Newly ID’d Mutation Linked to HLH Symptoms of Chronic Inflammation in Teen, Study Reports

Newly ID’d Mutation Linked to HLH Symptoms of Chronic Inflammation in Teen, Study Reports

A previously unknown mutation in a protein that regulates immune activation, called Roquin-1, was found to be the underlying cause of uncontrolled cytokine release and excessive inflammation — hallmarks of hemophagocytic lymphohistiocytosis (HLH), — in a young man, a study reported.

The study, “A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation,” was published in the journal Nature Communications.

HLH is a rare disorder characterized by an overactive, abnormal immune response that causes excessive inflammation and tissue damage. The condition can be inherited (primary), and mutations in several genes are associated with the disease. It can also be triggered by viral infections (secondary).

A team led by researchers at the Ghent University Hospital, in Belgium, reviewed the case of 18-year-old who first came to their center at age 11 with HLH symptoms. The boy was treated with the immunosuppressant therapy cyclosporin A (CSA), but continued to experience ongoing inflammation after stopping CSA use at age 13.

Further examination failed to identify an infectious agent or autoimmune trigger, and the patient had no known HLH mutations or other mutations in genes associated with immune disorders.  

This prompted the team to investigate the entire DNA sequence of the teenager’s genome, to identify an underlying genetic cause. 

The analysis uncovered a mutation (R688*) on both chromosomes in a gene called RC3H1 that led to the synthesis of a shorter version of a protein known as Roquin-1.

Roquin-1 helps to slow the production of proteins related to the immune system by triggering the degradation of their RNA — the molecule that carries the information from a gene to be translated into a protein — acting like an “off” switch (post-translational regulation). 

Researchers wondered if a dysfunctional Roquin-1 protein failed to dampen immune activation, leading to the excessive HLH-like inflammation as seen in this teenager. 

To find out, they isolated and identified immune cells from the patient’s blood to check for potential immunological abnormalities. 

Results showed that some types of immune cells were significantly overrepresented, while others were underrepresented. Immune cells that were overrepresented were also found to be those that are in excess with viral infections, chronic inflammation, and a number of autoimmune conditions. 

A more detailed look at the cells showed a marked increase in the production of a wide range of immune system signaling proteins known as cytokines. High levels of cytokines remained despite CSA treatment. 

To support these results, the researchers analyzed a mouse strain called sanroque that has a mutation in the Roquin-1 protein. These mice acquire a lupus-like disease (an autoimmune disease), becoming anemic, having low platelets counts, and enlarged spleens and lymph nodes. 

As in humans, excessive inflammation in these mice was linked to elevated levels of cytokines. Treating the animals with an antibody that inhibits cytokine production reduced spleen enlargement, the number of immune cells, and the levels of cytokines. 

Of note, the antibody Jakafi (ruxolitinib), marketed by Incyte, is an inhibitor of certain cytokines, and has been approved treat myelofibrosis (a rare form of bone marrow cancer) and polycythemia (high levels of red blood cells). This antibody is currently being evaluated as a potential treatment for HLH in two clinical trials (NCT03533790 and NCT02400463). 

“The accumulated evidence strongly suggests a causal relationship between the R688* RC3H1 variant and the observed disease,” the researchers concluded, adding that “post-transcriptional control by Roquin-1 is critical in the regulation of the human immune system.”

According to the team, the identification of mutations in post-transcriptional regulators of the immune system, like Roquin-1, can offer “novel insights in the regulation of the immune system and define new therapeutic opportunities.”