Scientists solve long-standing mystery of asthma

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In individuals with severe asthma, an inflammatory substance known as LIGHT seems to be the source of damage to the airways that might be potentially deadly. New research conducted by scientists at the La Jolla Institute for Immunology (LJI) suggests that therapeutics to stop LIGHT, which is associated to tumor necrosis factor, could change airway and lung damage in patients, and possibly improve a treatment for asthma that is effective over the long term.

Michael Croft, Ph.D., a LJI professor and a member of the LJI Center for Autoimmunity and Inflammation, was the senior author of the latest research and called this discovery very remarkable.  This research provides with a greater knowledge of the possibilities of therapeutic targeting of LIGHT and what we may do to decrease some of the symptoms and some of the inflammatory characteristics found in individuals who have severe asthma.

The results of this study were only just published in the Journal of Allergy and Clinical Immunology. Haruka Miki, M.D., Ph.D., an instructor at LJI, served as the study’s primary investigator and directed the studies in which human and mouse tissues were utilized.

Croft’s group has been researching LIGHT for more than a decade now. The T cells of the immune system are responsible for the production of a particular type of cytokine that is inflammatory. T cells’ usual function is to fight illness; however, in asthma, these cells have an exaggerated response to environmental stressors, which causes them to overwhelm the airways with LIGHT and other inflammatory substances known as cytokines. The action of some of the other dangerous cytokines produced by T cells has been blocked by medications created by researchers, but these therapies are ineffective for many people who suffer from severe asthma.

LIGHT is discovered in higher concentrations in the sputum of asthmatic patients who have severe symptoms. Croft’s earlier research shown that LIGHT is necessary in a process termed tissue “remodeling,” in which the lungs and airways grow thicker in response to an asthma attack. The thicker mucus that lines the airways might cause a person to have chronic breathing issues.

The primary goals of modern therapy for asthma are to reduce the symptoms of the disease and to calm the allergic inflammation that it causes. There is currently no medicine available that can fundamentally cure asthma. Underlying airway hyperresponsiveness and airway tissue changes (airway remodeling) typically continue, especially in severe asthma, even when inflammation is reduced by current medications.

Even while the researchers were aware that LIGHT had a role in this remodeling process, they were uncertain as to whether or not LIGHT has a direct influence on the smooth muscle tissue that lines the main airways of the lungs. In patients who have moderate to severe asthma, the number and size of these cells both increase, which is assumed to be the major cause of the decline in lung function.

Their research revealed that airway smooth muscle cells contained a high concentration of LTβR, which is one of the two receptors for the LIGHT molecule. Miki was able to demonstrate that the LIGHT’s interaction with LTβR is what causes tissue remodeling in the airway smooth muscles by using a technique called “knocking out” the genes for one receptor in mice and replacing them with a gene for the other receptor. The researchers added more support to their conclusion by confirming it using bronchial smooth muscle tissue taken from human samples.

According to Croft, when those cells in the lungs are unable to produce LTβR, then practically all of the markers of the smooth muscle response that are linked with severe asthma are either gone or they are very restricted.

According to the findings of the recent study, although LIGHT is not the only cytokine present in the body during an asthma episode, it appears to be the one that packs the most of a punch. LIGHT is responsible for the coordination of the remodeling process since it acts directly on the airway smooth muscle cells. The other cytokines are unable to make up the difference in the absence of active LIGHT and LTβR. In point of fact, the current research is the first of its kind to demonstrate that the lack of a single cytokine or the removal of a single receptor may put a stop to the remodeling of airway smooth muscle tissue.

According to Miki, unlike other inflammatory cytokines, LIGHT generates a delayed and continuous signal via its receptor, LTβR. This signal may be liable for the prolonged increase in contractility and bulk in airway smooth muscle.

According to Croft, this effectively separates LIGHT from all of the other inflammatory cytokines that have been involved in the process in severe asthma sufferers. It is a really dramatic and significant conclusion.

The pharmaceutical business Kiowa Kirin, which is a research partner of the LJI, is currently working to enhance a new medication based on Croft’s study. The long-awaited conclusion to Croft’s years of research may now be found in the paper. The researchers think it completes the loop that they started many years ago in first associating LIGHT to lung inflammation.


Haruka Miki et al. LTβR Signaling Directly Controls Airway Smooth Muscle Deregulation and Asthmatic Lung Dysfunction, Journal of Allergy and Clinical Immunology (2022). DOI: 10.1016/j.jaci.2022.11.016