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It is the case of an 11-year old girl who died in Paris after a hepatitis A infection, which alerted Prof. Casanova and his team. As stated by WHO “Unlike hepatitis B and hepatitis C, hepatitis A does not lead to chronic liver disease and is rarely fatal.” So why did a disease that can be treated relatively easily in most people cause the death of a young girl? This question is at the heart of Jean-Laurent Casanova’s research, professor at Paris Descartes University/Necker-Enfants Malades hospital (AP-HP), professor at Rockefeller University/Howard Hughes Medical Institute in New York and cofounder of the human genetics of infectious diseases Inserm laboratory, set up in two branches, one at Rockefeller in New York and the other at Imagine Institute: his team has already shown that many infectious diseases - tuberculosis, flu, etc. - also had a genetic origin.
In their last publication published in the Journal of Experimental Medicine, they identified, for thefirst time, a genetic cause of fulminant viral hepatitis. “This extremely severe form has no explanation up to now, reminds Prof. Casanova. It results in liver damage and, without a transplant, most often in the death of the patient.” Today, nothing can predict which infected patient will develop fulminant hepatitis.
Genome analysis of the young deceased girl uncovered a mutation of both copies of the IL18BP gene producing an altered protein. “This alteration prevents the protein from properly fulfilling its role, namely neutralization of the IL-18 cytokine, which causes an immune response and triggers inflammation, explains the professor. As a result, IL-18 increases the ability of the immune system “killer” cells to target and destroy liver cells.”
Again, Prof. Casanova’s team show that an infectious disease is in fact a genetic disease. In addition, this discovery paves the way for therapeutic avenues. For as Jean-Laurent Casanova emphasizes “the administration of IL-18 BP - already clinically used for other diseases [Editor’s note] could replace the defective protein and therefore neutralize the cytokine and its adverse effects.” Today, the researcher calls to continue in this pathway and identify other patients with fulminant hepatitis following the presence of a genetic alteration creating favorable ground for its development.
Inherited IL-18BP deficiency in human fulminant viral hepatitis
Serkan Belkaya, Eleftherios Michailidis, Cecilia B. Korol, Mohammad Kabbani, Aurélie Cobat, Paul Bastard, Yoon Seung Lee, Nicholas Hernandez, Scott Drutman, Ype P. de Jong, Eric Vivier, Julie Bruneau, Vivien Béziat, Bertrand Boisson, Lazaro Lorenzo-Diaz, Soraya Boucherit, Mylène Sebagh, Emmanuel Jacquemin, Jean-François Emile, Laurent Abel, Charles M. Rice, Emmanuelle Jouanguy, Jean-Laurent Casanova
DOI: 10.1084/jem.20190669 | Published June 18, 2019