Inherited IL-18BP deficiency in human fulminant viral hepatitis

We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.

Source: The Journal of Experimental Medicine - August 4, 2019 Category: Internal Medicine Authors: Belkaya, S., Michailidis, E., Korol, C. B., Kabbani, M., Cobat, A., Bastard, P., Lee, Y. S., Hernandez, N., Drutman, S., de Jong, Y. P., Vivier, E., Bruneau, J., Beziat, V., Boisson, B., Lorenzo-Diaz, L., Boucherit, S., Sebagh, M., Jacquemin, E., Emile, J Tags: Immunodeficiency, Innate Immunity and Inflammation, Infectious Disease and Host Defense, Human Disease Genetics Articles Source Type: research