People with severe asthma may not respond to the usual treatment. Researchers have examined what drives the inflammatory response in severe asthmatics at a molecular level and their findings may lead to the development of an effective treatment for the potentially life-threatening condition.
Asthma is a chronic condition that affects an estimated 334 million people worldwide, with 250,000 deaths attributed to the disease yearly. While less than 10% of people have severe asthma, the condition is unpredictable, difficult to control, and the symptoms often don’t respond well to standard therapies such as inhalers or steroids.
With an asthma flare-up, the walls of the airways become inflamed and swollen, and the airway lining may produce excess mucus. This causes the airways to narrow, making breathing difficult and reducing the amount of oxygen entering the lungs. In a severe asthma attack, the situation can worsen quickly to the point where the person stops breathing; for that reason, it’s regarded as a medical emergency.
The inflammatory response underlying asthma led researchers from the La Jolla Institute for Immunology to examine what was happening on a molecular level to drive severe asthma.
Mast cells are white blood cells that play an important role in the body’s immune system reactions, including allergic reactions. They reside at the border between tissues and the external environment, for example, the lining of the gut and the lungs. Mast cells can be activated by immunoglobulin E (IgE), a type of antibody produced by the immune system.
When the body detects a specific allergen – like pollen, dust mites, or pet dander – IgE binds to mast cells and causes them to produce histamine-releasing factor (HRF), which, as the name suggests, leads the cells to release histamine. Histamine causes the body’s small blood vessels (capillaries) to dilate and smooth muscles, including those in the lungs, to constrict. Histamine’s effect on lung smooth muscles makes breathing difficult during an allergic reaction.
Previous studies have found that IgE and HRF interact to produce harmful inflammatory reactions in mouse models of asthma. In the current study, the researchers looked at how IgE and HRF ‘talk’ to one another during a severe allergic reaction in hopes of better understanding the process and finding a way of switching it off.
Because some asthmatics don’t respond to treatment and others do, the researchers considered it important to study as many types of asthmatics as they could. They examined HRF levels and HRF-IgE interactions in various groups, including healthy adults, adults with mild-to-moderate asthma, moderate asthma, severe asthma, and adults infected with the virus that causes the common cold (rhinovirus). They also examined children whose asthma had been exacerbated by the rhinovirus and those whose asthma had been exacerbated in the absence of the virus.
Participants in the study underwent a bronchoscopy, a minimally invasive procedure where a flexible, lighted tube is passed through the mouth or nose into the airways. Samples of lung cells were collected from the participants’ airways and used to create a human cell line that the researchers tested in the lab.
They found that total IgE and HRF-reactive IgE levels were higher in severe asthmatics than in healthy controls. When the lung cells were infected with rhinovirus, the researchers found that HRF secretion increased dramatically. The same dramatic increase was seen when the cells were exposed to proteins from dust mites, a common allergen and asthma trigger.
The researchers say their study’s findings suggest that HRF-reactive IgE antibodies contribute to asthma severity and that people with severe asthma and asthma exacerbated by infection with the rhinovirus may benefit from therapies that block the communication between IgE and HRF.
The research team at La Jolla Institute are working on two therapies that might inhibit that interaction. The first uses a molecule called HRF-2CA, which has been found to inhibit asthma and severe food allergies in mice. The second involves a therapeutic antibody called SPF7-1, a kind of ‘fake’ HRF that binds to IgE and stops real HRF from binding.
“The best way forward would be to carry out clinical trials to study these two therapeutic options,” said Toshiaki Kawakami, corresponding author of the study.
The study was published in the Journal of Allergy and Clinical Immunology.