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
2022
Toward Precision Phenotyping of Multiple Sclerosis
Pitt D, Lo CH, Gauthier SA, Hickman RA, Longbrake E, Airas LM, Mao-Draayer Y, Riley C, De Jager PL, Wesley S, Boster A, Topalli I, Bagnato F, Mansoor M, Stuve O, Kister I, Pelletier D, Stathopoulos P, Dutta R, Lincoln MR. Toward Precision Phenotyping of Multiple Sclerosis. Neurology Neuroimmunology & Neuroinflammation 2022, 9: e200025. PMID: 36041861, PMCID: PMC9427000, DOI: 10.1212/nxi.0000000000200025.Peer-Reviewed Original ResearchConceptsMultiple sclerosisSecondary progressive multiple sclerosisPathological processesProgressive multiple sclerosisKey pathological processClinical trial designDevelopment of biomarkersPerilesional inflammationNeuroaxonal degenerationMS phenotypeTrial designClinical importancePersonalized careM phenotypeSclerosisPhenotypeRemyelinationInflammationSyndromePrognosticationDegenerationProgressionBiomarkersCareClinical trials in multiple sclerosis: past, present, and future
Manouchehri N, Shirani A, Salinas VH, Tardo L, Hussain RZ, Pitt D, Stuve O. Clinical trials in multiple sclerosis: past, present, and future. Neurologia I Neurochirurgia Polska 2022, 56: 228-235. PMID: 35712986, DOI: 10.5603/pjnns.a2022.0041.Peer-Reviewed Original ResearchConceptsDisease-modifying therapiesMultiple sclerosisClinical trialsManagement of MSEffective disease-modifying therapiesDisability Assessment ScaleDisease-specific interventionsDisease diagnostic criteriaBurden of diseaseClinical trial developmentDisease-specific biomarkersMS pathophysiologyDiagnostic criteriaClinical practiceTrial developmentAssessment ScaleSclerosisTrialsPatientsNeuroimmunologyPathophysiologyTherapyDiseaseDiagnosisContinued progressMagnetic Susceptibility Source Separation Solely from Gradient Echo Data: Histological Validation
Dimov AV, Gillen KM, Nguyen TD, Kang J, Sharma R, Pitt D, Gauthier SA, Wang Y. Magnetic Susceptibility Source Separation Solely from Gradient Echo Data: Histological Validation. Tomography 2022, 8: 1544-1551. PMID: 35736875, PMCID: PMC9228115, DOI: 10.3390/tomography8030127.Peer-Reviewed Original ResearchSusceptibility source separation from gradient echo data using magnitude decay modeling
Dimov AV, Nguyen TD, Gillen KM, Marcille M, Spincemaille P, Pitt D, Gauthier SA, Wang Y. Susceptibility source separation from gradient echo data using magnitude decay modeling. Journal Of Neuroimaging 2022, 32: 852-859. PMID: 35668022, DOI: 10.1111/jon.13014.Peer-Reviewed Original ResearchDimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions
Zinger N, Ponath G, Sweeney E, Nguyen TD, Lo CH, Diaz I, Dimov A, Teng L, Zexter L, Comunale J, Wang Y, Pitt D, Gauthier SA. Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions. Neurology Neuroimmunology & Neuroinflammation 2022, 9: e1138. PMID: 35046083, PMCID: PMC8771666, DOI: 10.1212/nxi.0000000000001138.Peer-Reviewed Original ResearchConceptsChronic active lesionsGlatiramer acetateRim lesionsHuman microgliaDimethyl fumarateMultiple sclerosisActive lesionsChronic active multiple sclerosis lesionsEffects of DMFActive multiple sclerosis lesionsClass III evidenceMarkers of inflammationRelapsing-remitting MSRetrospective observational studyQuantitative susceptibility mappingMultiple sclerosis lesionsActivation stateTreatment-induced changesMRI quantitative susceptibility mappingMicroglial activityGlial activityInflammatory activationMicroglial cellsObservational studyMS lesions
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 expressionDiabetesInflammationTET2MiceRecipientsCellsIn vivo evidence of differential frontal cortex metabolic abnormalities in progressive and relapsing‐remitting multiple sclerosis
Swanberg KM, Prinsen H, DeStefano K, Bailey M, Kurada AV, Pitt D, Fulbright RK, Juchem C. In vivo evidence of differential frontal cortex metabolic abnormalities in progressive and relapsing‐remitting multiple sclerosis. NMR In Biomedicine 2021, 34: e4590. PMID: 34318959, DOI: 10.1002/nbm.4590.Peer-Reviewed Original ResearchConceptsProgressive multiple sclerosisRelapsing-remitting multiple sclerosisMultiple sclerosis patientsMultiple sclerosisDisease durationSclerosis patientsRelapsing-remitting multiple sclerosis patientsSignificant negative correlationAvailable disease-modifying therapiesFrontal cortex metabolismH-MRS protocolDisease-modifying therapiesHealthy control adultsN-acetyl aspartateCross-sectional analysisCortex metabolismMetabolic abnormalitiesΓ-aminobutyric acidMetabolites glutamateFrontal cortexSclerosisNegative correlationControl adultsGABAProton MRSQSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions
Gillen KM, Mubarak M, Park C, Ponath G, Zhang S, Dimov A, Levine‐Ritterman M, Toro S, Huang W, Amici S, Kaunzner UW, Gauthier SA, Guerau‐de‐Arellano M, Wang Y, Nguyen TD, Pitt D. QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions. Annals Of Clinical And Translational Neurology 2021, 8: 877-886. PMID: 33704933, PMCID: PMC8045922, DOI: 10.1002/acn3.51338.Peer-Reviewed Original ResearchConceptsNormal-appearing white matterMyeloid cellsLesion rimReactive oxygen speciesQuantitative susceptibility mappingChronic active lesionsChronic glial activationPro-inflammatory cytokinesBlood-brain barrierWhite matter lesionsAdjacent normal-appearing white matterMultiple sclerosis lesionsGlial activationActivated microgliaHistopathological correlatesChronic inflammationActive lesionsCytokine productionMatter lesionsMS lesionsWhite matterHuman-induced pluripotent stem cellsSclerosis lesionsLesionsLesion perimeter
2020
Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS
Lucca LE, Lerner BA, Park C, DeBartolo D, Harnett B, Kumar VP, Ponath G, Raddassi K, Huttner A, Hafler DA, Pitt D. Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS. Neurology Neuroimmunology & Neuroinflammation 2020, 7: e712. PMID: 32269065, PMCID: PMC7188477, DOI: 10.1212/nxi.0000000000000712.Peer-Reviewed Original ResearchConceptsTumor-infiltrating T cellsT cellsPD-1/PD-L1Anti-TIGIT therapyExpression of CD226Expression of TIGITPostmortem CNS tissueLymphocytes of patientsFresh surgical resectionsLigand CD155TIGIT expressionSurgical resectionPD-1PD-L1CNS diseaseHealthy controlsHealthy donorsLymphocytic expressionImmune responseCNS tissueMS lesionsTIGITImmune pathwaysPatientsGlioblastoma multiforme
2019
The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions
Park C, Ponath G, Levine-Ritterman M, Bull E, Swanson EC, De Jager PL, Segal BM, Pitt D. The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions. Acta Neuropathologica Communications 2019, 7: 130. PMID: 31405387, PMCID: PMC6689891, DOI: 10.1186/s40478-019-0779-2.Peer-Reviewed Original ResearchConceptsMultiple sclerosis lesionsLesion rimAstrocyte phenotypeMyeloid cellsSclerosis lesionsActive multiple sclerosis lesionsAcute multiple sclerosis lesionsGlial activation markersActive MS lesionsNovel therapeutic targetDifferent lesion stagesPredominant cell typeAcute demyelinationDemyelinating lesionsCell typesActivation markersChronic inflammationDistinct myeloidCell-extrinsic factorsGlial cellsPhenotypic subsetsLesion stageGlial phenotypeMS lesionsLesion cellsMultiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry
Ramaglia V, Sheikh-Mohamed S, Legg K, Park C, Rojas OL, Zandee S, Fu F, Ornatsky O, Swanson EC, Pitt D, Prat A, McKee TD, Gommerman JL. Multiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry. ELife 2019, 8: e48051. PMID: 31368890, PMCID: PMC6707785, DOI: 10.7554/elife.48051.Peer-Reviewed Original ResearchConceptsMultiple sclerosisMS disease activityT-cell phenotypeMass cytometryTypes of lymphocytesMultiple sclerosis lesionsNatalizumab cessationDisease activityMS patientsInflammatory lesionsImmune cellsSpinal cordLesion morphometryMS lesionsB cellsLesion typeSclerosis lesionsLesionsBlood vesselsCell phenotypeFunctional stateCytometryCellular contentCell-cell interactionsPhenotype
2018
Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Ponath G, Lincoln MR, Levine-Ritterman M, Park C, Dahlawi S, Mubarak M, Sumida T, Airas L, Zhang S, Isitan C, Nguyen TD, Raine CS, Hafler DA, Pitt D. Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Nature Communications 2018, 9: 5337. PMID: 30559390, PMCID: PMC6297228, DOI: 10.1038/s41467-018-07785-8.Peer-Reviewed Original ResearchConceptsMultiple sclerosisAstrocyte responseRisk variantsLocal autoimmune inflammationPeripheral immune cellsCentral nervous system cellsPeripheral immune systemCultured human astrocytesNervous system cellsNF-κB signalingCNS accessDysfunctional lymphocytesAstroglial functionAutoimmune inflammationLymphocytic infiltrateLymphocyte recruitmentImmune cellsGenetic risk allelesGenetic risk variantsMS lesionsMS susceptibilityHuman astrocytesLesion sizeImmune systemSystem cellsQuantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions
Kaunzner UW, Kang Y, Zhang S, Morris E, Yao Y, Pandya S, Rua S, Park C, Gillen KM, Nguyen TD, Wang Y, Pitt D, Gauthier SA. Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions. Brain 2018, 142: 133-145. PMID: 30561514, PMCID: PMC6308309, DOI: 10.1093/brain/awy296.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntigens, CDAntigens, Differentiation, MyelomonocyticBrainCarbon RadioisotopesChronic DiseaseCross-Sectional StudiesFemaleHumansInflammationIronIsoquinolinesMacrophagesMagnetic Resonance ImagingMaleMicrogliaMiddle AgedMultiple SclerosisPositron-Emission TomographyRetrospective StudiesYoung AdultConceptsChronic active lesionsMultiple sclerosisChronic lesionsActive lesionsMultiple sclerosis lesionsHyperintense rimQuantitative susceptibility mappingChronic active multiple sclerosis lesionsSclerosis lesionsChronic multiple sclerosis lesionsActive multiple sclerosis lesionsPersistent inflammatory activityProgressive multiple sclerosisMicroglia/macrophagesInnate immune activationEarly disease stagesTranslocator proteinGreater tissue damagePost-mortem studiesProgressive patientsActivated microgliaInflammatory activityPersistent inflammationImmune activationDisease stageAstrocytes play a crucial role in the formation and evolution of MS lesions – Yes
Pitt D, Ponath G. Astrocytes play a crucial role in the formation and evolution of MS lesions – Yes. Multiple Sclerosis Journal 2018, 25: 15-17. PMID: 30136895, DOI: 10.1177/1352458518793026.Peer-Reviewed Original ResearchMagnetic 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 diseasesThe Role of Astrocytes in Multiple Sclerosis
Ponath G, Park C, Pitt D. The Role of Astrocytes in Multiple Sclerosis. Frontiers In Immunology 2018, 9: 217. PMID: 29515568, PMCID: PMC5826071, DOI: 10.3389/fimmu.2018.00217.Peer-Reviewed Original ResearchConceptsRole of astrocytesImmune cell accessCentral nervous systemMultiple sclerosis lesionsAstrocyte activationMultiple sclerosisGlial scarAstrocyte functionMS treatmentMS lesionsNervous systemAstrocytesSclerosis lesionsLesion formationFunctional polarizationLesionsCell accessSclerosisInflammationPathogenesisMyeloid 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
2017
Podoplanin is a negative regulator of Th17 inflammation
Nylander AN, Ponath GD, Axisa PP, Mubarak M, Tomayko M, Kuchroo VK, Pitt D, Hafler DA. Podoplanin is a negative regulator of Th17 inflammation. JCI Insight 2017, 2: e92321. PMID: 28878118, PMCID: PMC5621890, DOI: 10.1172/jci.insight.92321.Peer-Reviewed Original ResearchConceptsT cellsIL-17IL-17 secretionDistinct cytokine profilesInflammatory gene signatureTh17-polarizing conditionsTh17 cellsCytokine profileCell subsetsInflammatory responseSkin biopsiesMouse modelPDPN expressionMultiple organsSkin diseasesGene signatureInflammationLymphatic systemCLEC-2PDPNRecent dataDifferent subpopulationsCellsTranscriptional profilesShRNA gene