Human genetic basis of fulminant viral hepatitis

Abstract

In rare cases, hepatitis A virus (HAV) and hepatitis B virus (HBV) can cause fulminant viral hepatitis (FVH), characterized by massive hepatocyte necrosis and an inflammatory infiltrate. Other viral etiologies of FVH are rarer. FVH is life-threatening, but the patients are typically otherwise healthy, and normally resistant to other microbes. Only a small minority of infected individuals develop FVH, and this is the key issue to be addressed for this disease. In mice, mouse hepatitis virus 3 (MHV3) infection is the main model for dissecting FVH pathogenesis. Susceptibility to MHV3 differs between genetic backgrounds, with high and low mortality in C57BL6 and A/J mice, respectively. FVH pathogenesis in mice is related to uncontrolled inflammation and fibrinogen deposition. In humans, FVH is typically sporadic, but rare familial forms also exist, suggesting that there may be causal monogenic inborn errors. A recent study reported a single-gene inborn error of human immunity underlying FVH. A patient with autosomal recessive complete IL-18BP deficiency was shown to have FVH following HAV infection. The mechanism probably involves enhanced IL-18-and IFN-γ-dependent killing of hepatocytes by NK and CD8 T cytotoxic cells. Proof-of-principle that FVH can be genetic is important clinically, for the affected patients and their families, and immunologically, for the study of immunity to viruses in the liver. Moreover, the FVH-causing IL18BP genotype suggests that excessive IL-18 immunity may be a general mechanism underlying FVH, perhaps through the enhancement of IFN-γ immunity. (2013) Inherited human OX40 deficiency underlying classic Kaposi sarcoma in childhood. J Exp Med 210:1743-1759

Autosomal dominant chronic mucocutaneous candidiasis with STAT1 mutation can be associated with chronic active hepatitis: A case report

“…IFN-γ-strongly induces IL-18BP, which can buffer IL-18 activity in the liver through negative feedback. Excessive IL-18 immunity may be the pathogenic mechanism of fulminant liver failure (18,19). Therefore, we speculate that viral infection and GOF-STAT1 gene mutation are involved in the pathogenesis of chronic hepatitis in children.…”

Future directions in acute liver failure

“…It is unlikely that these viruses are abnormally virulent; no evidence of specific subvariants of HAV, for example, have been found to cause ALF 64 . Rather, it seems more likely that ALF due to common viruses may be caused, in some instances, by single-gene inborn errors of host immunity 65 . For example, the discovery of autosomal recessive IL-18BP deficiency as a genetic etiology of viral ALF provided proof of principle that viral ALF can be caused by single-gene inborn errors selectively disrupting liver-specific immunity to viruses.…”

“…[64] Rather, it seems more likely that ALF due to common viruses may be caused, in some instances, by single-gene inborn errors of host immunity. [65] For example, the discovery of autosomal recessive IL-18BP deficiency as a genetic etiology of viral ALF provided proof of principle that viral ALF can be caused by single-gene inborn errors selectively disrupting liver-specific immunity to viruses. It also pointed to IL-18 as an anchor molecule in the pathogenesis of viral ALF.…”

Clinical and molecular aspects of veterinary coronaviruses

“…MHV has been used as a suitable model to study human multiple sclerosis ( Lane and Hosking, 2010 ), hepatitis, encephalitis, and coronavirus-cell interactions ( Barthold, 1997 ; Compton et al, 1993 ; Jouanguy, 2020 ). MHV is highly contagious and spreads by the respiratory and fecal routes ( Barthold et al, 1993 ).…”