Fatal asthma is caused by immune system dysfunction that extends beyond the lungs to affect lymph nodes, the gut and other organs, according to Columbia University research analyzing tissue samples from fatal asthma patients. The study found that fatal asthma patients have abnormally high antibody levels, reduced regulatory immune cells and a strong connection between gut and lung immune responses that together create conditions for life-threatening asthma attacks.
- Fatal asthma involves immune dysfunction across multiple organs, not just the lungs, including lymph nodes and the digestive tract
- All fatal asthma patients studied had elevated levels of IgE antibodies and significant reductions in regulatory T cells that normally suppress excessive immune responses
- A strong connection exists between gut and lung immunity, suggesting intestinal immune events may trigger dangerous lung inflammation
Researchers at Columbia University Irving Medical Center in New York City have identified widespread immune system abnormalities in people who died from fatal asthma attacks, offering new clues about why asthma becomes life-threatening in a small number of patients. Their analysis in the paper, “Dysregulated Tissue Immunity in Human Fatal Asthma,” suggests fatal asthma is not a disease of the airways alone, but a disorder involving immune dysfunction across multiple organs, including the lungs, lymph nodes and gut. The paper was published in Nature Communications.
The study analyzed blood and tissue samples from 175 organ donors over a period of 15 years, comparing those who died from fatal asthma with donors who had a history of asthma and those with no asthma diagnosis. Researchers discovered extensive disruptions in immune regulation that were largely concentrated in tissues connected to the body’s mucosal immune system.
According to the study’s results, every fatal asthma donor had elevated levels of immunoglobulin E (IgE), an antibody strongly associated with allergic reactions. Compared with control subjects, fatal asthma patients also exhibited increased mucus production in the lungs, higher levels of inflammatory immune cells and significant alterations in immune memory cells within lung-associated and gut-associated lymph nodes.
Among the most interesting results of the study was evidence of a strong connection between immune activity in the intestines and immune responses in the lungs. Researchers noted that fatal asthma donors showed increased associations between immune responses occurring in gut-associated lymph nodes and those occurring in lung tissues.
Investigators said they believe their findings support a growing body of evidence to suggest the gut microbiome and intestinal immune system may play a role in severe asthma. The study found accelerated development of memory T cells and B cells in gut-associated lymph nodes, potentially indicating that immune events originating in the digestive tract may influence lung inflammation, they said.
Researchers also identified a significant reduction in regulatory T cells, or Tregs, within lung-associated lymph nodes of asthma patients. These cells normally help suppress excessive immune responses and maintain immune balance, they noted.
The study’s results observed a pronounced reduction in younger individuals with asthma that persisted over time. According to the researchers, this loss of immune regulation may allow inflammatory responses to become amplified, contributing to severe asthma attacks.
The team also found reduced levels of follicular helper T cells, another important immune population involved in maintaining healthy immune responses, suggesting a broader breakdown in immune regulation.
In observing the lungs of fatal asthma donors, investigators reported seeing elevated numbers of immune cells known to drive allergic inflammation, including Th2 cells, Th1 cells, type 2 innate lymphoid cells (ILC2s) and mast cells, all of which are known contributors to asthma pathology. The team also reported finding increased levels of lung-resident memory immune cells capable of rapidly responding to allergens. Many of these cells expressed receptors for IL-33, an inflammatory signaling molecule associated with asthma exacerbations, they said. This suggests that fatal asthma may result from the accumulation of highly reactive immune cells that remain embedded in lung tissue, poised to trigger excessive inflammation when activated, researchers said.
Finally, the study identified demographic trends among fatal asthma cases. Individuals who died from fatal asthma were more likely to be female, younger than 40 years old and of Hispanic or Black ethnicity compared with control donors who did not have asthma. Fatal asthma donors also had higher rates of severe, uncontrolled asthma and more frequent use of asthma medications and steroids, they study’s researchers noted.
Although the study’s authors cautioned that the analysis is observational and cannot prove causation, they suggested that targeting regulatory immune pathways, restoring Treg populations or modifying gut-associated immune responses could one day reduce the risk of life-threatening asthma attacks.
