Single-Cell Profiling Reveals Insights About Immunity in Idiopathic Pulmonary Fibrosis

Possible immune cell responses in idiopathic pulmonary fibrosis (IPF), a chronic and deadly lung disease characterized by lung scarring, have been suggested for years. Yet, until now, detailed profiles of these cells have been lacking.

In a new study, published in the American Journal of Respiratory and Critical Care Medicine, researchers used single-cell RNA sequencing to measure the gene expressions of individual peripheral blood mononuclear cells in patients with progressive IPF, patients with stable IPF, and lung-disease-free patients. Previously, the researchers had studied bulk samples of these cells but not examined them individually and in detail.

"Using this state-of-the-art single-cell profiling technology on around 10 to 20,000 cells per patient, we applied a very advanced method to get the profile of every cell,” said Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals, Inc. Professor of Medicine (Pulmonary). “We applied cutting-edge computer science and deep learning methods in this computationally intensive process.”

The multidisciplinary team was able to obtain detailed profiles of monocytic cells, building on prior studies from the Kaminski Lab showing that this type of immune cell is higher in patients with IPF, and even higher in individuals with progressive IPF, Kaminski said.

One unexpected finding was an elevated level of regulatory T-cells (Tregs), a type of white blood cell that controls inflammation, in those with progressive IPF.

“Unlike most types of lymphocytes that decrease in progressive compared to stable IPF, Tregs are actually increased in progressive disease, both in the blood and the lungs,” said first author Avraham Unterman, MD, MBA, formerly of the Kaminski Lab, who currently leads the Pulmonary Fibrosis Center and Genomic Research Laboratory for Lung Fibrosis at Tel Aviv Medical Center. “They interact with most immune cells in the IPF lung and are likely involved in disease pathogenesis.”

The researchers used data from the study to create a model of the interplay between cells of the peripheral immune system and the lung. To accelerate advancements, before publishing their results the team made their findings publicly available through the ILD Immune Cell Atlas, a multi-institutional collaboration that seeks to facilitate the exploration of single-cell RNA sequencing datasets related to IPF through an accessible web tool.

“Through these efforts, we provided the first comprehensive single-cell peripheral blood atlas for idiopathic pulmonary fibrosis, revealing key differences in cell populations associated with disease progression and proposing mechanisms for how these immune cells contribute to lung fibrosis,” said Amy Zhao, an MD/PhD student in the Kaminski Lab. “Seeing how these findings relate to the disease mechanisms and severity prediction in idiopathic pulmonary fibrosis was particularly enlightening."

“In addition to the IPF cell atlas we have previously published, we now have comprehensive, detailed maps of what’s happening in the immune system available to investigators all over the world,” Kaminski added.

Kaminski emphasizes that this type of translational research could not have been done without the collaboration among clinicians, immunologists, molecular biologists, and genomics experts from many institutions.

“Through our joint efforts, we are providing evidence that our findings are worth analyzing further to gain insights about IPF,” he said. “This new data should encourage the research community to better understand immune cells with the aim of developing new precision therapies.”

The Section of Pulmonary, Critical Care and Sleep Medicine is one of the eleven sections within Yale School of Medicine’s Department of Internal Medicine. To learn more about Yale-PCCSM, visit PCCSM's website, or follow them on Facebook and Twitter.