title: A multiple sclerosis-associated variant of CBLB links genetic risk with type I IFN function.
abstract: Multiple sclerosis (MS) is an autoimmune disease of the CNS, and autoreactive CD4(+) T cells are considered important for its pathogenesis. The etiology of MS involves a complex genetic trait and environmental triggers that include viral infections, particularly the EBV. Among the risk alleles that have repeatedly been identified by genome-wide association studies, three are located near the Casitas B-lineage lymphoma proto-oncogene b gene (CBLB). The CBLB protein (CBL-B) is a key regulator of peripheral immune tolerance by limiting T cell activation and expansion and hence T cell-mediated autoimmunity through its ubiquitin E3-ligase activity. In this study, we show that CBL-B expression is reduced in CD4(+) T cells from relapsing-remitting MS (RR-MS) patients during relapse. The MS risk-related single nucleotide polymorphism of CBLB rs12487066 is associated with diminished CBL-B expression levels and alters the effects of type I IFNs on human CD4(+) T cell proliferation. Mechanistically, the CBLB rs12487066 risk allele mediates increased binding of the transcription factor C/EBPβ and reduced CBL-B expression in human CD4(+) T cells. Our data suggest a role of the CBLB rs12487066 variant in the interactions of a genetic risk factor and IFN function during viral infections in MS.
authors.affiliation: Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
authors.forename: Klarissa Hanja
authors.initials: KH
authors.lastname: Stürner
authors.affiliation: Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
authors.forename: Uwe
authors.initials: U
authors.lastname: Borgmeyer
authors.affiliation: Systems Biology, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Schulze
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology, ScreeningPort, 22525 Hamburg, Germany; and.
authors.forename: Ole
authors.initials: O
authors.lastname: Pless
authors.affiliation: Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Neuroimmunology and MS Research Section, Department of Neurology, University Hospital Zürich, CH-8091 Zürich, Switzerland roland.martin@usz.ch.
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D022782:CCAAT-Enhancer-Binding Protein-beta; D007370:Interferon Type I; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl