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Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis
Seong-Hye Hwanga,1, Seung-Hyun Jungb,1, Saseong Leea, Susanna Choia, Seung-Ah Yooa, Ji-Hwan Parkc, Daehee Hwangc,d, Seung Cheol Shime, Laurent Sabbaghf, Ki-Jo Kima,g, Sung Hwan Parkg, Chul-Soo Choa,g, Bong-Sung Kimh, Lin Lengh, Ruth R. Montgomeryh, Richard Bucalah, Yeun-Jun Chungb,2, and Wan-Uk Kima,g,2

aPOSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea; 
bIntegrated Research Center for Genome Polymorphism, Department of Microbiology, College of Medicine, The Catholic University of Korea, Korea; 
cDepartment of Chemical Engineering, Pohang University of Science and Technology, Pohang, Korea; 
dCenter for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea; 
eDepartment of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea; 
fDepartment of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada; 
gDepartment of Internal Medicine, The Catholic University of Korea, Seoul, Korea; 
hDepartment of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 

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. 

leukocyte-specific protein 1, copy number variation, T-cell function, cell migration, rheumatoid arthritis

1S.-H.H. and S.-H.J. contributed equally to this work. 
2To whom correspondence may be addressed. 

Author contributions: S.-H.J., Y.-J.C., and W.-U.K. designed research; S.-H.H., S.L., S.C., S.-A.Y., B.-S.K., and L.L. performed research; S.C.S., L.S., S.H.P., C.-S.C., B.-S.K., R.R.M., and R.B. contributed new reagents/analytic tools; J.-H.P., D.H., C.-S.C., R.B., Y.-J.C., and W.-U.K. analyzed data; and S.-H.H., S.-H.J., J.-H.P., D.H., K.-J.K., and Y.-J.C. wrote the paper. 

- 형식: Research article
- 게재일: 2015년 11월 (BRIC 등록일 2015-11-11)
- 연구진: 국내(교신)+국외 연구진태극기
- 분야: Medicine
관련 보도자료
류마티스 관절염 유전자 발견...만성염증성 질환 새로운 치료제 개발 가능성 열어
가대의대·성모병원 연구팀이 류마티스 관절염을 일으키는 유전자와 기전을 처음으로 규명했다. 이로서 특정 유전자를 표적으로 한 새로운 류마티스 관절염 표적치료제 개발이 가능해질 전망이다.
광유전학의 과거, 현재와 미래[Neuron]
발표: 김윤석 (Stanford University)
일자: 2020년 7월 30일 (목) 오후 02시 (한국시간)
언어: 한국어
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