Two new studies published in the journal Science Translational Medicine point to a cycle of cell death and chronic inflammation involving blood cells called neutrophils, versatile soldiers of the immune system that race to the site of infection to destroy invaders, as a key engine in the disease.
The discoveries come during a week when the FDA is expected to announce its decision on the biologic drug Benlysta, which could be the first drug approved to treat lupus in nearly 50 years.
According to the Lupus Foundation of America, lupus affects about 1.5 million Americans, many of them younger women.
The Underlying Cause of a Body-Wide Attack
One of the hallmarks of lupus is that patients make antibodies to their own DNA, called anti-nuclear antibodies, or ANAs. Blood tests for ANAs are sometimes helpful as an initial step in diagnosing lupus.
Researchers had long wondered how that happens since DNA was thought to be protected inside cells. Then, in 2004, a team of researchers discovered that neutrophils can die in an explosive way, shooting strings of cellular material studded with proteins and bits of nuclear DNA out like webs to entangle harmful bacteria, viruses, or fungi.
A Body Tangled by NETs
These neutrophil extracellular traps, or NETs, get slung outside the cell.
“They’re called NETs because they really look like a net, like a spider web,” says study researcher Michel Gilliet, MD, a dermatologist at University Hospital Lausanne, in Switzerland. The cells, he says, “shoot them out.”
In healthy people, once these NETs enter the liquid space between cells, the bits of nuclear DNA degrade quickly and probably don’t cause any problems, but Gilliet and his team found that patients with lupus have antimicrobial proteins called LL37 and HNP that appear to protect these bits of DNA from being broken down by the body.
Together, these proteins and DNA can trigger another type of immune cell, a kind of chemical factory called a plasmacytoid dendritic cell, which pumps out proteins that stoke the immune response.
One of those proteins, called type 1 interferon, is often present in high amounts in patients that have lupus, which has largely been another mystery of the disease.
Type 1 interferon, it turns out, triggers neutrophils to release more NETs, setting up an apparently self-perpetuating disease process.
“What this suggests is that there is a vicious cycle between the production of interferon, the way the neurtrophils die and the increase in the production of auto-antibodies, so this is a very, very efficient pathogenic loop that amplifies itself,” says study researcher Virginia Pascual, MD, an instructor of medicine at Baylor Institute of Immunology Research in Dallas.
Better Diagnosis and Treatments
Gilliet and his team are already testing the blood of lupus patients to see if one of these proteins may turn out to be a more specific marker for the disease, and thus useful in diagnosis.
That’s important because right now, doctors have to rely on a set of 11 criteria, which can overlap with many other diseases, to try to make a diagnosis.
“It is one of the most complex clinical diagnoses,” says Pascual, who is also a practicing pediatric rheumatologist.
“It might lead to better diagnostic tests, but we don’t know that yet,” Pascual says. Other experts say the discoveries will most certainly lead to new drug targets.
“It really provides a model for understanding why interferon is released, and that’s important because the more we understand why this very inflammatory cytokine is released, the more we can think about therapeutic options to block its production,” says Joseph E. Craft, MD, a rheumatologist and immunologist at Yale University in New Haven, Conn., who wrote a perspective article on the discoveries.
“That’s important because there are no really good therapies for patients with severe lupus,” he says.