Deficiency of innate and acquired immunity caused by an IKBKB mutation.

Article Details

Citation

Pannicke U, Baumann B, Fuchs S, Henneke P, Rensing-Ehl A, Rizzi M, Janda A, Hese K, Schlesier M, Holzmann K, Borte S, Laux C, Rump EM, Rosenberg A, Zelinski T, Schrezenmeier H, Wirth T, Ehl S, Schroeder ML, Schwarz K

Deficiency of innate and acquired immunity caused by an IKBKB mutation.

N Engl J Med. 2013 Dec 26;369(26):2504-14. doi: 10.1056/NEJMoa1309199.

PubMed ID
24369075 [ View in PubMed
]
Abstract

BACKGROUND: Severe 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. METHODS: We 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. RESULTS: The patients had hypogammaglobulinemia or agammaglobulinemia, and their peripheral-blood B cells and T cells were almost exclusively of naive phenotype. Regulatory T cells and gammadelta T cells were absent. All patients carried a homozygous duplication--c.1292dupG in exon 13 of IKBKB, which encodes IkappaB kinase 2 (IKK2, also known as IKKbeta)--leading to loss of expression of IKK2, a component of the IKK-nuclear factor kappaB (NF-kappaB) 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. CONCLUSIONS: A 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-kappaB signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.).

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Inhibitor of nuclear factor kappa-B kinase subunit betaO14920Details