Oliver Skinner, Marcia Munoz and Mike Rogers

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Australian scientists have uncovered part of the process that leads to ‘inflammatory flares’ in patients with a rare immune disorder.

A driver of inflammation in a rare childhood condition

Inflammation is crucial to keeping the body healthy, for example in response to infection – but in excess, it can be devastating.

A study led by Professor Mike Rogers and Dr Marcia Munoz from the Garvan Institute of Medical Research, published in 

, has revealed a piece of the puzzle of how a genetic variant triggers flares of inflammation in a condition known as mevalonate kinase deficiency (MKD). The finding brings new hope for treatment to those affected by this rare autoinflammatory disease and their families.

MKD is a rare genetic condition that affects several hundred individuals worldwide, most of whom are children. People with MKD experience high fevers or ‘inflammatory flares’ that can last for days and can be accompanied by other symptoms, including skin rash and pain in the joints, muscles and abdomen. In its severest form, MKD can be life-threatening.

In the hope of developing better treatments for MKD, Garvan researchers are trying to understand the process that leads to inflammatory flares.

 gene somehow lead to the inflammation we see in MKD patients, but exactly how this happens hasn’t been clear. What we’ve now discovered is a key part of the process, which could have implications for developing better therapies for these patients,” says Professor Rogers, who heads the Bone Therapeutics Lab at the Garvan Institute.

In the current study, the researchers investigated ‘inflammasomes’ – molecules which assemble together into larger structures within cells, much like a mosaic, to trigger an inflammatory response.

In white blood cells , the researchers simulated the 

 gene variants found in MKD patients and also removed the genes of two molecules, called NLRP3 and pyrin – the building blocks of two different types of inflammasome ‘mosaics’. The team discovered that without pyrin, the cells were able to trigger an inflammatory response, but without NLRP3 inflammation was significantly reduced. Further, when the team blocked NLRP3 in cells from MKD patients, this also blocked inflammation.

“Our findings show that the NLRP3 inflammasome likely plays a key role in the imbalanced inflammation that occurs in MKD patients,” says Dr Marcia Munoz, co-senior author of the study.

The team’s evidence challenges other studies that suggest the pyrin inflammasome alone is responsible for inflammatory flares in MKD and shows the NLRP3 inflammasome may be an alternative, or additional, mechanism leading to inflammation.

Currently, individuals suffering from MKD are treated with anti-inflammatory therapies, which are not effective in all patients. Blocking inflammation more specifically via the NLRP3 inflammasome may provide a better alternative, says Professor Rogers.

He adds that the findings could extend beyond those affected by rare inflammatory conditions and may have implications in a wider range of diseases.

“Inflammation is fast becoming understood as an underlying process across many diseases, including diabetes and cancer, so this work has reverberations that may extend beyond rare autoinflammatory disorders,” Professor Rogers explains. “The 

 gene is part of an essential metabolic pathway in all human cells, so understanding how inflammation happens in one disease context may ultimately shed light on the cause of inflammation in other, more common diseases.”