Allergens that chop up a clotting protein contribute to reactions
A common blood-clotting protein turns out to play a role in 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, and 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, the researchers report in the Aug. 16 Science.
Further tests indicated that this fibrinogen cleaving inhibited fungal infection in the mice, says study coauthor David Corry, an immunologist and pulmonologist at Baylor College of Medicine in Houston. “We suspect asthma is a protective response against fungi” in many people, he says. 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 says.
“The fibrinogen finding makes perfect sense,” says Stephanie Eisenbarth, a physician and immunologist at the Yale School of Medicine who wasn’t part of this study. “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 says.
While the fibrinogen finding offers a curious addition to the allergy literature, Corry says 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 says, the specifics are still unknown.
V. Millien et al. Cleavage of fibrinogen by proteinases elicits allergic responses through toll-like receptor 4. Science. Volume 341, Aug. 16, 2013, p. 792. doi: 10.1126/science.1240342. [Go to]
P. McGuirk et al. The role of regulatory T cells in respiratory infections and allergy and asthma. Current Allergy and Asthma Reports. Volume 10, 2010, p. 21.
H. Hammad et al. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nature Medicine. Volume 15, online March 29, 2009, p. 410. doi:10.1038/nm.1946. [Go to]
S. Eisenbarth et al. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. Journal of Experimental Medicine. Volume 196, Dec. 16, 2002, p. 1645. doi: 10.1084/jem.20021340. [Go to]