Severe eosinophilic asthma is a type of asthma that is driven by an overactive immune response, particularly involving certain immune cells called eosinophils. For patients with this condition, managing symptoms often requires systemic medications like corticosteroids and biologics that target specific immune pathways. While these treatments, especially those targeting type 2 cytokines (like IL-4, IL-5, and IL-13), have proven effective in controlling symptoms, the exact molecular mechanisms behind their success have been unclear.
Researchers at the Seoul National University aimed to better understand how biologic treatments, which block key immune signals, affect the gene expression of immune cells in patients with severe eosinophilic asthma. The researchers used a powerful technique called single-cell RNA sequencing (scRNA-seq) to look at the gene expression in individual immune cells from the blood of eight patients before and after treatment with different biologics, such as mepolizumab, reslizumab, or dupilumab. This technique allows scientists to see how the immune cells are changing at a very detailed level.
Changes in the transcriptional profiles of blood immune cells
at least one month after treatment with biologics
a Experimental design illustrating the sample preparation for the study. b UMAP plots of all cells classified into T/NK cells, myeloid cells, B cells, or platelets and separated according to treatment duration. c UMAP plots showing the subtypes of myeloid cells (left panel) and their distributions according to treatment duration (right panel). d Line plots displaying the frequencies of myeloid cell subtypes, where the x-axis represents the treatment duration and the y-axis represents the frequency. Each line type represents a patient, and the colors indicate the biologics with which they were treated: mepolizumab/reslizumab or dupilumab. Asterisks denote significant differences between the two treatment durations with an FDR of 0.01. e Dot plots showing the top 5 highly expressed genes in IL-1B+ CMs (first five) and S100A+ CMs (last five) compared with other myeloid cell subtypes.
What Did the Researchers Find?
The study found that, overall, biologic treatment had significant effects on the way immune cells in the blood expressed their genes. Here’s a breakdown of what happened:
- Immune Cell Types:
The treatment didn’t significantly change the overall proportions of T cells, natural killer (NK) cells, myeloid cells, or B cells. However, there was a notable change in a specific type of immune cell known as classical monocytes (CMs).- IL1B+ CMs (a subgroup of monocytes) decreased.
- S100A+ CMs (another subgroup) increased.
- Gene Expression Changes:
The most striking finding was that biologic treatment caused a downregulation of the NF-κB pathway, a critical pathway involved in inflammation. This pathway controls a lot of immune responses, and its reduction indicates that the immune cells were less active and less inflammatory after treatment. Specifically:- The genes linked to the NF-κB pathway were suppressed in T/NK cells, myeloid cells, and B cells.
- Time-Dependent Changes:
After just one month of treatment, there were no major changes in gene expression. However, by the six-month mark, the researchers observed clear shifts in how the immune cells were functioning. This suggests that the effects of biologic treatments on immune cell gene expression may take time to fully manifest.
What Does This Mean?
The findings highlight that biologics targeting type 2 cytokines, like IL-4, IL-5, and IL-13, not only reduce the number of eosinophils but also lead to broader changes in immune cell behavior. The suppression of the NF-κB pathway across different types of immune cells helps explain the clinical improvement seen in patients. It indicates that biologics help “calm down” the immune system by interfering with a key pathway involved in inflammation.
However, despite these positive changes, the exact link between these molecular shifts and long-term clinical outcomes, like symptom control and lung function, is still unclear. Further research is needed to identify potential biomarkers that could help predict which patients will benefit most from biologic treatments and how these treatments affect long-term outcomes.
Next Steps
The study calls for more research into the specific molecular changes induced by biologic treatments in severe eosinophilic asthma. Understanding these changes could help improve patient care by identifying biomarkers that predict treatment response and by offering insights into the long-term effectiveness of biologic therapies.
As biologic treatments continue to evolve, these findings may help doctors refine their approaches to asthma treatment, ultimately improving the quality of life for patients living with this challenging condition.