Clues Emerge to Explain Allergic Asthma

The protein interacts with better-known immune system players already implicated in allergy, providing a missing piece of the biological puzzle underlying such respiratory attacks. The finding exposes a biological chain of events that could offer targets for allergic asthma treatments, researchers say.

Asthma symptoms triggered by allergies are marked by inflammation of the respiratory tract, which leaves a person gasping for breath, coughing and wheezing. There are many players in this overreaction, including an immune protein called TLR4, or toll-like receptor 4, enzymes in fungi and other allergens called proteinases.

In the new study, a team of scientists induced allergic asthma attacks in mice by exposing the animals to proteinases found in molds, which are common fungal allergens. These proteinases break down a blood-clotting protein called fibrinogen. The resulting shards of fibrinogen then bind to and activate TLR4, a receptor protein found on immune cells and other cells lining the airways. That in turn triggers inflammation — the hallmark of allergic asthma.

Further tests indicated that this fibrinogen cleaving inhibited fungal infection in the mice, study coauthor David Corry, an immunologist and pulmonologist at Baylor College of Medicine in Houston said. “We suspect asthma is a protective response against fungi” in many people, he said. But in others, “it’s an aberrant response induced by extreme sensitivity to the proteinases.”

When the researchers prevented fibrinogen breakdown, the mice had a reduced reaction to mold spores. The same thing happened in mice lacking TLR4, suggesting that both proteins are part of a protective biological chain of events that goes awry in some people. The precise chunk of disassembled fibrinogen responsible for this chain reaction is still unknown, Corry said.

“The fibrinogen finding makes perfect sense,” Stephanie Eisenbarth, a physician and immunologist at the Yale School of Medicine who wasn’t part of this study stated. “Fibrinogen may be a canary in a coal mine — acting as a detector of something pathogenic that may not be detected by classic mechanisms,” she said.

While the fibrinogen finding offers a curious addition to the allergy literature, Corry said the somewhat primitive TLR4 pathway “is only half the story.”

Many scientists maintain that true allergy results only when another side of defense called adaptive immunity runs amok. That involves more sophisticated immune warriors called T and B cells. While adaptive immunity might also be steered by reactions to proteinases, Corry said, the specifics are still unknown.