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: Seong-Hye Hwang, Seung-Hyun Jung, Saseong Lee, Susanna Choi, Seung-Ah Yoo, Ji-Hwan Park, Daehee Hwang, Seung Cheol Shim, Laurent Sabbagh, Ki-Jo Kim, Sung Hwan Park, Chul-Soo Cho, Bong-Sung Kim, Lin Leng, Ruth R Montgomery, Richard Bucala, Yeun-Jun Chung, Wan-Uk Kim
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 47 Pg. E6535-43 (Nov 24 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26554018 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• LSP1 protein, human
• Lsp1 protein, mouse
• Microfilament Proteins
• Receptors, Antigen, T-Cell
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Arthritis, Experimental (immunology, pathology)
• Arthritis, Rheumatoid (genetics, immunology, pathology)
• Calcium-Binding Proteins (deficiency, metabolism)
• Cell Movement
• Cells, Cultured
• Chronic Disease
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Dosage
• Gene Expression Profiling
• Genetic Predisposition to Disease
• Humans
• Hypersensitivity, Delayed (immunology, pathology)
• Inflammation (pathology)
• Mice
• Microfilament Proteins (genetics, metabolism)
• Phosphorylation
• Receptors, Antigen, T-Cell (metabolism)
• T-Lymphocytes (immunology, pathology)