Research Reveals Novel Molecular Mechanisms Specific to Allergic Asthma

Physician-investigators at Massachusetts General Hospital recently published findings in Science Immunology that offer novel insights into pathways that distinguish the airway response to allergen in allergic asthmatics from that in allergic individuals without asthma.

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"Current asthma treatments broadly focus on addressing the symptoms but not modifying the disease," says Jehan Alladina, MD, first author of the paper and a physician in the Division of Pulmonary and Critical Care Medicine at Mass General. "Our research reveals molecular mechanisms that distinguish allergy alone from asthma pathobiology, with the ultimate goal of translating these findings into therapies that can lead to disease remission."

Identifying the Mechanisms Underlying an Incurable Condition

Asthma is among the most common non-communicable diseases, affecting over 260 million people worldwide and representing a substantial cause of premature death and reduced quality of life. Data from 2020 reported asthma affecting over 25 million individuals in the U.S., including over 3.8 million school-aged children.

Although allergic inflammation in the lower airways is seen in both allergic asthmatics and allergic non-asthmatics, asthmatics additionally demonstrate mucus production, airway reactivity and airway remodeling.

Efforts to identify asthma-specific biomarkers have revealed multiple phenotypes related to differences in asthma onset and type of inflammation, with allergic asthma being the most common. However, many characteristics within these phenotypes overlap, and not everyone exposed to environmental allergens develops asthma. Moreover, baseline measurements of immune cell activity and infiltration before allergen exposure also tend to be similar between asthmatics and non-asthmatics.

"Both subsets of patients share common hallmarks of allergic inflammation, including infiltrating eosinophils and T cells," explains Benjamin Medoff, MD, senior author on the paper and principal investigator in the Division of Pulmonary and Critical Care Medicine. The major distinguishing factor between responses involves structural changes to the airways that occur due to sustained type 2 inflammation only observed in asthmatics.

"In this study, we applied methods that allowed us to examine the phenotypic differences associated with these structural changes and determine where and how these pathways diverge," Dr. Medoff says. "Our expertise with the in vivo model of asthma exacerbation and the availability of single-cell RNA sequencing (scRNA-seq) as an analytical technique allowed that level of investigation."

Capitalizing on Powerful Research Methods

A previous collaboration between Dr. Medoff and Andrew Luster, MD, PhD, chief of the Division of Rheumatology, Allergy and Immunology at Mass General, employed bronchoscopic segmental allergen challenge (SAC) to reveal subtle differences in the inflammatory response between airways of asthmatics and non-asthmatics (published in Science Translational Medicine).

The SAC model enables administration of allergen in a segment of the lung and in a controlled manner. Following a pre-challenge bronchoalveolar lavage (BAL) to establish baseline measurements, different areas of the lung undergo challenge with control solution or allergen. After 24 hours, BAL samples are collected from these sites for subsequent analyses.

In addition to control and experimental BAL samples, the present study performed endobronchial brushings at each site to obtain samples of the airway mucosal lining.

"Because the airway mucosa harbors both epithelial and immune cells, we expected these samples would offer key insights into variations in both the inflammatory response and structural phenotype between patient subsets," says Dr. Alladina.

These samples were then evaluated using scRNA-seq to identify transcriptional differences between individual cells according to each intervention and patient profile. In the case of hyperresponsive immune cells, comparing the transcriptomes of single cells can highlight subtle differences in gene expression and signaling pathways not obtainable using traditional methods.

Dr. Alladina explains that the ability of certain immune cells to alter their phenotype according to their local environment signifies a level of plasticity that could not be appreciated without this advanced technique. "Using this method not only allowed us to identify multiple interconnected pathways driving the responses in asthmatic airways, but also offered novel insight into the mechanisms underlying how non-asthmatics avoid the pathogenic phenotype."

Revealing Distinct Pathways Associated With the Asthmatic Response

The findings constitute the first detailed identification of cell subsets and their respective transcriptomes in the lower airways of asthmatics and non-asthmatics subjected to allergen challenge. Furthermore, comparison of these profiles revealed potential pathways related to the observed phenotypic differences in the inflammatory response between the two patient groups.

The following results were highly specific to the asthmatic response:

• Altered transcription in airway epithelial cells (AECs) to promote inflammatory cell recruitment and signaling, mucus production, and tissue remodeling
• Increased populations of pathogenic T cells expressing pro-inflammatory cytokines and receptors for ligands supporting polarization to a pro-inflammatory phenotype
• Enrichment of immune cell subsets that sustain type 2 inflammation
• Polarization of monocyte-derived cells into an activated, pro-inflammatory phenotype that may also contribute to airway remodeling

Notably, baseline measurements of both transcriptional profiles and cell populations demonstrated minimal differences between groups before SAC. Additionally, post-challenge outcomes observed in non-asthmatics were underrepresented in asthmatics, suggesting that type 2 cytokines might "reprogram" pathway activation in asthmatics toward airway inflammation and remodeling.

"One of the particularly exciting aspects of the results was a recognition of the crosstalk between airway epithelial and immune cells, and how this specific interaction may drive the distinction between asthmatics and non-asthmatic controls," says Dr. Alladina.

"Part of our ongoing work involves determining why airway epithelial cells in asthmatics demonstrate a much greater response to allergen and allergic inflammation compared to non-asthmatics," Dr. Alladina explains. "One hypothesis is the existence of epigenetic programming that may confer a level of "inflammatory memory" enabling these cells to sense and respond to microenvironmental changes in a context specific to asthma."

A Training Environment Built to Tackle Intractable Diseases

Dr. Alladina emphasizes the opportunity to undergo training in Dr. Medoff's lab, as well as access to the Mass General ecosystem, as invaluable to her growth as a physician-investigator.

"Mass General is one of only a handful of places in the world where SAC is performed, which is a direct reflection of the outstanding scientists and infrastructure that facilitate the use of this method," she says. "The benefits of being able to train with world-leading experts in this technique and perform translational research in patients this early in my career are invaluable."

Similarly, Dr. Medoff credits an ability to continuously drive cutting-edge research to the outstanding trainees attracted to Mass General by its reputation. In fact, this study was a continuation of work by Josalyn Cho, MD, who recently transitioned to University of Iowa Health Care.

Dr. Alladina adds that the value Mass General confers on physician-led research offers early investigators a unique perspective on their roles as both clinicians and scientists. "My role as a physician informs how I identify the clinically relevant research questions and findings that are most likely to directly impact patients," she explains. "That perspective reinforces the importance of time spent with patients and how that translates to my research."

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