Cellular Differences in Asthma Identified in First Lung Mapping Project

For the first time, the interactions of lung-resident structural and inflammatory cells have been profiled in both healthy individuals and those with asthma. The results of the analysis were published in Nature Medicine.

Researchers from the Wellcome Sanger Institute in Cambridge, United Kingdom, used healthy human respiratory tissue from nasal brushes, endobronchial biopsies, and brushes from living donors, and tissue samples and transplant lungs from deceased donors. They discovered a diversity of epithelial, endothelial, stromal, and immune cells, all of which can be viewed in a web portal online.

A broad range of airway epithelial cell types contributed to the chronic inflammation and airway remodeling related to asthma; analysis of the asthma genome-wide association study (GWAS) gene expression particularly highlighted an interleukin 4/interleukin 13-induced change in mucous ciliated cells (which have themselves demonstrated expression of key asthma genes) that led to a metaplasia in mucus cells in this process. In the immune and stromal cell populations of the bronchial biopsies, B and T cells, neutrophils, macrophages, dendritic cells, mast cells, fibroblasts, smooth muscle cells, and endothelial cells were present.

Mast cells have been associated with increased disease severity. The researchers found that this may be a result of accumulation in type 2 helper T cells (T_H2) CD4 T cells via expression of a biosynthesis enzyme, which makes mast cells the major producers of prostaglandin 2. Two distinct cell states of each basal, goblet, and ciliated epithelial cells were also identified. In addition, when the researchers excluded the widely expressed HLA genes from their analysis, fibroblasts and CD4 T cells expressed the highest number of asthma GWAS genes, which are mostly upregulated in asthma. Researchers noted that specifically, T_H2 CD4 T cells were significantly increased in the airway walls of patients with asthma, with no difference to other T-cell subsets, and were also more likely to express more cytokines and transcription factors that are associated with increased inflammation.

Further, the researchers explained that they were able to identify potential airway cell-cell interactions and determine their changes in asthma. Some changes were specific to the diseased or healthy states. In healthy individuals, lung structural cells (eg, mesenchymal and epithelial cells) were the most predominant cell-cell interaction: they are known to communicate both with one another and with tissue-resident memory and tissue migratory CD4 T cells. However, in individuals with asthma, the number of interactions was substantially lower between epithelial and mesenchymal cells. The cell-cell interactions in people with asthma were predominated by T_H2 cells. In addition, T_H2 cells also increased interactions with other immune cells, epithelial cells, mesenchymal cells, fibroblasts, and smooth muscle cells, and an array of growth factor receptors related to these cells, all of which are known to play a part in asthma pathophysiology.

“Unbiased analysis of cell-cell interactions identifies a shift from airway structural cell communication in healthy lungs to a T_H2-dominated interaction in asthmatic lungs,” the researchers wrote. “This global view of the airway wall cellular landscape opens up new perspectives on lung biology and molecular mechanisms of asthma.”

Disclosures: Drs Affleck and van Oosterhout are employees of GlaxoSmithKline, and Drs Berg, Carpaij, Brouwer, van den Berge, and Nawijn received project funding from GlaxoSmithKline.

Reference

Vieira Braga FA, Kar G, Berg M, et al. A cellular census of human lungs identifies novel cell states in health and in asthma [published online June 17, 2019]. Nat Med. doi:10.1038/s41591-019-0468-5