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

Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis
Hwang, SH[Hwang, Seong-Hye]Jung, SH[Jung, Seung-Hyun]Lee, S[Lee, Saseong]Choi, S[Choi, Susanna]Yoo, SA[Yoo, Seung-Ah]Park, JH[Park, Ji-Hwan]Hwang, D[Hwang, Daehee]Shim, SC[Shim, Seung Cheol]Sabbagh, L[Sabbagh, Laurent]Kim, KJ[Kim, Ki-Jo]Park, SH[Park, Sung Hwan]Cho, CS[Cho, Chul-Soo]Kim, BS[Kim, Bong-Sung]Leng, L[Leng, Lin]Montgomery, RR[Montgomery, Ruth R.]Bucala, R[Bucala, Richard]Chung, YJ[Chung, Yeun-Jun]Kim, WU[Kim, Wan-Uk]
DGIST Authors
Hwang, D[Hwang, Daehee]
Issue Date
Proceedings of the National Academy of Sciences of the United States of America, 112(47), E6535-E6543
Article Type
Article; Conference Paper
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 DosageGene ExpressionGene LocationGene LossGene OverexpressionGenetic AssociationGenome AnalysisGenomic DNAGlucuronosyltransferaseGlucuronosyltransferase 2B28High Risk PatientHumanHuman CellImmune ResponseImmunoglobulin Blood LevelImmunoglobulin GIn Vitro StudyIn Vivo StudyInflammationInterleukin-1 BetaInterleukin-10Interleukin-2Interleukin-4Joint SwellingJurkat Cell LineLeukocyte-Specific Protein 1Leukocyte MigrationLeukocyte Specific Protein 1Lymphocyte ActivationLymphocyte CountLymphocyte MigrationLymphocytic InfiltrationMacrophage Inflammatory Protein 3BetaMessenger RNAMolecular WeightMonocyte Chemotactic Protein 1MouseNon-HumanPathogenesisPeripheral Blood Mononuclear CellPriority JournalProstaglandin SynthaseProstaglandin Synthase 2ProteinProtein DeficiencyProtein DepletionProtein ExpressionProtein FunctionProtein InductionProtein Kinase BProtein Protein InteractionRegulatory MechanismRheumatoid ArthritisSignal TransductionStable TransfectionT-Cell FunctionT LymphocyteT Lymphocyte ActivationT Lymphocyte ReceptorT Lymphocyte SubpopulationTranscription Factor Gli3Transcription Factor Sox9TranscriptomeTroponin TTroponin T3Tumor Necrosis Factor-AlphaUnclassified DrugUpregulation
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.
National Academy of Sciences
Related Researcher
  • Author Hwang, Daehee Systems Biology and Medicine Lab
  • Research Interests Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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Department of New BiologySystems Biology and Medicine Lab1. Journal Articles

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