Cytotoxic CD8 T-Cell Subsets in Scleroderma Lung Disease
Abstract
Systemic sclerosis (scleroderma) is a chronic autoimmune disease characterized by progressive fibrosis of the skin and internal organs. Lung involvement is very common and is one of the main determinants of morbidity and mortality in patients affected by this condition. Yet, the immune mechanisms and cell types that cause injury to the lungs are not fully understood. While the decline in lung function can be measured using pulmonary function testing, there are no available clinical tools with the power to quantify the amount of pathologic immune activation in subjects with ongoing active lung damage. The ability to predict lung disease progression or adequate response to therapeutic intervention will have a major impact on the quality of life and even survival of scleroderma patients. To pursue the discovery of such critical biomarker, we have established a robust collaboration between Dr. Francesco Boin, a recognized investigator in scleroderma research and care, and Dr. Deepak Rao, a new investigator with extensive expertise in phenotyping immune cells in patients affected by autoimmune rheumatic diseases. Our overarching goal is to identify and characterize features of immune activation that are associated with the development of interstitial lung disease and other target tissues damage in scleroderma. In preliminary experiments, using detailed evaluation of circulating immune cells, we have identified a specific CD8 T cell population that is highly expanded in the blood of patients with interstitial lung disease. Initial data analysis suggests that these cells may be highly activated killer T lymphocytes. We hypothesize that these CD8 T cells may directly infiltrate and damage the lungs in scleroderma patients and that may be a useful tool to monitor lung disease activity and progression. In this project, we aim to define the functions, development, and gene expression patterns in this expanded CD8 T cell population using in vitro experiments and single cell RNA sequencing of circulating cells obtained from scleroderma patients with interstitial lung disease. We also seek to determine if this unique T cell population can be found within affected lung tissues. Finally, we will test whether measuring levels of these CD8 T cells in the blood of scleroderma patients can predict ongoing lung disease activity as well as the associated decline of lung function. We hypothesize that high levels of this CD8 T cell population will be indicative of a more aggressive and progressive underlying interstitial lung disease process. Important advances in the care of scleroderma patients can potentially arise from this proposal. First, we will define the features and function of a new pathologic immune cell type that possibly drives interstitial lung disease in scleroderma and therefore may represent a suitable target for a more direct and focused therapeutic strategy to prevent lung injury. Second, results from our work may lead to the development of a new biomarker that can be easily measured in the blood of patients with lung disease to precisely quantify the ongoing pathologic immune activation. This assessment can be very useful in the clinical setting as it may allow to properly identify scleroderma patients who may truly benefit from immunosuppression as well as to effectively and reliably monitor the response to treatment interventions. Finally, the increasing numbers of women and minorities in the military, and the possible exposure of military personnel to important risk factors associated with the development of scleroderma make the objectives of this proposal of direct relevance to FY20 Scleroderma Research Program Translational Research Partnership Award.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110768
Entities
People
- Francesco Boin
Organizations
- Cedars-Sinai Medical Center
- United States Army