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Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis.
Hwang, Seong-Hye; Jung, Seung-Hyun; Lee, Saseong; Choi, Susanna; Yoo, Seung-Ah; Park, Ji-Hwan; Hwang, Daehee; Shim, Seung Cheol; Sabbagh, Laurent; Kim, Ki-Jo; Park, Sung Hwan; Cho, Chul-Soo; Kim, Bong-Sung; Leng, Lin; Montgomery, Ruth R; Bucala, Richard; Chung, Yeun-Jun; Kim, Wan-Uk.
Afiliação
  • Hwang SH; POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea;
  • Jung SH; Integrated Research Center for Genome Polymorphism, Department of Microbiology, College of Medicine, The Catholic University of Korea, Korea;
  • Lee S; POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea;
  • Choi S; POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea;
  • Yoo SA; POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea;
  • Park JH; Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, Korea;
  • Hwang D; Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, Korea; Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea;
  • Shim SC; Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea;
  • Sabbagh L; Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada;
  • Kim KJ; POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea; Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;
  • Park SH; Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;
  • Cho CS; POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea; Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;
  • Kim BS; Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT.
  • Leng L; Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT.
  • Montgomery RR; Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT.
  • Bucala R; Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT.
  • Chung YJ; Integrated Research Center for Genome Polymorphism, Department of Microbiology, College of Medicine, The Catholic University of Korea, Korea; yejun@catholic.ac.kr wan725@catholic.ac.kr.
  • Kim WU; POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea; Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea; yejun@catholic.ac.kr wan725@catholic.ac.kr.
Proc Natl Acad Sci U S A ; 112(47): E6535-43, 2015 Nov 24.
Article em En | MEDLINE | ID: mdl-26554018
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Artrite Reumatoide / Proteínas de Ligação ao Cálcio / Linfócitos T / Movimento Celular / Proteínas dos Microfilamentos Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Artrite Reumatoide / Proteínas de Ligação ao Cálcio / Linfócitos T / Movimento Celular / Proteínas dos Microfilamentos Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article