No IL-18BP? Avoid HAV

Abstract

Fulminant viral hepatitis occurs in a very small number of infected individuals. Until now, the basis for this phenotype has remained unknown. In this issue of JEM, Belkaya et al. (https://doi.org/10.1084/jem.20190669) identify a deletion in the IL18BP gene in a severely affected child that results in excessive natural killer cell activation and uncontrolled killing of hepatocytes.

Insights from Michael S. Diamond.

Scheme of HAV-induced fulminant liver injury and the role of IL-18BP. Hepatitis viruses infect hepatocytes in the liver. In response to infection, resident and/or infiltrating macrophages and possibly hepatocytes themselves produce IL-18, which activates NK cells to produce IFN-γ and mature their cytolytic responses. As part of a negative feedback loop, hepatocytes, stellate cells, fibroblasts, and endothelial cells also produce soluble IL-18BP, which neutralizes the activity of IL-18 and prevents excessive liver damage. The child described in the current study had a 40-nucleotide deletion across an exon–intron boundary in her IL18BP gene and produced no functional IL-18BP, and thus IL-18 activity was unchecked. Activated NK cells can kill both infected and uninfected hepatocytes, leading to massive liver injury. It is possible that administration of recombinant IL-18BP therapy (e.g., Tadekinig Alfa) would scavenge the free IL-18 in vulnerable hosts and lessen NK cell activation and damage. A major question with therapeutic implications is whether unrestrained IL-18 activity is a common or dominant mechanism for virus-induced fulminant liver disease or whether other immune mediators (e.g., hepatocyte-produced IL-15 and cytotoxic CD8⁺ T cells) account for a significant fraction of severe cases.