Smoking? Pollution? Maybe not – Startling Findings Point to a New Root Cause of Asthma in Men Over 40

Researchers at the La Jolla Institute for Immunology (LJI) and the University of Southampton, UK, have unveiled a group of immune cells believed to be the driving force behind severe asthma.

These immune cells, known as cytotoxic CD4+ tissue-resident memory T cells, accumulate in the lungs and appear to possess the molecular arsenal responsible for causing significant harm in men who develop asthma later in life.

“If you are male and you develop asthma after age 40, there’s a high chance this T cell population is in your lungs,” reveals LJI Research Assistant Professor Gregory Seumois, Ph.D., who co-led the study alongside LJI Professor Pandurangan Vijayanand, M.D., Ph.D.

The discovery of these pathogenic T cells was made possible through volunteers participating in the NHS-clinic-based WATCH study, which tracks hundreds of asthma patients across different ages, genders, and disease severities. This longitudinal study, combined with immune cell analysis, is forging new connections between asthma symptoms and immune cell activity.

Ramesh Kurukulaaratchy, BM, DM, FRCP, Associate Professor at the University of Southampton and researcher at the NIHR Southampton Biomedical Research Centre, and director of the WATCH study, emphasizes, “Once you understand the role of cells like these T cells better, you can start to develop treatments that target those cells.”

Scientists now aim to deepen their understanding of these cells and their role in asthma development, as they strive to bring personalized therapies to asthma patients.

New Research Shatters Old Beliefs: What Really Causes Asthma in Middle-Aged Men

So, how do these cytotoxic CD4+ tissue-resident memory T cells, referred to as “cytotoxic,” trigger asthma in older men? The issue might be attributed to a combination of immune cell “memory” and the absence of beneficial cells in the lungs.

These T cells are categorized as “memory” cells because they react to molecules that the body has encountered in the past. This type of immune cell memory is beneficial in defending the body against viruses and bacteria. Unfortunately, this same T cell memory becomes problematic for asthma patients. These misdirected T cells respond to harmless molecules like pollen and provoke a harmful inflammatory response.

New research suggests that asthma patients harboring these T cells in their lungs may be predisposed to hard-to-treat and potentially life-threatening asthma attacks.

The reason why these T cells tend to cause issues in older men remains a mystery. Gregory Seumois is keen on unraveling this mystery through LJI’s Center for Sex-Based Differences in the Immune System, noting, “We know that females have a different immune landscape. So we’re interested in investigating this question further.”

LJI graduate student Sara Herrera de la Mata employed single-cell RNA sequencing to gain further insights into immune cells in these patients. Her findings indicated that certain anti-inflammatory T cells, meant to counteract severe asthma symptoms, were scarce in airway fluid samples (BAL samples) from this patient group.

Instead, men who developed asthma later in life had an overwhelming presence of potentially harmful T cells. Typically, a diverse range of CD4+ T cell types should be found in their lungs, but for this group, more than 65 percent of their cells were cytotoxic CD4+ tissue-resident memory T cells.

“Normally, a doctor would give a severe asthma patient a steroid or biologics therapy to dampen their immune response, and that should be it,” says Herrera de la Mata, co-first author of the study. “But these cells may not respond to these treatments.”

“Normally, a doctor would give a severe asthma patient a steroid or biologics therapy to dampen their immune response, and that should be it,” notes Herrera de la Mata, who served as co-first author of the study. “But these cells may not respond to these treatments.

Identifying this imbalance of immune cells was a critical clue that this patient group represents a new subtype of asthma.

Breakthrough Holds Promise for Tailored Asthma Therapies

The sequencing work at LJI has provided scientists with a “biomarker” to aid in the detection of cytotoxic CD4+ tissue-resident memory T cells in more patients in the future.

This discovery marks a “paradigm shift” in asthma research, according to Ramesh Kurukulaaratchy. Previously, scientists and clinicians categorized asthma patients into just two groups: “T2 high” and “T2 low.” This oversimplified categorization wasn’t beneficial for patients or clinicians. It failed to account for the diversity of patient demographics and symptoms within the T2 high category.

“We’ve studied a subgroup of male patients who developed asthma later in life—and they do badly. They need a lot of treatments, such as high doses of toxic steroid treatments,” notes Kurukulaaratchy.

In a study published earlier this year, the research team emphasized the importance of identifying numerous asthma patient subgroups. Their analysis revealed that 93 percent of WATCH subjects with severe asthma fell into the T2 high category, which is far too broad to effectively guide individualized treatment strategies.

S. Hasan Arshad, MBBS, DM, FRCP, Chair in Allergy and Clinical Immunology at the University of Southampton, researcher at the NIHR Southampton Biomedical Research Centre, and Director of The David Hide Asthma and Allergy Research Centre, Isle of Wight, stresses the need for tailoring treatments according to these subtypes, emphasizing that “one size does not fit all.”

The researchers’ ongoing mission is to employ sequencing tools and other methods to identify additional biomarkers and asthma patient subtypes. Gregory Seumois anticipates continued collaboration with Southampton scientists and the WATCH cohort, with plans to explore immune cells in various patient groups, including those from understudied demographic groups like African American and Hispanic patients, who are known to have a higher risk of developing severe asthma.

The research findings were published in the journal Med.

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