Mutations in the IL18BP gene causes the body’s immune system to attack and kill healthy liver cells


Researchers have identified a genetic mutation that caused an 11-year-old girl to suffer a fatal reaction to infection with the Hepatitis A virus (HAV).

The study, which will be published June 18 in the Journal of Experimental Medicine, reveals that mutations in the IL18BP gene causes the body’s immune system to attack and kill healthy liver cells, and suggests that targeting this pathway could prevent the deaths of patients suffering rapid liver failure in response to viral infection.

HAV infects the liver and usually causes a relatively mild illness that clears up in a matter of weeks or months.

But as many as 1 in 200 HAV patients suffer a much more severe response known as fulminant viral hepatitis (FVH) that is characterized by a rapid loss of liver tissue and catastrophic liver failure, resulting in the release of toxins that damage the brain.

The condition is usually fatal unless the patient receives a liver transplant.

Other hepatitis viruses can also cause FVH, but the reason why some patients suffer such a severe response to infection is unclear.

It typically occurs in children and young adults who are otherwise healthy and have no prior history of liver disease or immunodeficiencies.

A team of researchers led by Professor Jean-Laurent Casanova at The Rockefeller University in New York identified an 11-year-old girl in France who died of FVH after becoming infected with HAV.

The researchers sequenced the girl’s DNA and discovered that she carried identical mutations in both copies of the IL18BP gene, which encodes a protein called interleukin-18 binding protein (IL-18BP).

IL-18BP can bind and neutralize interleukin-18 (IL-18), a powerful ‘cytokine’ molecule that the body produces in response to infection in order to activate certain types of immune cells and promote inflammation.

Casanova and colleagues determined that the mutation identified in the patient’s IL18BP gene prevented the IL-18BP protein from neutralizing IL-18.

To understand how this might affect the body’s response to HAV infection, the researchers incubated human liver cells with Natural Killer (NK) cells, a type of immune cell that targets virally infected cells.

Casanova and colleagues discovered that, in the absence of IL-18BP, IL-18 enhanced NK cells’ ability to target and kill liver cells, whether they were infected with HAV or not.

Addition of IL-18BP blocked this IL-18-induced toxicity, suggesting that IL-18BP usually prevents an excessive reaction to HAV infection but that patients carrying mutations in this gene are susceptible to FVH.

“Our findings provide a proof of principle that FVH can be caused by inborn errors in single genes,” Casanova says.

“Human IL-18BP injections have been approved for clinical use for indications unrelated to liver conditions and has been proposed as a treatment for preventing acetaminophen-induced liver damage.

Neutralizing IL-18 with IL-18BP might be beneficial to patients with FVH caused by HAV and possibly other viruses as well.”

Hepatitis C virus (HCV) infection is estimated to affect 170 million people worldwide and remains a major cause of chronic liver disease (24).

HCV is a small, enveloped, positive-strand RNA virus that has been classified in a separate genus (Hepacivirus) of the Flaviviridae family.

An important feature of the HCV genome is its high degree of genetic variability; 6 major virus genotypes and about 100 subtypes, which often have distinct geographic distributions, have been identified (20).

HCV infection results in chronic active hepatitis in more than 80% of infected patients; 20 to 30% of these patients develop progressive fibrosis and cirrhosis, whereas only approximately 10 to 20% of the infected people spontaneously eliminate the virus (24).

The factors required for the generation of this effective immune response are largely unknown, and different factors have been evaluated as predictors of the sustained response to treatment, with controversial results (9).

Recently, the interleukin-28B (IL28B) gene was strongly associated with sustained virological response to treatment (62223), with natural viral clearance (25), and with different rates of viral genotype infection (1216).

A study reporting an analysis of 112 selected immune response genes identified 4 gene regions as candidates for HCV natural clearance or persistence in both African-American and European-American populations (17): the TNFSF18, TANK, HAVCR1, and IL18BP gene regions.

One of these genes is the hepatitis A virus cellular receptor 1 (HAVCR1, or TIM-1) gene, a member of the HAVCR family of genes encoding type 1 transmembrane glycoproteins with a conserved structure, which includes the immunoglobulin domain and the mucin domain (348).

HAVCR1 expression has been found on several cell types, such as Th2, mast, NKT, B lymphocytes, and tubular epithelial cells of kidney (413).

Some studies indicated that Tim-1 (the mouse ortholog of HAVCR1) can bind to other Tim-1 proteins (19) and to Tim-4 (14).

Thus, Tim-1 homophilic interactions (Tim-1–Tim-1) have been found in crystallography studies (19), and others have reported interactions between Tim-1 and Tim-4 via phosphatidylserine in exosomes (15).

Tim-1 has a costimulatory and immunomodulatory effect on T cell responses, since the use of anti-Tim-1 antibodies simultaneously with T cell receptor (TCR) stimulation greatly enhanced Th proliferation and Th2 cytokine production (26).

Nevertheless, Tim-1 costimulation prevents allogeneic transplant tolerance by reducing Foxp3 expression while enhancing development of Th1 and Th17 responses (2).

Moreover, administration of agonistic anti-Tim-1 monoclonal antibodies (MAbs) during the induction phase of experimental autoimmune encephalomyelitis (EAE) enhanced pathogenic Th1 and Th17 responses and increased the severity of EAE (28).

Additionally, in vitro stimulation of activated B cells with anti-TIM-1 MAbs enhanced proliferation and Ig production (1127).

The HAVCR1 gene is highly polymorphic in promoter regions as well as in coding regions, with single nucleotide polymorphisms (SNPs) and insertion/deletion (ins/del) variants located throughout the gene and, more specifically, in the exon 4 encoding the functional mucin domain.

In a previous study, we reported the 4 most common HAVCR1 gene haplotypes in our population; one of them, haplotype B, was associated with higher mRNA expression levels and susceptibility to rheumatoid arthritis (5).

Because of the high degree of variability of this gene, it is possible that the variants associated with HCV infection depend on the population studied. T

he aims of the present study were, first, to replicate the association of the HAVCR1 gene with the natural clearance of HCV infection in the Spanish population and, second, to explore the influence of this gene in the outcome of HCV infection, taking into account the haplotypes described in our population.

More information: Belkaya et al. Journal of Experimental Medicine(2019). DOI: 10.1084/jem.20190669

Journal information: Journal of Experimental Medicine
Provided by Rockefeller University Press


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