title: Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis.
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.
authors.affiliation: POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea;
authors.forename: Seong-Hye
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Integrated Research Center for Genome Polymorphism, Department of Microbiology, College of Medicine, The Catholic University of Korea, Korea;
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Jung
authors.affiliation: POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea;
authors.forename: Saseong
authors.initials: S
authors.lastname: Lee
authors.affiliation: POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea;
authors.forename: Susanna
authors.initials: S
authors.lastname: Choi
authors.affiliation: POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea;
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.affiliation: Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, Korea;
authors.forename: Ji-Hwan
authors.initials: JH
authors.lastname: Park
authors.affiliation: 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;
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea;
authors.forename: Seung Cheol
authors.initials: SC
authors.lastname: Shim
authors.affiliation: Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, QC, Canada;
authors.forename: Laurent
authors.initials: L
authors.lastname: Sabbagh
authors.affiliation: POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea; Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;
authors.forename: Ki-Jo
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul, Korea; Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea;
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.affiliation: Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT.
authors.forename: Bong-Sung
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.affiliation: Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
authors.affiliation: Department of Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: 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.
authors.forename: Yeun-Jun
authors.initials: YJ
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D002908:Chronic Disease; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018628:Gene Dosage; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*
chemical_list: D002135:Calcium-Binding Proteins; C489183:LSP1 protein, human; C057701:Lsp1 protein, mouse; D008840:Microfilament Proteins; D011948:Receptors, Antigen, T-Cell; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: T-cell function; cell migration; copy number variation; leukocyte-specific protein 1; rheumatoid arthritis