Investigating the Role of Natural Killer Cells in Systemic Sclerosis ILD
April 3, 2025
Cristina Padilla, MD, assistant professor of Medicine in the Division of Rheumatology and Clinical Immunology at the University of Pittsburgh, focuses on systemic sclerosis, particularly its complications in the lungs. Her research explores how immune cells contribute to interstitial lung disease (ILD) in systemic sclerosis, with a particular emphasis on natural killer (NK) cells and their role in disease progression.
In addition to her research, Dr. Padilla is actively involved in patient care, treating individuals with systemic sclerosis and other complex autoimmune diseases. Through her work in both research and clinical settings, she is aiming to improve understanding of systemic sclerosis and expand available treatment options for affected patients.
Dr. Padilla’s research is centered on understanding how natural killer (NK) cells contribute to the progression of systemic sclerosis ILD. Her work builds on a study she and her colleagues published in 2023 that provided the first in-depth look at T cells and NK cells derived directly from lung tissue samples of patients with systemic sclerosis. That study found that NK cells in diseased lung tissue exhibited an activated and cytotoxic phenotype compared to NK cells from healthy lungs.
"What we observed was unexpected," says Dr. Padilla. "Previous studies of NK cells in systemic sclerosis relied on blood samples, which suggested a different, often conflicting picture of their role in the disease. Our study demonstrated that what happens at the tissue level may be vastly different from what we see in blood samples.”
This discrepancy between blood and lung tissue findings highlights a significant challenge in systemic sclerosis research – understanding how immune cells behave at the actual site of disease pathology.
A critical factor that enables this research is the ability to obtain lung tissue samples from patients with systemic sclerosis ILD. At UPMC, a collaboration between the Rheumatology Division, the Simmons Center for Interstitial Lung Disease, and the lung transplant team has created a system that allows researchers like Dr. Padilla to access these invaluable samples.
"Pittsburgh has a long history of being at the forefront of lung transplantation for systemic sclerosis patients. Our ability to obtain lung tissue from transplant recipients gives us a rare opportunity to study this disease at the level where it matters most," says Dr. Padilla. "Without access to these tissues, we would be limited to studying blood samples, which as we are finding out do not always reflect what is happening in the lungs."
Characterizing the Function of NK Cells in Fibrosis and Autoimmune Activity
One of the objectives of Dr. Padilla’s ongoing research is to characterize the phenotype and function of NK cells in systemic sclerosis ILD and determine their role in fibrosis. The challenge is that NK cells have been reported to exhibit both protective and pathogenic effects in autoimmune diseases, making it difficult to define their precise contribution to SS-ILD.
"Some studies suggest that NK cells help regulate the immune response and may even limit fibrosis, while others indicate that they drive inflammation and tissue damage," says Dr. Padilla. "We are trying to determine where they fall in SS-ILD. Are they contributing to the fibrotic process, or are they playing a regulatory role that we need to harness therapeutically?"
To answer these questions, Dr. Padilla and her colleagues have adopted a two-part approach using tissue level characterization and computational analysis of gene regulation.
For work related to tissue-level characterization, Dr. Padilla and the team have developed and continue to refine protocol to isolate NK cells from lung tissue. This approach enables her and the team to study the cells directly in their disease-relevant environment rather than relying on blood-derived NK cells, which, as noted previously, may not reflect the true immunological landscape of the disease at the tissue level.
Using high-throughput sequencing techniques, Dr. Padilla is analyzing gene expression and chromatin accessibility in NK cells from systemic sclerosis ILD lung tissue.
"We have identified transcription factors that appear to be regulating NK cell behavior in systemic sclerosis ILD," says Dr. Padilla. "By understanding which genes are turned on or off in these cells, we can start to piece together their role in disease progression."
One observation has been the differential expression of genes associated with interferon signaling, a pathway known to be involved in systemic sclerosis.
"We see that certain transcription factors are much more active in NK cells from systemic sclerosis lungs than in controls. This suggests a fundamental shift in their regulatory program, which could be influencing their activation and cytotoxic function," says Dr. Padilla.
Clinical Implications: A Potential Therapeutic Target
Dr. Padilla’s research could have important implications for systemic sclerosis treatment strategies. If NK cells are indeed driving fibrosis, targeting them could be a viable therapeutic approach. Conversely, if they are found to have a protective role, then strategies to enhance their function could be explored.
"In oncology, NK cell therapies are already being used to target cancer cells," says Dr. Padilla. "We are now considering whether similar strategies could be applied to modulate NK cell activity in systemic sclerosis. If we can determine whether they are contributing to fibrosis or restraining it, then we can begin to think about therapeutic interventions."
Clinical Work: Advancing Systemic Sclerosis Patient Care
In addition to her research, Dr. Padilla is actively involved in patient care, specializing in systemic sclerosis and other autoimmune diseases. She has scleroderma clinics at UPMC Presbyterian (Falk Medical Building) and in Cranberry where she works closely with pulmonologists and transplant specialists to manage patients living with systemic sclerosis ILD.
Dr. Padilla also engages with the patient community beyond the clinic. She recently participated in the 2024 National Scleroderma Foundation’s annual conference, where she met with patients and provided education on systemic sclerosis ILD. She was also featured on the Mogil Podcast, a program focused on the experiences of individuals with systemic sclerosis and the latest research developments in the field.
"For many patients, being diagnosed with a rare disease can be isolating. These conferences and resources like the Mogil podcast provide not only education but also a sense of connection and support," says Dr. Padilla.
Academic Contributions and Mentorship
Beyond her clinical and research roles, Dr. Padilla is contributing to the broader academic field. She, along with division colleague Robyn Domsic, MD, MPH, recently co-authored a chapter on systemic sclerosis for the upcoming 11th edition of Cecil Essentials of Medicine, a widely used medical textbook. Additionally, she was recently selected for the Burroughs Wellcome Fund Physician-Scientist Incubator Program, which supports early-career MD-only physician-scientists.
"This program has been invaluable in providing mentorship and resources as I continue to build my research career," says Dr. Padilla. "Being a physician-scientist requires a unique balance between clinical work and research, and having institutional support makes all the difference."
Dr. Padilla also is an active member of the Division’s P50 grant program led by Robert Lafyatis, MD, contributing to collaborative projects focused on systemic sclerosis and other rheumatic diseases. Additionally, Dr. Padilla was invited to present on some of her latest research findings as a speaker at Boston University Medical Center. She has also been invited to serve as session chair at the 19th International Workshop on Scleroderma Research in the United Kingdom.
"At the end of the day, everything we do in the lab is about making a difference for patients," says Dr. Padilla. "Systemic sclerosis is a challenging disease, but by advancing our knowledge of its underlying mechanisms, we can work towards finding better treatment approaches."
References and Further Reading
