse models, and find early damage occurs at the myelin sheath before spreading to the oligodendrocyte cell body.
- Elisa Romanelli
- , Doron Merkler
- & Martin Kerschensteiner
-
Article
| Open AccessAlterations of the human gut microbiome in multiple sclerosis
The gut microbiome has been implicated in several autoimmune disorders. Here, the authors study the gut microbiome of patients with multiple sclerosis, and find correlations between altered abundance of certain gut microorganisms and changes in expression of immune defence genes.
- Sushrut Jangi
- , Roopali Gandhi
- & Howard L. Weiner
-
Article
| Open AccessAn inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination
Chondroitin sulfate proteoglycans (CSPGs) secreted by astrocytes are known to inhibit OPC differentiation and remyelination. Here, the authors identify a novel CSPG synthesis inhibitor and find it can rescue OPC differentiation in vitroand accelerate remyelination in mice following focal demyelination.
- Michael B. Keough
- , James A. Rogers
- & V. Wee Yong
-
Article
| Open AccessKappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination
Current treatments of multiple sclerosis are aimed at immunosuppression. Here the authors show that kappa opioid receptor is important for oligodendrocyte differentiation and myelination and the receptor agonists are protective in a mouse model of multiple sclerosis.
- Changsheng Du
- , Yanhui Duan
- & Xin Xie
-
Article
| Open AccessNeuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors
Myelin regeneration can occur spontaneously in demyelinating diseases but the underlying mechanisms are incompletely understood. Here the authors show that neuronal activity and glutamatergic synapses instruct oligodendrocyte progenitor cells to differentiate into new myelinating oligodendrocytes.
- Hélène O. B. Gautier
- , Kimberley A. Evans
- & Ragnhildur T Káradóttir
-
Article
| Open AccessEomesodermin-expressing T-helper cells are essential for chronic neuroinflammation
Eomesodermin is a master regulator of effector CD8+ T cells. Here the authors show that it also plays a critical role in pathogenic CD4+ cells in a mouse model of multiple sclerosis, and its inactivation ameliorates the chronic stage of the disease.
- Ben J. E. Raveney
- , Shinji Oki
- & Takashi Yamamura
-
Article
| Open AccessPharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic
Current multiple sclerosis treatments focus on prevention of immune attack on oligodendrocytes and myelin. Here the authors show a different strategy to ameliorate disease in several mouse models, protecting oligodendrocytes from inflammation-induced death with an FDA-approved drug, guanabenz.
- Sharon W. Way
- , Joseph R. Podojil
- & Brian Popko
-
Article
| Open AccessNAD+ protects against EAE by regulating CD4+ T-cell differentiation
The mechanism by which NAD+ alters the systemic immune response is unclear. Here the authors show that NAD+ induces systemic homeostasis and protects against experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis, by regulating CD4+T cell differentiation and promoting myelin and axonal regeneration.
- Stefan G. Tullius
- , Hector Rodriguez Cetina Biefer
- & Abdallah ElKhal
-
Article |
Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells
Genetic studies have connected polymorphisms in the IL-2 receptor alpha (IL2RA) gene with susceptibility to multiple sclerosis, but the mechanisms underlying this association are not clear. Here, the authors show that a polymorphism in IL2RA increases responsiveness to IL-2 and GM-CSF production in human THcells.
- Felix J. Hartmann
- , Mohsen Khademi
- & Burkhard Becher
-
Article |
An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling
Polysaccharide A (PSA) from the human intestinal commensal Bacteroides fragilis mediates protection against the experimental autoimmune encephalomyelitis in mice. Here, Wang et al. show that the protective function of PSA is exerted through its action on CD39+regulatory CD4 T cells via Toll-like receptor 2 signalling.
- Yan Wang
- , Kiel M. Telesford
- & Lloyd H. Kasper
-
Article |
Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation
T cells that mediate neuroinflammation in EAE, a mouse model of multiple sclerosis, act through their production of cytokines. Here, the authors show that the transcription factor Bhlhe40 regulates the expression of GM-CSF and IL-10 by autoreactive T cells and is crucial for EAE induction.
- Chih-Chung Lin
- , Tara R. Bradstreet
- & Brian T. Edelson