A new autoinflammatory disease has been discovered by Institute researchers Professor John Silke and Dr Najoua Lalaoui, in collaboration with Dr Dan Kastner and colleagues at the National Institutes of Health (NIH), US.

The disease, CRIA (cleavage-resistant RIPK1- induced autoinflammatory) syndrome, is caused by a mutation in RIPK1 – a critical molecule in the cell death pathway.

The new discovery suggests that compounds inhibiting cell death might be useful in treating autoinflammatory diseases.

A potent killer

Autoinflammatory diseases are caused by abnormal activation of the innate immune system, leading to recurrent and debilitating episodes of high fever and inflammation.

Professor Silke, who has been studying cell death for more than 20 years, said RIPK1 was a critical regulator of inflammation and cell death.

“RIPK1 is a potent killer and cells have developed ways of managing its effects. This includes cleaving the molecule into two pieces to ‘disarm’ and halt its inflammatory activity. However in CRIA syndrome, the mutation in RIPK1 prevents the molecule from being cleaved, resulting in uncontrolled cell death and inflammation," he said.

"In patients, that translates to recurring episodes of high fever and painful swollen lymph nodes, as well as a range of other inflammatory symptoms that begin in childhood and last their whole lives."

The RIPK1 link

The study, published in Nature, describes patients from three families with a history of recurring fevers and inflammatory symptoms who were later diagnosed with CRIA syndrome.

After sequencing the patients’ DNA, the NIH research team found mutations in the exact same amino acid of RIPK1 in each of the three families. This provided the first clue linking CRIA syndrome with defects in RIPK1 function and cell death.

Dr Lalaoui said Institute researchers confirmed the link between the RIPK1 mutations and CRIA syndrome in the laboratory.

“We showed that mice with mutations in the same location in RIPK1 as in the CRIA syndrome patients had a similar exacerbation of inflammation,” she said.

‘Precision’ medicine potential

NIH researcher and ‘father of autoinflammatory disease’ Dr Kastner said RIPK1 inhibitors – which are already available on a research basis – may provide a focused, ‘precision medicine’ approach to treating patients.

“Understanding the molecular mechanism by which CRIA syndrome causes inflammation affords an opportunity to get right to the root of the problem. RIPK1 inhibitiors may be just what the doctor ordered for these patients,” he said.

The discovery of CRIA syndrome also suggests a possible role for RIPK1 in a broad spectrum of inflammatory diseases such as colitis, arthritis and psoriasis.