Researchers find missing piece of the asthma puzzle

An inflammatory molecule called LIGHT appears to be the cause of life-threatening airway damage in patients with severe asthma. According to new research from scientists at the La Jolla Institute for Immunology (LJI), therapies to stop LIGHT (which is related to tumor necrosis factor) could reverse airway and lung damage in patients, and potentially offer long-term treatment for asthma.

“This is a very, very significant finding,” says LJI professor Michael Croft, Ph.D., lead author of the new study and a member of LJI’s Center for Autoimmunity and Inflammation. “This research gives us a better understanding of the therapeutic targeting potential of LIGHT and what we might do to alleviate some of the symptoms and some of the inflammatory features seen in patients who have asthma.”

This research was recently published in the Journal of Allergy and Clinical Immunology. The study included experiments with mice and human tissues and was led by LJI instructor Haruka Miki, MD, Ph.D.

Croft’s team has studied LIGHT for more than a decade. LIGHT protein is a type of inflammatory “cytokine” produced by T cells of the immune system. T cells normally fight disease, but in asthma, T cells overreact to environmental triggers, flooding the airways with LIGHT and other inflammatory cytokines. Researchers have developed therapies to block the activity of some of the other harmful cytokines produced by T cells, but these therapies 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 earlier work showed that LIGHT is essential in a process called tissue “remodeling,” where the lungs and airways thicken after of one asthma attack. These thickened airways can leave a person with long-term breathing problems.

“Current asthma treatments are primarily to suppress symptoms and control allergic inflammation. No treatment has been developed to fundamentally cure asthma,” says Miki. “Even when current treatments suppress inflammation, the respiratory tract hyperresponsiveness and changes in airway tissue (airway remodeling) often remain, especially in severe asthma.”

Although they knew that LIGHT was involved in this remodeling, the researchers did not know if LIGHT directly affects the smooth muscle tissue that lines the main airways of the lungs. These cells increase in number and size in moderate and severe asthmatics, which is believed to be the main cause of loss of lung function.

Their research showed that one of the two LIGHT receptors, called the LTβR, was strongly expressed in the airways. smooth muscle cells. By then “knocking out” the genes for one or the other receptor in mice, Miki was able to show that the binding of LIGHT to LTβR is what triggers tissue remodeling in airway smooth muscle. The researchers further confirmed this finding using bronchial smooth muscle tissue from human samples.

“When those cells in the lungs cannot express LTβR, then essentially all of the features of the smooth muscle response associated with severe asthma gone or very limited,” says Croft.

Of course, LIGHT isn’t the only cytokine in the mix during an asthma attack, but the new study suggests that LIGHT has the biggest impact. By acting directly on airway smooth muscle cells, LIGHT coordinates the remodeling process. Without LIGHT and LTβR activity, the other cytokines cannot take up the slack. In fact, the new study is the first to show that the deletion of a single receptor or the absence of a single cytokine can limit airway smooth muscle tissue remodeling.

“Unlike other inflammatory cytokines, LIGHT induces a persistent and delayed 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 surprising and significant result that essentially sets LIGHT apart from any of the other inflammatory cytokines that have been implicated in the process in severe asthmatics,” Croft adds.

At this time, LJI’s pharmaceutical company and research partner, Kiowa Kirin, is advancing a potential therapy based on Croft’s finding. For Croft, the study is the long-awaited conclusion of years of research. “I think it completes the circle that we started many years ago in linking LIGHT to lung inflammation,” he says.