New Research Suggests NK Cells, T Cells, Have Possible Role in Pathophysiology of Systemic Sclerosis Associated Interstitial Lung Disease

New research findings from a team in the UPMC Division of Rheumatology and Clinical Immunology and the University of Pittsburgh School of Medicine suggest that cytotoxic natural killer (NK) cells, CD8+ T cells, and regulatory T (Treg) cells might play critical roles in the autoimmune pathology of systemic sclerosis-associated interstitial lung disease (SSc-ILD). This new evidence comes from observing elevated numbers of these cells found in human explant lung tissues of patients with SSc-ILD compared to human lung tissue from healthy controls.

The study, published in the journal Rheumatology (Oxford) in June 2023, was led by Cristina M. Padilla, MD, clinical instructor and T32 postdoctoral research associate. Robert Lafyatis, MD, professor of medicine and director of the UPMC and University of Pittsburgh Scleroderma Center, was the study's senior author.

Study Highlights and Findings

Systemic sclerosis is a heterogeneous autoimmune disease leading to pronounced levels of systemic inflammation and fibrosis. SSc mainly affects the skin and organs, including the lungs. Interstitial lung disease (ILD) is a frequent and severe manifestation of SSc and is the leading cause of death in patients with the disease.

In general, lymphocytes are thought to contribute to the abnormal immune response in SSc. Previous studies focused on analyzing these cells in the blood and skin of patients. They found various changes, such as a rise in specific T cells (CD4+), a decrease in others (CD8+), and inconsistent findings for regulatory T cells (Tregs) – immune cells known to control harmful immune responses.

Dr. Padilla and colleagues' new research is the first to examine cell populations directly within lung tissue from patients with SSc to characterize the cellular landscape and possible cell-cell interactions and signaling expressions.

“This is important because we are getting a first glimpse within lung tissue itself of cell populations that may be active and could be responsible for lung destruction in the setting of SSc,” says Dr. Padilla.

In the new study, Dr. Padilla’s team observed unusually high activity of NK cells in the lungs of patients with SSc-ILD. These NK cells produced large amounts of interferon-gamma, which can stimulate the immune response and cause damage to the lungs. Furthermore, these activated NK cells can influence other immune cells and indirectly cause damage.

A significant finding from the study was the increased production of a molecule named amphiregulin by NK cells in SSc-ILD patients. Amphiregulin interacts with a protein on the surface of cells called the epidermal growth factor receptor. The rise in amphiregulin might encourage the growth of certain lung cells, a common feature in SSc-ILD lungs.

The research also highlighted an expansion of specific T cells (CD8+ tissue-resident memory T cells, or TRMs) in the lungs of patients with SSc-ILD. These cells can persist in tissues and may contribute to lung inflammation and scarring.

Interestingly, contrary to most previous studies showing fewer Tregs in SSc patients, Dr. Padilla’s study found more Tregs in SSc-ILD. This might be due to the movement of Tregs from the blood to the lung tissue in these patients.

The findings from the study open new avenues for understanding SSc-ILD. It suggests that activated NK cells, CD8+ T cells, and Tregs may play a crucial role in the propagation of ILD. Understanding which kinds of cells and their signaling are at play may guide the development of new treatment approaches for SSc-ILD that target the cells most responsible for ILD.

“Given the limited pharmaceutical options we currently have available to treat SSc patients and knowing that what we have available does not work for everyone or is only modestly efficacious in slowing disease progression, new cellular and molecular targets for translational research are crucial,” says Dr. Padilla. “Seeing which cell types are actively working to promote disease in human lung tissues is crucial to that investigative process.”

Reference

Padilla CM, Valenzi E, Tabib T, Nazari B, Sembrat J, Rojas M, Fuschiotti P, Lafyatis R. Increased CD8+ Tissue Resident Memory T Cells, Regulatory T Cells and Activated Natural Killer Cells in Systemic Sclerosis Lungs. Rheumatology. 2023; 00, 1-9. Online ahead of print.

More About Dr. Padilla

Dr. Padilla earned a Master of Science in Biomedical Forensic Sciences from Boston University and then earned her medical degree from the University of Texas Southwestern Medical School. She conducted her residency training at the University of Rochester-Strong Memorial Hospital, followed by her rheumatology fellowship at the University of Pittsburgh, immediately before joining the Division as a clinical instructor and T32-supported postdoctoral associate.

From an early age, Dr. Padilla says medicine was her calling, and her initial interests and plans were to pursue work as a forensic pathologist. However, while working on her master’s degree, she also became a research coordinator at Boston University in the Rheumatology division, primarily working in the laboratory of Dr. Lafyatis before he joined the University of Pittsburgh.

Dr. Padilla’s initial work in the lab led to further interest in pursuing research and ultimately moving toward becoming a physician-scientist concentrating in the field of rheumatology.

“My experiences working in Dr. Lafyatis’ lab in Boston were transformational. I got more involved in the work they were conducting in scleroderma and lupus and began to take on additional responsibilities as a research assistant working on clinical trials, protocols, and other investigations, one of which utilized an investigational drug, fresolimumab, provided by Genzyme,” says Dr. Padilla.

Through this work, Dr. Padilla became more interested in rheumatology as a possible career path because of the interesting nature of the research and her interactions with scleroderma patients while working in the lab.

"I knew that I wanted to be heavily involved with research after my medical training, but I also wanted to be invested in day-to-day patient care," explains Dr. Padilla. "I wanted to be able to care for these patients facing a lot of challenges with a rare and chronic disease, but also say to them, 'here's what we're working on in the lab to figure out your condition, here are new clinical trials and investigational drugs that are being developed, we're going to be partners through this whole process.’"

During residency training and subsequent fellowship, Dr. Padilla's work began to concentrate on scleroderma, particularly translational research related to ILD that often accompanies SSc and remains the number one cause of death among these patients.

“Coming to the University of Pittsburgh and UPMC for fellowship was a natural choice,” says Dr. Padilla. “My prior work with Dr. Lafyatis in Boston was a factor, and the fact that UPMC and the University of Pittsburgh house probably the largest and most esteemed clinical and research centers for scleroderma in the U.S.”

At present, Dr. Padilla is focused on lymphocyte research in SSc-ILD, and the findings from this latest paper will propel her investigational efforts to dig deeper into how natural killer cells and T cells work within the lungs of SSc patients to drive ILD.

"We have new studies in progress along these lines," says Dr. Padilla. "We need to learn more about how this disease process works to find pathways that could lead to much more effective therapeutics that can prevent or stop the process of lung damage in our patients. If we can do that, we will greatly impact this disease.”