2024
Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways
Gurrea-Rubio M, Wang Q, Mills E, Wu Q, Pitt D, Tsou P, Fox D, Mao-Draayer Y. Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways. International Journal Of Molecular Sciences 2024, 25: 2454. PMID: 38473703, PMCID: PMC10931690, DOI: 10.3390/ijms25052454.Peer-Reviewed Original ResearchConceptsSecondary progressive MSRelapsing-remitting MSCentral nervous systemMultiple sclerosisProgressive MSModulator of sphingosine-1-phosphateCytokine tumor necrosis factor-alphaEffects of siponimodTumor necrosis factor-alphaHeterogeneous clinical courseBouts of inflammationNeuroprotective effectsPreclinical animal modelsAutoimmune demyelinating diseaseNecrosis factor-alphaMitochondrial oxidative phosphorylationHuman induced pluripotent stem cell (iPSC)-derived neuronsSphingosine-1-phosphateCytokine signaling pathwaysClinical courseLive cell analysisProgressive diseaseOral treatmentMitochondrial pathwayFactor-alpha
2021
Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
Rui J, Deng S, Perdigoto AL, Ponath G, Kursawe R, Lawlor N, Sumida T, Levine-Ritterman M, Stitzel ML, Pitt D, Lu J, Herold KC. Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes. Nature Communications 2021, 12: 5074. PMID: 34417463, PMCID: PMC8379260, DOI: 10.1038/s41467-021-25367-z.Peer-Reviewed Original ResearchConceptsImmune cellsΒ-cellsNOD/SCID recipientsDiabetogenic immune cellsDiabetogenic T cellsBone marrow transplantType 1 diabetesExpression of TET2Human β-cellsIslet infiltratesSCID recipientsMarrow transplantInflammatory pathwaysTransfer of diseaseT cellsInflammatory genesImmune killingPathologic interactionsReduced expressionDiabetesInflammationTET2MiceRecipientsCells
2018
Magnetic susceptibility increases as diamagnetic molecules breakdown: Myelin digestion during multiple sclerosis lesion formation contributes to increase on QSM
Deh K, Ponath GD, Molvi Z, Parel G, Gillen KM, Zhang S, Nguyen TD, Spincemaille P, Ma Y, Gupta A, Gauthier SA, Pitt D, Wang Y. Magnetic susceptibility increases as diamagnetic molecules breakdown: Myelin digestion during multiple sclerosis lesion formation contributes to increase on QSM. Journal Of Magnetic Resonance Imaging 2018, 48: 1281-1287. PMID: 29517817, PMCID: PMC6129234, DOI: 10.1002/jmri.25997.Peer-Reviewed Original ResearchSignificance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions
Gillen KM, Mubarak M, Nguyen TD, Pitt D. Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions. Frontiers In Immunology 2018, 9: 255. PMID: 29515576, PMCID: PMC5826076, DOI: 10.3389/fimmu.2018.00255.Peer-Reviewed Original ResearchConceptsCentral nervous systemChronic active lesionsMultiple sclerosisActive lesionsWhite matterWhite matter MS lesionsQuantitative susceptibility mappingNovel MS therapiesResident immune cellsChronic inflammatory activityWhite matter lesionsMyeloid cell activationAdjacent white matterWhite matter multiple sclerosis lesionsChronic tissue damageMultiple sclerosis lesionsMS therapyInflammatory activityMagnetic resonance imaging techniquesChronic inflammationMatter lesionsAged brainImmune cellsMyelin phagocytosisChronic diseasesMyeloid cell plasticity in the evolution of central nervous system autoimmunity
Giles DA, Washnock‐Schmid J, Duncker PC, Dahlawi S, Ponath G, Pitt D, Segal BM. Myeloid cell plasticity in the evolution of central nervous system autoimmunity. Annals Of Neurology 2018, 83: 131-141. PMID: 29283442, PMCID: PMC5876132, DOI: 10.1002/ana.25128.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArginaseAutoimmune Diseases of the Nervous SystemBone Marrow CellsCell PlasticityChimeraDisease ProgressionEncephalomyelitis, Autoimmune, ExperimentalHumansImmunohistochemistryLectins, C-TypeMannose ReceptorMannose-Binding LectinsMiceMice, Inbred C57BLMultiple SclerosisMyeloid CellsNitric Oxide Synthase Type IIPhenotypeReceptors, Cell SurfaceConceptsInducible nitric oxide synthaseExperimental autoimmune encephalomyelitisCNS myeloid cellsCentral nervous systemCentral nervous system autoimmunityChronic active MS lesionsActive MS lesionsMultiple sclerosisMyeloid cellsMS lesionsAnimal model experimental autoimmune encephalomyelitisRemission of EAEModel experimental autoimmune encephalomyelitisMyeloid cell plasticityEncephalitogenic T cellsNitric oxide synthaseMyeloid cell phenotypeFuture therapeutic strategiesHuman myeloid cellsAnn NeurolNoninflammatory phenotypePolarized subsetsClinical remissionAutoimmune encephalomyelitisProinflammatory markers
2016
Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology
Ponath G, Ramanan S, Mubarak M, Housley W, Lee S, Sahinkaya FR, Vortmeyer A, Raine CS, Pitt D. Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. Brain 2016, 140: 399-413. PMID: 28007993, PMCID: PMC5841057, DOI: 10.1093/brain/aww298.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnimalsAnimals, NewbornAstrocytesCell ProliferationCells, CulturedChild, PreschoolCultureCytokinesDemyelinating Autoimmune Diseases, CNSEndocytosisFemaleHumansHydrazonesMacrophagesMaleMiddle AgedMyelin SheathPhagocytosisRatsRats, Sprague-DawleyStrokeTime FactorsTransforming Growth Factor betaConceptsMyelin injuryMyelin phagocytosisMyelin debrisMultiple sclerosis lesionsMultiple sclerosisLesion pathologySclerosis lesionsAcute multiple sclerosis lesionsCentral nervous system pathologyProgressive multifocal leukoencephalopathyNervous system pathologySecretion of chemokinesNF-κB activationElevated chemokine expressionHypertrophic astrocytesMost astrocytesMyelin uptakeMultifocal leukoencephalopathyFirst-line responseAcute lesionsMyelin damageReactive astrocytesChemokine expressionAstroglial responseImmune cellsIron in Multiple Sclerosis and Its Noninvasive Imaging with Quantitative Susceptibility Mapping
Stüber C, Pitt D, Wang Y. Iron in Multiple Sclerosis and Its Noninvasive Imaging with Quantitative Susceptibility Mapping. International Journal Of Molecular Sciences 2016, 17: 100. PMID: 26784172, PMCID: PMC4730342, DOI: 10.3390/ijms17010100.Peer-Reviewed Original ResearchConceptsMultiple sclerosisMagnetic resonance imagingBrain tissueQuantitative susceptibility mappingMS brain tissueAdvanced MRI methodsMS patientsChronic inflammationImmunohistochemical investigationBrain ironMyeloid cellsResonance imagingNon-invasive studyHistological studyRole of ironOxidative stressNoninvasive imagingSclerosisInflammationCellular distributionMRI methodsNeurodegenerationTissueImagingPatients
2015
Concise Review: Modeling Multiple Sclerosis With Stem Cell Biological Platforms: Toward Functional Validation of Cellular and Molecular Phenotypes in Inflammation-Induced Neurodegeneration
Orack JC, Deleidi M, Pitt D, Mahajan K, Nicholas JA, Boster AL, Racke MK, Comabella M, Watanabe F, Imitola J. Concise Review: Modeling Multiple Sclerosis With Stem Cell Biological Platforms: Toward Functional Validation of Cellular and Molecular Phenotypes in Inflammation-Induced Neurodegeneration. Stem Cells Translational Medicine 2015, 4: 252-260. PMID: 25593207, PMCID: PMC4339849, DOI: 10.5966/sctm.2014-0133.Peer-Reviewed Original ResearchConceptsSomatic cell reprogrammingStem cellsInduced pluripotent stem cell (iPSC) technologyPluripotent stem cell (iPSC) technologyOligodendrocyte progenitor cellsMultiple sclerosisGeneration of neuronsNew mechanistic insightsCell reprogrammingNovel stem cellFunctional validationStem cell technologyMolecular mechanismsBiological toolsMesenchymal stem cellsMolecular phenotypesNovel mechanismProgenitor cellsImmune cell functionPhase I clinical trialMechanistic insightsBiological platformCell functionSignificant unmet needBrain atrophy
2009
Dysmyelinated axons in shiverer mice are highly vulnerable to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated toxicity
Pitt D, Gonzales E, Cross AH, Goldberg MP. Dysmyelinated axons in shiverer mice are highly vulnerable to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated toxicity. Brain Research 2009, 1309: 146-154. PMID: 19896473, PMCID: PMC7343376, DOI: 10.1016/j.brainres.2009.10.066.Peer-Reviewed Original ResearchMeSH KeywordsAlpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic AcidAnimalsBiomarkersBrainDisease Models, AnimalExcitatory Amino Acid AgonistsFemaleHereditary Central Nervous System Demyelinating DiseasesLuminescent ProteinsMiceMice, Inbred C57BLMice, Neurologic MutantsMovement DisordersMyelin Basic ProteinNerve DegenerationNerve Fibers, MyelinatedNeurotoxinsN-MethylaspartateReceptors, AMPAConceptsNMDA receptorsShiverer miceAMPA/kainate receptorsLumbar dorsal columnWhite matter injuryWidespread axonal degenerationSpinal cord axonsActivation of receptorsReceptor-mediated toxicitySubset of axonsMyelin basic proteinAxonal vulnerabilityNeuroprotective therapiesGlutamate excitotoxicityNMDA injectionAxonal degenerationAxonal injuryDorsal columnsRotarod performanceAxon damageGlutamate toxicityCentral axonsGlial cellsS-AMPAAxonal toxicity
2003
Experimental Autoimmune Encephalomyelitis (EAE) in CCR2−/− Mice Susceptibility in Multiple Strains
Gaupp S, Pitt D, Kuziel WA, Cannella B, Raine CS. Experimental Autoimmune Encephalomyelitis (EAE) in CCR2−/− Mice Susceptibility in Multiple Strains. American Journal Of Pathology 2003, 162: 139-150. PMID: 12507897, PMCID: PMC1851120, DOI: 10.1016/s0002-9440(10)63805-9.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DivisionCrosses, GeneticDisease Models, AnimalEncephalomyelitis, Autoimmune, ExperimentalGenetic Predisposition to DiseaseGlycoproteinsImmunity, InnateImmunohistochemistryIn Situ HybridizationLymphocytesMiceMice, Inbred BALB CMice, Inbred C57BLMice, Inbred StrainsMice, KnockoutMyelin SheathMyelin-Oligodendrocyte GlycoproteinNuclease Protection AssaysPeptide FragmentsReceptors, CCR2Receptors, ChemokineRNA, MessengerSpecies SpecificityConceptsExperimental autoimmune encephalomyelitisCentral nervous systemAutoimmune encephalomyelitisLow molecular weight cytokinesLack of CCR2Deletion of CCR2Sites of inflammationWild-type animalsDifferent mouse strainsCCR2 deletionCNS lesionsMultiple sclerosisWeight cytokinesAutoimmune diseasesMouse susceptibilityNervous systemImmune systemCompensatory mechanismsBalb CCCR2Mouse strainsChemokinesMonocytesEncephalomyelitisAppropriate receptors
2000
Insulin-Like Growth Factor-1 Fails to Enhance Central Nervous System Myelin Repair during Autoimmune Demyelination
Cannella B, Pitt D, Capello E, Raine C. Insulin-Like Growth Factor-1 Fails to Enhance Central Nervous System Myelin Repair during Autoimmune Demyelination. American Journal Of Pathology 2000, 157: 933-943. PMID: 10980132, PMCID: PMC1885703, DOI: 10.1016/s0002-9440(10)64606-8.Peer-Reviewed Original ResearchConceptsInsulin-like growth factor-1Experimental autoimmune encephalomyelitisCentral nervous system tissueGrowth factor-1Nervous system tissueAcute phaseChronic phaseChronic time pointsTime pointsVehicle-treated groupIGF-1 administrationVehicle-treated controlsFactor 1Oligodendrocyte progenitor populationClinical ameliorationAutoimmune encephalomyelitisCytokine levelsDifferent time pointsTreatment regimenAutoimmune demyelinationMultiple sclerosisSJL miceMyelin regenerationMyelin repairTGF-beta2Glutamate excitotoxicity in a model of multiple sclerosis
Pitt D, Werner P, Raine C. Glutamate excitotoxicity in a model of multiple sclerosis. Nature Medicine 2000, 6: 67-70. PMID: 10613826, DOI: 10.1038/71555.Peer-Reviewed Original ResearchConceptsGlutamate excitotoxicityMultiple sclerosisAMPA/kainate antagonist NBQXAMPA/kainate typeCentral nervous system inflammationAMPA/kainate antagonistAntigen-primed T cellsCentral nervous system2Nervous system inflammationExperimental autoimmune encephalomyelitisCentral nervous systemMyelin-producing cellsLack of effectDemyelinating modelKainate typeSystem inflammationAutoimmune encephalomyelitisInflammatory attacksKainate antagonistAntagonist NBQXAutoimmune demyelinationPathologic featuresClinical differencesReceptor damageOligodendrocyte survivalGlutamate excitotoxicity — a mechanism for axonal damage and oligodendrocyte death in Multiple Sclerosis?
Werner P, Pitt D, Raine CS. Glutamate excitotoxicity — a mechanism for axonal damage and oligodendrocyte death in Multiple Sclerosis? Journal Of Neural Transmission. Supplementa 2000, 375-385. PMID: 11205156, DOI: 10.1007/978-3-7091-6301-6_27.Peer-Reviewed Original ResearchConceptsCentral nervous systemAMPA/kainate antagonistMultiple sclerosisGlutamate excitotoxicityImmune cellsKainate antagonistAxonal damageAntigen-primed T cellsMyelin-producing cellsLack of effectSite of entryCNS inflammationInflammatory attacksExperimental autoimmunePerivascular cuffsAutoimmune demyelinationInflammatory lesionsClinical differencesOligodendrocyte survivalEffective therapyGlutamate receptorsOligodendrocyte deathT cellsExcitotoxicityLesion size