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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 Cell; Animal Experiment; Animal Model; Animal Tissue; Calcium Homeostasis; Calcium Ion; Calcium Signaling; CD3 Antigen; CD4+ T Lymphocyte; CD8+ T Lymphocyte; Cell Migration; Cell Proliferation; Chemokine Receptor CXCR4; Chronic Inflammation; Colony Stimulating Factor 1; Complementary Dna; Conference Paper; Controlled Study; Copy Number Variation; CXCL9 Chemokine; Cytokine Production; Cytokine Response; Disease Course; Disease Exacerbation; Disease Predisposition; Disease Severity; Down-Regulation; Enzyme Activation; Enzyme Activity; Enzyme Phosphorylation; Enzyme Regulation; Gamma Interferon; Gene Dosage; Gene Expression; Gene Location; Gene Loss; Gene Overexpression; Genetic Association; Genome Analysis; Genomic DNA; Glucuronosyltransferase; Glucuronosyltransferase 2B28; High Risk Patient; Human; Human Cell; Immune Response; Immunoglobulin Blood Level; Immunoglobulin G; In Vitro Study; In Vivo Study; Inflammation; Interleukin-1 Beta; Interleukin-10; Interleukin-2; Interleukin-4; Joint Swelling; Jurkat Cell Line; Leukocyte-Specific Protein 1; Leukocyte Migration; Leukocyte Specific Protein 1; Lymphocyte Activation; Lymphocyte Count; Lymphocyte Migration; Lymphocytic Infiltration; Macrophage Inflammatory Protein 3Beta; Messenger RNA; Molecular Weight; Monocyte Chemotactic Protein 1; Mouse; Non-Human; Pathogenesis; Peripheral Blood Mononuclear Cell; Priority Journal; Prostaglandin Synthase; Prostaglandin Synthase 2; Protein; Protein Deficiency; Protein Depletion; Protein Expression; Protein Function; Protein Induction; Protein Kinase B; Protein Protein Interaction; Regulatory Mechanism; Rheumatoid Arthritis; Signal Transduction; Stable Transfection; T-Cell Function; T Lymphocyte; T Lymphocyte Activation; T Lymphocyte Receptor; T Lymphocyte Subpopulation; Transcription Factor Gli3; Transcription Factor Sox9; Transcriptome; Troponin T; Troponin T3; Tumor Necrosis Factor-Alpha; Unclassified Drug; Upregulation
- 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
Hwang, Dae Hee
Systems Biology and Medicine Lab
Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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