It usually takes decades, sometimes centuries, between the discovery of a new disease and finding its cause, but one autoinflammatory condition has been explained in the same paper that describes it, along with strong prospects for treatment.
A genetic mutation causes some people to suffer frequent outbreaks of sometimes extreme fever and pain. During the outbreaks, lymph glands swell and other unusual symptoms can occur. The team who have explained its workings think what they have learned will improve our understanding of other forms of autoinflammatory disease, spreading the benefits much more widely.
Dr Dan Kastner of the National Human Genome Research Institute is known as the “father of autoinflammatory disease”, having done so much to overcome our ignorance of these poorly understood conditions. Kastner's attention was drawn to a group of people who run fevers every 2-4 weeks, suffering for a day to a week at a time. Besides swollen lymph glands, the fevers can be accompanied by an enlarged spleen or liver, and sometimes mouth ulcers. Beginning from birth or soon after, the outbreaks never go away of their own accord – one patient still has them in her 80s.
The condition runs in three families Kastner studied, indicating it is genetic, and testing revealed all those with it have mutations on the RIPK1 gene. RIPK1 has recently come in for considerable attention, with geneticists thinking it could be important in a range of conditions, so Kastner got in touch with a team of RIPK1 experts at the Walter and Eliza Hall Institute, including Dr Najoua Lalaoui.
In Nature, Lalaoui and co-authors name the condition cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome and reveal it operates by inducing cell death.
“Cell death pathways have developed a series of inbuilt mechanisms that regulate inflammatory signals and cell death, because the alternative is so potentially hazardous,” Lalaoui said in a statement. “However in this disease, the mutation in RIPK1 is overcoming all the normal checks and balances that exist, resulting in uncontrolled cell death and inflammation.”
Oddly, the three families all carry different mutations of RIPK1, but they produce the same outcome, preventing the RIPK1 protein from cleaving.
Lalaoui explained to IFLScience the cell death is restricted to limited sites in the body, particularly around the lymph glands rather than running rampant and killing whole organs, but the impact on people's lives is still severe. Some treatments for other autoinflammatory conditions ease the effects for some, but not all, CRIA patients.
However, Lalaoui noted, several RIPK1-inhibitors are already under development for other conditions, and these may provide more targeted relief.
Meanwhile, Lalaoui added, the discovery could lead to greater recognition of the importance of cell death in a range of autoinflammatory conditions, something she said has not been given much consideration.