Inherited IL-18BP deficiency in two Egyptian siblings with fulminant viral hepatitis

Abstract

An inherited deficiency of IL-18BP, a soluble antagonist of IL-18, was previously reported in an otherwise healthy Algerian patient who died of fulminant viral hepatitis A at the age of 11 years. We describe here an Egyptian family with two siblings who died at the ages of two years and seven months of fulminant viral hepatitis (FVH) following infection with hepatitis A virus.

Figure 1.

IL18BP c.15-16del is loss-of-function. (A) Pedigree and familial segregation of the mutations and schematic representation of IL-18BP. (B) CADD vs. MAF graph for homozygous IL18BP variants from gnomAD and Bravo and the patients’ allele. (C) CoNeS score of IL-18BP. (D) Representative western blot for secreted IL-18BP (His-tag) in non-concentrated supernatant (10 μg protein/lane) (left) and for intracellular IL-18BP (His-tag) in lysates (20 μg protein/lane) (right) from transiently transfected COS7 cells. Data are representative of five independent experiments. (E) Relative luciferase activity (Firefly to Renilla signal ratio) in HEK293 cells transiently transfected with NF-κB–Firefly luciferase + IL-18RAP + Renilla luciferase plasmids upon 12-h stimulation with recombinant IL-18 (5 ng/ml) and/or recombinant WT IL-18BP-His (100 ng/ml) or concentrated supernatant (100 μg/ml of total protein) from COS7 cells transiently transfected with empty, WT, or mutant IL-18BP–tagged constructs. Relative luciferase activity was normalized against non-stimulated (NS) cells, for which the value was set to 1. (F) IFN-γ production detected by ELISA on the supernatant of KG-1 cells stimulated for 24 h with recombinant TNF (20 ng/ml), recombinant IL-18 (20 ng/ml), and/or recombinant WT IL-18BP-His (100–200 ng/ml) or concentrated supernatant (175 μg/ml of total protein) from COS7 cells transiently transfected with empty, WT, or mutant IL-18BP–tagged constructs. (E and F) Data are presented as the mean ± SEM of five independent experiments. All IL-18BP constructs and supernatants were generated as previously described (2). WT, wild-type; M, mutated; E?, unknown genotype; SP, Signal peptide; P, patient; MAF, minor allele frequency; HOM, homozygous; IEI, Inborn errors of Immunity; AD, autosomal dominant. Source data are available for this figure: SourceData F1.