23 July 2021
Mutation implicated in auto-inflammatory disease
Published online 4 April 2016
Scientists identify a gene mutation that causes one of the body’s proteins to initiate a chronic inflammatory response leading to repetitive fevers and severe skin lesions.
Analysing genes of 12 individuals affected by an unknown inflammatory disease, scientists found that a mutation at a specific gene site caused changes in the protein pyrin, which is normally responsible for “sensing” pathogens and initiating an inflammatory response.
The disease is characterized by recurrent fever, severe acne and gangrenous ulceration of the skin. The genes studied all come from a Belgian family afflicted with the disease.
Pathogen sensors are normally triggered by binding to molecules generated by pathogens. Up until now, however, it has been unclear how pyrin senses pathogens. The international team, which includes researchers from the Lebanese University in Beirut and the Arabian Gulf University in Bahrain, found that pyrin, instead, is triggered when it senses an unhealthy cellular environment.
This in turn leads to the production of an immune-response protein called interleukin 1β. Targeting this interleukin could prove a successful way to resolve the disease, called pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND).
“Until now there was no genetic test or clinical criteria for PAAND,” says immunologist Adrian Liston from the University of Leuven in Belgium. “We expect that more patients with previously unexplained inflammatory disease will be diagnosed with PAAND now that our study is published.”
Learning how pyrin functions may also help researchers understand how inflammatory responses are triggered in other chronic inflammatory conditions, including diabetes and some cardiovascular and neurodegenerative diseases, Liston explains.
The team is now testing the safety and effectiveness of an anti-arthritic therapy, which resolved the condition in one patient, on a larger set of individuals.
Masters, S. L. et al. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci. Transl. Med. 8, 332ra45 (2016).