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Aug. 23 (UPI) -- Researchers have found the source of chronic allergic inflammation in the sinus: epithelial cells that line the respiratory tract. Performing genome-wide analysis of thousands of single cells from human patients, researchers at MIT and Brigham and Women's Hospital determined why people have chronic rhinosinusitis and some develop nasal polyps. Their findings were published Wednesday in the journal Nature.
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Besides potentially leading to better treatment for chronic rhinosinusitis, researchers also believe the finding could help patients with chronic inflammatory diseases of barrier tissues, such as asthma, eczema, and inflammatory bowel disease.
"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," Dr. Alex K. Shalek, an assistant professor of chemistry at MIT, said in a press release.
Chronic rhinosinusitis, unlike seasonal allergies, causes the sinuses to become inflamed and swollen for several years. Patients have difficulty breathing and have other symptoms. While this condition produces tissue outgrowths, known as nasal polyps, they may have to be removed surgically.
"We saw major gene-expression differences in subsets of epithelial cells which had been previously obscured in bulk tissue analyses," Shalek said.
The MIT and Brigham and Women's researchers last year developed portable technology, known as Seq-Well, for rapid sequencing of the RNA contents of several thousand single cells in parallel from tiny clinical samples. They were able to observe when transcriptional programs are turned on inside individual cells.
They applied this technology to cells from the upper respiratory tract of patients with chronic rhinosinusitis.
They noticed big differences in the genes expressed in basal epithelial cells from patients with and those without nasal polyps. Normally, these cells form a flat base layer of tissue that coats the inside of the nasal passages. But in patients with polyps, they begin to pile up and form thicker layers instead of differentiating into epithelial cell subsets for host defense.
These basal cells from patients with polyps had turned on a specific program of gene expression. It appears to be sustained directly by IL-4 and IL-13, immune response cytokines known to drive allergic inflammation when overproduced at pathologic levels. These basal cells also retain a "memory" of their exposure to IL-4 and IL-13.
Unstimulated cells from patients with polyps expressed many of the genes that were induced in those without polyps when they removed basal cells from nonpolyps and polyps, grew them in equivalent conditions for a month and then exposed them to IL-4 and IL-13.
Genes from a cell signaling pathway known as Wnt controls cell differentiation. The researchers found the cells memory may influence their subsequent patterns of gene expression and ability to generate mature specialized epithelial cells.
"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 said. "Otherwise you're not actually dealing with a root cause of the problem."
Researchers believe that chronic rhinosinusitis can be treated by blocking the effects of IL-4 and IL-13.
They validated their hypothesis by using an antibody that blocks a common receptor for the two cytokines, which has already been approved to treat eczema and is undergoing tests for other uses.
The researchers treated one patient who had polyps with the antibody. They found most, but not all, of the genes stimulated by IL-4 and IL-13 returned to normal expression levels.
"It suggests that blockade of IL-4 and IL-13 can help to restore basal cells and secretory cells towards a healthier state," said Dr. Jose Ordovas-Montanes, a Medical Engineering and Science postdoctoral fellow. "However, there's still some residual genetic signature left. So now the question will be, how do you intelligently target that remainder?"
The researchers plan to develop additional drugs by further studying molecular mechanisms of how basal cells store inflammatory memory.
In addition, they are studying inflammatory diseases in other parts of the body, such as inflammatory bowel disease, where inflammation often leads to polyps that can become cancerous.
