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Front Immunol. 2018 Jan 18;8:1978. doi: 10.3389/fimmu.2017.01978. eCollection 2017.

Human NF-κB1 Haploinsufficiency and Epstein-Barr Virus-Induced Disease-Molecular Mechanisms and Consequences.

Hoeger B1,2, Serwas NK1,2, Boztug K1,2,3,4.

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Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Department of Pediatrics, St. Anna Kinderspital and Children's Cancer Research Institute, Medical University of Vienna, Vienna, Austria.


Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κB1)-related human primary immune deficiencies have initially been characterized as defining a subgroup of common variable immunodeficiencies (CVIDs), representing intrinsic B-cell disorders with antibody deficiency and recurrent infections of various kind. Recent evidence indicates that NF-κB1 haploinsufficiency underlies a variable type of combined immunodeficiency (CID) affecting both B and T lymphocyte compartments, with a broadened spectrum of disease manifestations, including Epstein-Barr virus (EBV)-induced lymphoproliferative disease and immediate life-threatening consequences. As part of this review series focused on EBV-related primary immunodeficiencies, we discuss the current clinical and molecular understanding of monoallelic NFKB1 germline mutations with special focus on the emerging context of EBV-associated disease. We outline mechanistic implications of dysfunctional NF-κB1 in B and T cells and discuss the fatal relation of impaired T-cell function with the inability to clear EBV infections. Finally, we compare common and suggested treatment angles in the context of this complex disease.


B cells; Epstein–Barr virus; T cells; combined immunodeficiency; common variable immunodeficiency; haploinsufficiency; lymphoproliferation; nuclear factor kappa-light-chain-enhancer of activated B cells 1

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