Link found between chronic inflammation, autoimmune disorders and “false alarms”

Viruses (pictured here) have a genetic signature that a receptor called MDA5 recognizes. But when MDA5 confuses the body's own genetic material with that of a virus, disease ensues.
Viruses have a genetic signature that a human receptor called MDA5 recognizes, causing the immune system to attack. But when MDA5 confuses the body’s own genetic material for that of a virus, disease ensues.

The human body’s innate immune system employs a variety of “sensors” for identifying foreign invaders such as viruses. One such viral sensor is a receptor called MDA5, found in every cell of the body.

Inside each cell, MDA5 constantly scans genetic material, checking if it’s native to the body or not. As soon as MDA5 identifies the genetic signature of a viral invader, it trips a system-wide alarm, triggering a cascade of immune activity to neutralize the threat.

But if a genetic mutation to MDA5 causes it to confuse some of the body’s own genetic material for being foreign, “false alarms” can lead to unchecked inflammation and disease. Scientists from Boston Children’s Hospital have discovered a new link between MDA5’s ability to discriminate between “self” and “non-self” genetic material — called RNA duplexes — and a spectrum of autoimmune disorders.

“We’ve found that chronic inflammation and autoinflammatory disorders can originate from genetic mutations to MDA5 that cause it to misrecognize ‘self’ as ‘non-self,’ essentially launching the immune system into self-attack mode,” says Sun Hur, PhD, senior author of the study published in the journal Cell.

Picking apart chronic inflammation

A key player in this complex interplay is an ancient element of the human genome called the Alu retroelement. Alu elements make up around 10 percent of our genome and — without any obvious purpose — appear to be a relic of the primordial ancestry we share with primates.

“Alu is what we call a retro-element; generally, it is considered to be a ‘junk’ component of the human genome,” says Hur, who is a principal investigator in the Boston Children’s Program in Cellular and Molecular Medicine.

Normally, MDA5 recognizes Alu RNA as native — and nothing happens. But in the case of autoinflammatory diseases like Aicardi-Goutières syndrome (AGS), something goes wrong and MDA5 interprets Alu as a threat.

“We found that Alu RNA can often form duplexes in human cells and that these duplexes can confuse and activate MDA5 under these pathologic conditions.”

Hur’s team — led by postdoctoral fellows Sadeem Ahmad, PhD, and Xin Mu, PhD — made this discovery while investigating the role of MDA5 mutations in AGS, a disorder characterized by inflammation and tissue damage throughout the central nervous system. Babies born with AGS show symptoms associated with congenital viral infection and a type of lupus. As the disease progresses, loss of neurological function and organ damage are eventually fatal; few individuals with the disease reach adulthood.

“Analyzing these AGS mutations, we observed that AGS-associated MDA5 mutants aren’t capable of discerning between true viral RNA and native Alu duplex RNA,” Ahmad says.

Once a cell containing mutant MDA5 misidentifies Alu duplex RNA as having viral origin, it begins to emit signaling molecules called antiviral cytokines, alerting nearby cells and the body’s immune system to go on attack mode.

A way to ramp back autoinflammatory disorders?

For children with AGS and a number of other related immune disorders, chronic false alarms like this can be life-threatening.

“Antiviral cytokines generated by ‘infected’ cells flood the circulatory system and cause inflammation throughout the body,” Mu says. “In the case of real infection in otherwise healthy individuals, inflammation can help elicit a better immune response. But in autoinflammatory disease, when the body is stuck in false alarm mode, inflammation can wreak havoc.”

Hur’s team believes their findings are important because they open the door to a new therapeutic approach to treating autoinfammatory diseases.

“Although completely inhibiting MDA5’s function — chemically or through genetic knockout — would leave the body vulnerable to viral infection, it’s possible that dulling MDA5’s ability to trip the alarm could help alleviate inflammation in people with autoinflammatory disorders like AGS.

“In theory, it would be quite beneficial if we could therapeutically modulate MDA5 in a way that reduces its ability to harm the ‘self’ while still preserving some of its ability to identify ‘non-self,’” Hur says.

In addition to Hur, Ahmad and Mu, the paper’s other authors are Fei Yang, Emily Greenwald, Ji Woo Park, Etai Jacob and Cheng-Zhong Zhang.

This work was supported by the Cancer Research Institute, the National Institute of Health (R01AI106912, R01AI111784, and R21AI130791), the March of Dimes and the Burroughs Wellcome Fund.

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