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Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis

Title
Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis
Author(s)
Hwang, Seong-HyeJung, Seung-HyunLee, SaseongChoi, SusannaYoo, Seung-AhPark, Ji-HwanHwang, DaeheeShim, Seung CheolSabbagh, LaurentKim, Ki-JoPark, Sung HwanCho, Chul-SooKim, Bong-SungLeng, LinMontgomery, Ruth R.Bucala, RichardChung, Yeun-JunKim, Wan-Uk
Issued Date
2015-11-24
Citation
Proceedings of the National Academy of Sciences of the United States of America, v.112, no.47, pp.E6535 - E6543
Type
Article
Author Keywords
leukocyte-specific protein 1copy number variationT-cell functioncell migrationrheumatoid arthritis
Keywords
Animal CellAnimal ExperimentAnimal ModelAnimal TissueCalcium HomeostasisCalcium IonCalcium SignalingCD3 AntigenCD4+ T LymphocyteCD8+ T LymphocyteCell MigrationCell ProliferationChemokine Receptor CXCR4Chronic InflammationColony Stimulating Factor 1Complementary DNAConference PaperControlled StudyCOPY-NUMBER VARIATIONCXCL9 ChemokineCytokine ProductionCytokine ResponseDisease CourseDisease ExacerbationDisease PredispositionDisease SeverityDown RegulationEnzyme ActivationEnzyme ActivityEnzyme PhosphorylationEnzyme RegulationGamma InterferonGENE-EXPRESSIONGene DosageGene ExpressionGene LocationGene LossGene OverexpressionGenetic AssociationGENOME-WIDE ASSOCIATIONGenome AnalysisGenomic DNAGlucuronosyltransferaseGlucuronosyltransferase 2B28High Risk PatientHumanHuman CellImmune ResponseImmunoglobulin Blood LevelImmunoglobulin GIn Vitro StudyIn Vivo StudyInflammationInterleukin 10Interleukin 1BetaInterleukin 2Interleukin 4Joint SwellingJurkat Cell LineKAPPA-BLeukocyte-Specific Protein 1Leukocyte MigrationLSP1Lymphocyte ActivationLymphocyte CountLymphocyte MigrationLymphocytic InfiltrationMacrophage Inflammatory Protein 3BetaMessenger RNAMolecular WeightMonocyte Chemotactic Protein 1MouseNEUTROPHIL POLARIZATIONNonhumanPATHOGENESISPeripheral Blood Mononuclear CellPriority JournalProstaglandin SynthaseProstaglandin Synthase 2PROTEINProtein DeficiencyProtein DepletionProtein ExpressionProtein FunctionProtein InductionProtein Kinase BProtein Protein InteractionRECEPTORRegulatory MechanismRheumatoid ArthritisSignalSignal TransductionStable TransfectionSUSCEPTIBILITYT-Cell FunctionT LymphocyteT Lymphocyte ActivationT Lymphocyte ReceptorT Lymphocyte SubpopulationTranscription Factor Gli3Transcription Factor Sox9TranscriptomeTRANSENDOTHELIAL MIGRATIONTroponin TTroponin T3Tumor Necrosis Factor AlphaUnclassified DrugUp-Regulation
ISSN
0027-8424
Abstract
Copy number variations (CNVs) have been implicated in human diseases. However, it remains unclear how they affect immune dysfunction and autoimmune diseases, including rheumatoid arthritis (RA). Here, we identified a novel leukocyte-specific protein 1 (LSP1) deletion variant for RA susceptibility located in 11p15.5. We replicated that the copy number of LSP1 gene is significantly lower in patients with RA, which correlates positively with LSP1 protein expression levels. Differentially expressed genes in Lsp1-deficient primary T cells represent cell motility and immune and cytokine responses. Functional assays demonstrated that LSP1, induced by T-cell receptor activation, negatively regulates T-cell migration by reducing ERK activation in vitro. In mice with T-cell-dependent chronic inflammation, loss of Lsp1 promotes migration of T cells into the target tissues as well as draining lymph nodes, exacerbating disease severity. Moreover, patients with RA show diminished expression of LSP1 in peripheral T cells with increased migratory capacity, suggesting that the defect in LSP1 signaling lowers the threshold for T-cell activation. To our knowledge, our work is the first to demonstrate how CNVs result in immune dysfunction and a disease phenotype. Particularly, our data highlight the importance of LSP1 CNVs and LSP1 insufficiency in the pathogenesis of RA and provide previously unidentified insights into the mechanisms underlying T-cell migration toward the inflamed synovium in RA.
URI
http://hdl.handle.net/20.500.11750/2811
DOI
10.1073/pnas.1514152112
Publisher
National Academy of Sciences
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Department of New Biology Systems Biology and Medicine Lab 1. Journal Articles

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