The pathway to asthma winds through toll-like receptor 4

Microscope image of fibrin plug in a human asthmatic airway. The fibrin plug is blocking this medium-sized airway's luemn. This condition is termed plastic bronchitis and results from the presence of airway proteinases that cleave the protein fibrinogen, which leads to the deposition of fibrin that, over time, aggregates and hardens into the mature, stiff fibrin plug depicted here. This image is from the lung of a patient who died of asthma. It illustrates the crucial importance of fibrinogen cleavage to allergic inflammation. Credit: Dr. Martha Warnock, University of California at San Francisco

In a report that appears online in the journal Science, Dr. David Corry of Baylor College of Medicine and colleagues describe a molecule called toll-like receptor 4 that plays a key role in prompting the innate or immediate response that drives allergic disease and asthma.

Dr. David Corry compares the to a computer.

"The core of a computer is its CPU () or chip. We are looking for the chip that drives allergic disease," said the professor of medicine, chief of the section of immunology, allergy and in Baylor College of Medicine's department of medicine and director of the Biology of Inflammation Center at BCM. In a report that appears online in the journal Science, he and colleagues at BCM describe an important component of that chip – a molecule called toll-like receptor 4 that plays a key role in prompting the innate or immediate response that drives allergic disease and asthma.

Asthma is part of a battle that takes place as the immune system marshals its forces to fight off an invading organism-or what mimics such invaders. The ensuing fight takes a significant toll on the human airway and lungs, often generating a violent and itself potentially deadly reaction – asthma.

In 2002, Corry and his colleagues found that proteinases, enzymes that chop up other proteins, are important in initiating the that prompts generation of the critical T-cells and B-cells that populate the adaptive immune system. The adaptive immune system specifically targets , and Corry knew that the more immediate innate immune system also played an important role in asthma and allergy.

"If you take many proteinases and give them to mice, they will induce an allergic disease that resembles asthma," he said.

With that key finding in the , the researchers turned their attention to the puzzle presented by the innate immune system.

"What is the relationship between proteinases and asthma?" he said. Other work in the field pointed to another immune molecule called toll-like receptor 4 that was believed to play a role in activating T-helper type 2 (Th2) cells.

Instead, he and his colleagues found that the proteinases carve up a protein known as fibrinogen, leaving behind fragments that signal through the crucial toll-like receptor 4 to activate the cells of the – the macrophages of the airway and airway epithelia.

"Toll-like receptor 4 is not required for the Th2 response itself," said Corry. "But, the Th2 response is proteinase dependent."

"When the macrophages are activated by fibrinogen cleavage products in culture, you get beautiful activation," said Corry.

In the airway, the same fibrinogen fragments that are part of the blood clotting process can cause clotting that is a barrier to breathing, said Corry.

In his studies, he used proteinase-producing fungi as the environmental trigger for asthma. Laboratory mice that lacked toll-like receptor 4 did not mount a robust allergic airway disease when challenged by proteinase, viable fungi or other triggers but did have a normal Th2 immunity.

"Why do our bodies do this?" said Corry. The answer is both simple and complicated. The system developed to allow organisms to survive infection with deadly organisms such as fungi. How it achieves that is complicated. In this "survival mode," the generates symptoms that can themselves create disease.

Against the insidious onslaught of organisms such as fungi, which can kill if left unchecked, asthma may be a better alternative, said Corry.

"If you don't fight fungi off, they will get you," he said.

More information: "Cleavage of Fibrinogen by Proteinases Elicits Allergic Responses Through Toll-Like Receptor 4," by V.O. Millien et al Science, 2013.

Related Stories

Rewiring DNA circuitry could help treat asthma

Jul 05, 2012

(Medical Xpress) -- Reprogramming asthma-promoting immune cells in mice diminishes airway damage and inflammation, and could potentially lead to new treatments for people with asthma, researchers have found.

Study reveals new link to asthma

Aug 23, 2012

(Medical Xpress)—Researchers at King's have established a significant link between asthma and an immune response called 'Th17', previously only attributed to inflammatory conditions such as multiple sclerosis.

Rage against the disease

Aug 05, 2013

Imagine a world where asthma wasn't a chronic disease, rather an inconvenient illness whose first symptoms could be easily treated. This vision could one day become a reality thanks to cutting-edge research into an immune ...

Recommended for you

New perspective on sepsis

Apr 17, 2014

In a review published in the April issue of Immunity, Kevin J. Tracey, MD, president of The Feinstein Institute for Medical Research, says it's time to take a fresh look at the medical community's approach to treating sepsis ...

Some immune cells defend only one organ

Apr 17, 2014

(Medical Xpress)—Scientists have uncovered a new way the immune system may fight cancers and viral infections. The finding could aid efforts to use immune cells to treat illness.

User comments