Highlights:
Scientists at the La Jolla Institute for Immunology (LJI) investigated the role of specialized "tissue-resident" immune cells in inflammation and disease development.
The researchers found that these cells , which reside in the lungs, express a range of genes associated with autoimmune disease risk.
These immune cells may actively drive the development of autoimmune diseases that can affect the lungs, such as rheumatoid arthritis and lupus.
The researchers uncovered stark differences when they compared lung tissue-resident immune cells from female and male study volunteers—and they found genes which may be connected to the often higher risk of autoimmune disease in women.
LA JOLLA, CA—A massive analysis of immune cells in human tissue is yielding clues to the root cause of lung and autoimmune diseases.
In a new Nature Immunology study, LJI scientists analyzed more than 1.1 million immune cells found in the lungs of 128 human study volunteers. These immune cells are considered "tissue-resident" cells, and they reside in the lungs to defend the body from respiratory infections, disease, and even lung cancer. In recent years, scientists have shown that these tissue-resident immune cells show substantial differences to immune cells circulating in the blood.
Immune cells are meant to protect the body from harm, but for some people, tissue-resident immune cells in the lungs can be dysfunctional and cause inflammation in the lungs. Patients with autoimmune diseases such as lupus, rheumatoid arthritis, or scleroderma often have chronic lung inflammation.
So what makes good immune cells turn bad?
The LJI researchers discovered that these immune cells can express certain genes associated with genetic risk factors linked to lung and autoimmune diseases. These genes may put tissue-resident immune cells on a path to become dysfunctional, unable to prevent—or actively causing—disease.
"This is a foundational paper for any researcher asking whether genetics has a role in an autoimmune disease," says LJI's William K. Bowes Distinguished Professor Pandurangan Vijayanand, M.D., Ph.D.
How the new study worked
The researchers worked with healthy sections of lung tissue samples donated by 128 patients newly diagnosed with lung cancer and undergoing surgery. Lung tissue samples and extensive clinical metadata were obtained from participants enrolled in the Target Lung study, led by University of Liverpool Professor Christians Ottensmeier, MD, Ph.D.
This work was part of the Database of Immune Cell Epigenomics ( DICE ) project, where scientists connect genetic variations to immune cell function. The overall DICE mission is to shed light on why some people are more susceptible to autoimmune disease, infectious diseases, and other conditions.
For the new study, LJI researchers used a technique called single-cell RNA-seq to study gene expression in each patient's tissue-resident immune cells. This kind of analysis allows scientists to learn how different immune cells function, find genetic factors that affect their protective role, and better understand what might be going wrong in cases of chronic inflammation and disease.
"We analyzed thousands of immune cells from lung tissue for each study volunteer," says LJI Assistant Professor Benjamin Schmiedel, Ph.D. . "No study has produced and analyzed a dataset at this scale and resolution before."
The enormous scope of this study also allowed the scientists to uncover around 1,000 genes impacted by genetic factors specifically. These genetic differences appeared in tissue-resident immune cells and were not detected in immune cells studied in the blood.
Scientists uncover sex-based differences
The researchers also uncovered intriguing differences between female and male study volunteers: 1,700 genes showed a sex-based difference in their expression levels and may play important roles in the development of infectious and autoimmune diseases.
In fact, several of these genes are associated with cellular pathways that contribute to inflammation. These same genes often showed sex bias, meaning they were more highly expressed in individuals of one sex. This finding is especially interesting because most autoimmune diseases are more common in female patients.
This research suggests that tissue-resident immune cells behave very differently in lung tissue, compared to circulating cells in the blood, and these cells work differently depending on whether a person is male or female.
The scientists emphasize that more analysis needs to be done to gain a deeper understanding of how tissue-resident immune cells influence disease development in the lungs. Fortunately, the DICE project offers LJI scientists a unique window into immune cell function in volunteers of different ages, sexes, and genetic backgrounds. "DICE is a rich resource," says Vijayanand.
Publication details:
Additional authors of the study, " Tissue-resident immune cells drive genetic risk in autoimmune and lung diseases ," are Cristian Gonzalez-Colin, Vicente Fajardo-Rosas, Job Rocha, Hayley Simon, Johannes Ottensmeier, Ignacio E. Ramírez-Bernabé, April Cano, Angel De la Cruz Castillo, Elizabeth Márquez-Gómez, Brendan Ha, Jason A. Greenbaum, Lindsey Chudley, Judith Cave, Aiman Alzetani, Edwin Woo, Michael Shackcloth, Serena J. Chee, Vivek Chandra, Mitchell Kronenberg, Bjoern Peters, Christian H. Ottensmeier, and Anusha-Preethi Ganesan
This research was supported by the National Institute of Health (grants R24 AI108564, K08 CA230164, R21 AI173927, S10 RR027366, and S10 OD026929), the William K. Bowes, Jr. Foundation, Kyowa Kirin, Inc. (KKNA-Kyowa Kirin North America), Wessex and North West Coast Clinical Research Networks, and the National Institute of Health Research, UK.
