Researchers track down metabolic enzyme that protects against inflammation

July 24, 2020

A new study from scientists at the La Jolla Institute for Immunology (LJI) shows that a previously poorly understood enzyme actually inhibits inflammation in blood vessels. According to the study, the research offers a potential path to treating DADA2, an inflammatory blood vessel disease in children that is similar to Kawasaki disease.

“This is all pretty uncharted because for a long time, this was a very misunderstood enzyme,” says Sonia Sharma, PhD, associate professor at LJI and senior author of the new study in Science Advances. “But we showed that the metabolic activity of this enzyme, ADA2, is very important for restraining the immune system in both vascular cells and immune cells.”

Sharma and her colleagues looked at a group of uncharacterized human disease genes linked to lupus-like autoimmune diseases that all cause multi-organ systemic inflammation or vasculitis. All the diseases were linked to single-gene mutations, but in most cases, no one had uncovered exactly how each mutation affects the innate immune system. For the new study, the researchers asked if any of the disease-linked genes play a role in how stromal cells respond to threats by initiating an innate immune response.

Sharma says that a better understanding of ADA2 and purine nucleoside metabolism may open the door to new therapies for treating DADA2 and other types of multi-organ systemic inflammation. She believes that targeting the roots of these diseases will likely require a gene therapy approach or bone marrow transplants to reconstitute ADA2 in patients who cannot make the enzyme themselves. Going forward, Sharma plans to further study ADA2 function in human cells and develop in vivo models of ADA2 deficiency. She also sees a link between ADA2 research and COVID-19 studies.

Sharma’s lab is currently studying how the novel coronavirus may infect stromal endothelial cells and other cells involved in stimulating the body’s innate immune response. They are hoping to shed light on how the viral pathogenesis is linked to vascular complications and Multisystem Inflammatory Syndrome in Children (MIS-C), which has similarities to Kawasaki disease and DADA2. By tracking ADA2 activity and purine nucleoside levels in the blood of COVID-19 patients, Sharma’s lab may be able to see if the virus really is targeting the vascular system.

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