by An inflammatory molecule called LIGHT appears to be the cause of life-threatening airway damage in patients with severe asthma. According to new research by scientists at the La Jolla Institute of Immunology (LJI), therapeutics that stop LIGHT (related to tumor necrosis factor) can reverse airway and lung damage in patients and potentially provide a long-term cure for asthma. .
D., senior author of the new study and member of the LJI Center for Autoimmunity and Inflammation. “This is a very, very important finding,” says LJI Professor Michael Croft. “This research provides us with a better understanding of the therapeutic targeting potential of LIGHT and what we can do to alleviate some of the symptoms and some of the inflammatory properties seen in patients with severe asthma.”
This research was recently published in the journalism. Journal of Allergy and Clinical Immunology. The work included experiments with both mouse and human tissues, and LJI Instructor Haruka Miki, MD, Ph.D.
Croft’s team has been working on LIGHT for over a decade. The LIGHT protein is a type of inflammatory “cytokine” produced by the T cells of the immune system. T cells normally fight disease, but in asthma, T cells overreact to environmental triggers and flood the airways with LIGHT and other inflammatory cytokines. Researchers have developed treatments to block the activity of several other harmful cytokines made by T cells, but these treatments are not effective for many people with severe asthma.
LIGHT can be found elevated in the sputum of asthmatic patients with severe disease, and Croft’s previous work has shown that LIGHT is required in a process called tissue “remodeling,” where the lungs and airways grow thicker after an asthma attack. These thicker airways can leave a person with long-term breathing problems.
“Current treatments for asthma are mainly for suppressing symptoms and suppressing allergic inflammation. No treatments have been developed to cure asthma fundamentally,” says Miki. “Even when inflammation is suppressed with current treatments, the underlying airway hyperresponsiveness and airway tissue changes (airway remodeling) often persist, especially in severe asthma.”
Although the researchers knew that LIGHT was involved in this remodeling, they did not know whether LIGHT directly affected the smooth muscle tissue lining the lungs’ main airways. These cells increase in number and size in moderate to severe asthmatics, which is thought to be the primary cause of lung function loss.
Their research showed that one of the two receptors for LIGHT, called LTβR, is strongly expressed in airway smooth muscle cells. Miki was then able to show that the binding of LIGHT with LTβR is what triggers tissue remodeling in airway smooth muscle, by “destroying” genes for one receptor or the other in mice. The researchers further confirmed this finding using bronchial smooth muscle tissue from human samples.
“When these cells in the lungs are unable to express LTβR, essentially all the features of the smooth muscle response associated with severe asthma are either lost or highly limited,” says Croft.
Of course, LIGHT isn’t the only cytokine in the mix during an asthma attack, but the new study shows that LIGHT provides the greatest effect. LIGHT coordinates the remodeling process by acting directly on airway smooth muscle cells. Without LIGHT and LTβR activity, other cytokines cannot clear the gap. In fact, the new study is the first to show that deletion of a single receptor or absence of a single cytokine can limit airway smooth muscle tissue remodeling.
“Unlike other inflammatory cytokines, LIGHT induces a delayed and persistent signal through its receptor LTβR, which may be responsible for the sustained increase in contractility and mass in airway smooth muscle,” says Miki.
“This is a very striking and important result that essentially distinguishes LIGHT from any of the other inflammatory cytokines involved in the process in severe asthma patients,” adds Croft.
Currently, pharmaceutical company and LJI research partner Kiowa Kirin is developing a potential therapeutic based on Croft’s finding. For Croft, the work is the long-awaited result of years of research. “I think he has completed the cycle we started years ago in linking LIGHT to pulmonary inflammation,” he says.
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materials provided by La Jolla Institute of Immunology. The original was written by Madeline McCurry-Schmidt. Note: Content can be edited for style and length.
