by University of Pittsburgh

Mouse lymph node with hotspots of IL2 activity circled. Credit: Kun He

New research from the University of Pittsburgh uncovers how inhaled house dust mites, a common trigger of allergic asthma, activate the immune system and drive this disease in mice.

The findings, published recently in Nature Immunology, offer important insights into how seemingly harmless substances such as dust mites, pet dander and pollen can overcome the immune system to trigger allergic reactions and could eventually pave the way for identifying new therapeutics to treat and manage allergic asthma.

"We often think of the immune system as an army that fights the bad guys," said senior author Amanda C. Poholek, Ph.D., director of the Health Sciences Sequencing Core and assistant professor in the Department of Immunology at Pitt's School of Medicine.

"And while that's true, most of the time your immune system is not encountering pathogens but dealing with dust and pollen that you breathe in, plants and animals that you eat, and things that you touch in the environment. A big question that motivates my research is: How does our immune system know to respond to pathogens and not to self and the environment?"

When the immune system does this job correctly, it's known as immune tolerance. But when tolerance breaks down, typically harmless environmental allergens can activate T Helper 2 (T_H2) cells, which are a type of immune cell that drives inflammation in allergic asthma and other allergic diseases.

Allergic asthma is the most common form of asthma, characterized by symptoms such as coughing, chest tightness, shortness of breath and wheezing. This debilitating condition is on the rise worldwide and places a substantial burden on the health care system, according to Poholek.

To learn more about how allergens activate T_H2 cells and cause allergic asthma, Poholek and her team used a mouse model of the disease triggered by inhalation of house dust mites. This model is a more accurate representation of how humans encounter allergens compared to studies that used under-the-skin or systemic injections of allergen.

Using new tools that allowed them to track T_H2 cells and see exactly when they get activated and where they went, the researchers found that in response to inhaled house dust mite, a specific molecular pathway involving a protein called BLIMP1 was needed to generate T_H2 cells in the lymph node. These cells then move to the lung and drive disease. In contrast, when house dust mite is injected, that molecular pathway is not needed.

They also found that two signaling molecules, or cytokines, called IL2 and IL10 were required for expression of BLIMP1.

"IL10 is normally thought of as an anti-inflammatory cytokine, which dampens immune responses, so we were really surprised to find that it was actually promoting inflammation," said Poholek. "This finding opens that door to therapeutic options targeting IL10, which hadn't previously been considered, particularly for newly diagnosed patients."

According to Poholek, most patients with allergic asthma receive steroids, which treat the symptoms but not the root of the disease. There is a huge need for new treatments that allow early intervention before allergic asthma causes long-term damage to the airways.

When the researchers mapped the location of T_H2 activation in the lymph node, they were also surprised to find hotspots of IL2 activity.

"IL2 is a very prominent cytokine, so we expected that it would be dispersed throughout the lymph node," said Poholek. "Instead, we discovered that IL2 was localized to certain regions. Now, we have a lot more work to figure out how these regions form and whether disrupting these regions could disrupt the formation of T_H2 cells, halting allergic asthma."

In collaboration with colleagues in the Pitt Division of Pulmonology, Allergy, Critical Care and Sleep Medicine, Poholek is also planning to look at lung tissue samples to investigate whether IL2 and IL10 could also be important drivers of T_H2 cells in patients with allergic asthma and explore potential avenues for developing new therapeutic options.

More information: Kun He et al, Spatial microniches of IL-2 combine with IL-10 to drive lung migratory TH2 cells in response to inhaled allergen, Nature Immunology (2024). DOI: 10.1038/s41590-024-01986-8

Journal information: Nature Immunology 

Provided by University of Pittsburgh