Deficiency of Innate and Acquired Immunity Caused by an IKBKB Mutation

BackgroundSevere combined immunodeficiency (SCID) comprises a heterogeneous group of heritable deficiencies of humoral and cell-mediated immunity. Many patients with SCID have lymphocyte-activation defects that remain uncharacterized. MethodsWe performed genetic studies in four patients, from four families of Northern Cree ancestry, who had clinical characteristics of SCID, including early onset of severe viral, bacterial, and fungal infections despite normal B-cell and T-cell counts. Genomewide homozygosity mapping was used to identify a candidate region, which was found on chromosome 8; all genes within this interval were sequenced. Immune-cell populations, signal transduction on activation, and effector functions were studied. ResultsThe patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and T cells were absent. All patients carried a homozygous duplication c.1292dupG in exon 13 of IKBKB, which encodes IB kinase 2 (IKK2, also known as IKK) leading to loss of expression of IKK2, a component of the IKK-nuclear factor B (NF-B) pathway. Immune cells from the patients had impaired responses to stimulation through T-cell receptors, B-cell receptors, toll-like receptors, inflammatory cytokine receptors, and mitogens. ConclusionsA form of human SCID is characterized by normal lymphocyte development despite a loss of IKK2 function. IKK2 deficiency results in an impaired response to activation stimuli in a variety of immune cells, leading to clinically relevant impairment of adaptive and innate immunity. Although Ikk2 deficiency is lethal in mouse embryos, our observations suggest a more restricted, unique role of IKK2-NF-B signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.)