Individual
ESR projects

Research project

IKBKB deficiency

Rationale and Objectives

Inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β or IKK2), encoded by the gene IKBKB, is a critical subunit of the IKK kinase complex. By phosphorylation of the inhibitor of NF-κB IκBα it permits the activation of the canonical NF-κB-mediated transcriptional program.  Currently, over 20 patients with homozygous mutations in IKBKB have been described , . Inborn errors in IKBKB lead to a profound combined immunodeficiency with early onset of a broad spectrum of infections. Together with Stepensky’s group, we have identified a family with two siblings with deleterious homozygous deletion frameshift mutation. Both siblings suffered from mycobacterial infections and underwent HSCT after discovery of their profound immunodeficiency and died subsequent to secondary loss of graft.

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1) to investigate the altered chromatin accessibility and transcriptome of B-, T cells and monocytes before and after respective activation in comparison to pre-existing data from patients with NFKB1 haploinsufficiency (manuscript in preparation) and data produced by the group of Bodo Grimbacher (DC4) in this consortium for A20 deficiency.

2) to confirm identified target genes by flow cytometry and functionally evaluate them in vitro.

3) to compare data to the results from the respective lymphocyte and monocyte populations from healthy controls treated with IKK-β inhibitors, a potential targeted therapy under current clinical evaluation. These experiments will allow us to explore the concordance of the respective findings between the natural knock-out and the drug-induced changes.

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Expected results

1) Determination of alterations in B, T and monocytes in patients with NFKB1 haploinsufficiency.

2) Functional data from the aforementioned cell types.

3) Relationships with lymphocyte and monocyte populations from healthy controls treated with IKK-β inhibitors.

Planned secondments

RFHMO (Stepensky/Schejter) to optimise sample preparation and recruitment, m6-m8 (2 months); IJC to perform epigenetic analyses, m10-m12 (2 months); EMBL (Zaugg) to perform transcription factor network analyse, m20-21 (1 month); GRL (Vento-Tormo) to learn multi-omics data analysis, m21-22 (1 month). Finally, the DC will do a secondment at Alia Therapeutics to learn novel gene editing protocols, m25-27 (2 months).

PhD programme

PhD in Biology, Albert-Ludwig Freiburg University, Germany