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.