A multiple sclerosis-associated variant of CBLB links genetic risk with type I IFN function

TY - JOUR

T1 - A multiple sclerosis-associated variant of CBLB links genetic risk with type I IFN function

AU - Stürner, Klarissa Hanja

AU - Borgmeyer, Uwe

AU - Schulze, Christian

AU - Pless, Ole

AU - Martin, Roland

N1 - Copyright © 2014 by The American Association of Immunologists, Inc.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Alleles

KW - CCAAT-Enhancer-Binding Protein-beta

KW - CD4-Positive T-Lymphocytes

KW - Gene Expression Regulation

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genotype

KW - Humans

KW - Interferon Type I

KW - Multiple Sclerosis

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Protein Binding

KW - Proto-Oncogene Proteins c-cbl

KW - Treatment Outcome

U2 - 10.4049/jimmunol.1303077

DO - 10.4049/jimmunol.1303077

M3 - SCORING: Journal article

C2 - 25261476

VL - 193

SP - 4439

EP - 4447

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 9

ER -