Chronic rhinosinusitis is different from allergies; it leads to serious inflammation and swelling in the sinuses that can last for years. That condition leads to difficulty breathing and abnormal tissue growth called polyps, which must be surgically removed. Those polyps grow from the cells that line the respiratory tract. Researchers at MIT have now learned more about the cellular processes that underlie chronic rhinosinusitis by creating a map of gene activity in barrier tissues when inflammation occurs.
“We saw major gene-expression differences in subsets of epithelial cells which had been previously obscured in bulk tissue analyses,” said Alex K. Shalek, the Pfizer-Laubach Career Development Assistant Professor of Chemistry, a core member of MIT’s Institute for Medical Engineering and Science (IMES), and an extramural member of the Koch Institute for Integrative Cancer Research, as well as an associate member of the Ragon and Broad Institutes.
“When you look across the entire transcriptome, comparing cells from patients with different disease statuses over thousands of genes, you can start to understand the relationships between them and discover which transcriptional programs have supplanted the usual ones,” Shalek added. (The transcriptome is a snapshot of genes that are being expressed at any moment).
This work, which was reported in Nature, may have implications for other inflammatory disorders that are seen in barrier tissues, like eczema, inflammatory bowel disease, and asthma.
The research team utilized a tool they created called Seq-Well to look at what was happening on the molecular level in individual cells. In this case, they studied cells harvested from chronic rhinosinusitis patients’ upper respiratory tract.
There were big differences between patients with and without polyps in basal epithelial cells. While that has previously been seen, now genes have been implicated in the process. Genes called IL-4 and IL-13, which are known to promote inflammation from allergies were found at excessive levels in polyp patients.
These basal cells are a type of stem cell that also retains a kind of memory of the IL-4 and IL-13 gene activity. That suggests that allergies are not only due to the memories that B and T immune cells have, but also because of basal cells. They also generate other respiratory tract cells, and may in turn influence how genes are expressed in those cells as well.
“Once you know that IL-4 and IL-13 act on stem cells, it changes the way in which you have to think about intervening, versus if they acted on differentiated cells because you have to erase that memory in order to bring the system back to homeostasis,” Shalek explained. “Otherwise you’re not actually dealing with a root cause of the problem.”
It’s important that factors other than immune cells are considered when studying chronic allergies, noted Shruti Naik, an assistant professor of pathology, medicine, and dermatology at New York University School of Medicine.
“They examined the tissue as a whole rather than biasing the study toward one cell type or another, and what they found is that other components of the tissue are irreversibly impacted by inflammation,” says Naik, who was not a part of this study.
This work could help drug developers aiming to treat chronic allergies. An antibody that blocks IL-4 and IL-13 has already been approved for the treatment of eczema.
“It suggests that blockade of IL-4 and IL-13 can help to restore basal cells and secretory cells towards a healthier state,” study author and postdoc Jose Ordovas-Montanes said. “However, there’s still some residual genetic signature left. So now the question will be, how do you intelligently target that remainder?”