In a Heartbeat: Understanding autoinflammation
Children's Hospital of Pittsburgh of UPMC has recruited Dr. Scott Canna to research autoinflammatory disorders, which can cause the body's immune system to attack its own tissues. Canna joins the Richard King Mellon Foundation Institute for Pediatric Research, a grant-funded program that the hospital says supports “high-risk, high-reward” research. Canna outlines his work below.
How common are the autoinflammatory disorders you study and what makes some children susceptible to them?
From Alzheimer's to Zika, inflammation is a critical part of what drives almost every disease. Autoinflammation occurs without known infection, cancer, or other external cause, and is slightly different than autoimmunity. If you include diseases like gout and inflammatory bowel disease, autoinflammation is actually very common. We intensively study patients who have genetic causes because these patients have a really great “starting point” for understanding why they become ill. Some children are susceptible because they have one really severe genetic change, often that they have “de novo” (not inherited from their parents). More commonly, it's an important mix of more subtle genetic changes with environmental factors — and that's the hard work of figuring out the important pathways.
How does your research target these disorders?
When I was doing my training, I was always dumbfounded how almost every child I treated, whether it was asthma or an ear infection or arthritis, was suffering because of an immune or inflammatory problem. For almost all of them, we either ignored the inflammation, or simply tried to club the immune system with corticosteroids. We now have the tools to be much more precise in targeting the specific part of the inflammatory response, and are working hard to know which patients need which tools. When we make the right connection between patient and target, we're able to deal with inflammation much more effectively and with far fewer side effects.
We've found that there are definitely different “flavors” of inflammation. My group focuses on a sepsis-like condition called Macrophage Activation Syndrome. We still lose far too many children to MAS, or complications from the drugs we use to treat it.
We recently made one of these “connections” where we found that children with mutations in a specific gene, called NLRC4, developed MAS. Along with this, we found that these children had really high levels of an inflammatory protein called IL-18. With some drugs that are not yet approved, we can target IL-18 or other proteins that cause the same flavor of inflammation, and hopefully make a big impact.
What could be the clinicalapplications of your work?
Broadly, we think that by studying MAS we are helping define one of these “flavors” of inflammation, and that this will facilitate a new paradigm of treatment for all diseases where inflammation is important. For instance, in many infections the damage caused by your inflammatory response is much worse than the damage caused by the bug itself. With better understanding of different immune responses, and with targeted therapy, we may be able to prevent the damage but still clear the infection. We're focused on patients with “sepsis-like” responses, but this concept extends to treating infections, cancer, trauma, surgical recovery, (and other ailments that trigger an immune response).