title: Gene expression profiling of the response to interferon beta in Epstein-Barr-transformed and primary B cells of patients with multiple sclerosis.
abstract: The effects of interferon-beta (IFN-β), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-β. To identify gene expression changes and pathways induced by IFN-β in B cells, we studied the in vitro response of human Epstein Barr-transformed B cells (lymphoblast cell lines-LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-β exposure, with over 50 previously unrecognized as IFN-β response genes. Pathways analysis demonstrated that IFN-β affected LCLs in a similar manner to other cell types by activating known IFN-β canonical pathways. Additionally, IFN-β increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, NEXN, DDX60L, IGFBP4, and HAPLN3, B cell receptor pathway genes, CD79B and SYK, and lymphocyte activation genes, LAG3 and IL27RA, were validated as IFN-β response genes in primary B cells. In this study new IFN-β response genes were identified in B cells, with possible implications to B cell-specific functions. The study's results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component.
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Rana
authors.initials: R
authors.lastname: Khsheibun
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Paperna
authors.affiliation: Division of Neuroimmunology and Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Volkowich
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Izabella
authors.initials: I
authors.lastname: Lejbkowicz
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Nili
authors.initials: N
authors.lastname: Avidan
authors.affiliation: Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Division of Neuroimmunology and Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Miller
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D002461:Cell Line, Transformed; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D016131:Lymphocyte Subsets; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D016899:Interferon-beta