A recent study published in JCI Insight and led by Northwestern Medicine scientists has uncovered new clues as to why people with systemic sclerosis, also known as scleroderma, frequently develop debilitating esophageal complications.
The findings shed light on how chronic acid reflux damages the lining of the esophagus and may contribute to more serious disease, said Matthew Dapas, PhD, first author of the study and research assistant professor of Medicine in the Division of Rheumatology.
Systemic sclerosis is a rare autoimmune disease characterized by inflammation, blood vessel damage and fibrosis affecting the skin and internal organs. Gastrointestinal involvement is among the most common complications, with many patients experiencing severe acid reflux, swallowing difficulties and impaired esophageal motility.
“One of the most commonly affected organs in scleroderma is the gastrointestinal tract,” Dapas said. “In particular, these patients lose their ability to effectively swallow. A lot of them suffer from acid reflux and difficulty eating. It’s a huge impact on their quality of life.”
In the study, Dapas and his collaborators used single-cell RNA sequencing to analyze more than 306,000 cells from esophageal tissue samples collected from patients with systemic sclerosis, individuals with gastroesophageal reflux disease (GERD) and healthy controls. The findings provide the most detailed view to date of cellular changes occurring in the esophagus of patients with scleroderma.
Dapas said the current study grew out of ongoing collaborations aimed at understanding gastrointestinal symptoms in patients with scleroderma.
“This was born from a collaboration between the rheumatology division and gastroenterology,” Dapas said. “Because scleroderma is a disease with symptoms that span many different organ systems, we end up working a lot with different divisions in care and in research.”
Using single-cell and spatial transcriptomic technologies, the team examined the stratified squamous epithelium, the protective tissue that lines the esophagus. They found that patients with systemic sclerosis had fewer mature cells in the outermost layer of the esophagus compared with healthy individuals. Most of the gene expression changes were concentrated within this cell population, where expression of genes involved in extracellular matrix production and keratinization was significantly increased.
“What we found was that, at a cellular level, the changes in gene expression and cell composition pretty closely mirror those seen in non-scleroderma GERD patients, which are patients that just have chronic acid reflux,” Dapas said.
The results suggest that many of the epithelial abnormalities observed in systemic sclerosis are likely a consequence of chronic acid exposure rather than evidence that the esophageal lining itself is driving disease. The investigators found that these reflux-associated changes were more pronounced in the upper section of the esophagus among patients with systemic sclerosis. That finding may help explain why the disease can have effects beyond the digestive tract, Dapas said.
“This suggests that, with a lack of motility, there’s greater acid exposure higher up into the esophagus, and that could lead to micro-droplets of acid getting into the lung, which can exacerbate lung injury,” Dapas said.
Although the epithelial changes appeared largely reflux-driven, the study also identified biological signals unique to systemic sclerosis. Scientists detected dysregulation of immunoregulatory pathways and evidence of increased communication between fibroblasts and other cell types, according to the study.
“To the extent that we could measure scleroderma-specific effects, we found disrupted immunoregulatory pathways and elevated crosstalk between fibroblasts and smooth muscle cells, which is what we suspect may be causing the disrupted esophageal motility,” Dapas said.
Because the study was limited to tissue obtained during routine esophageal examination, which primarily sample the epithelial lining, future research will need to examine deeper tissues, Dapas said.
“I think this highlights how, if we really want to get a sense for what’s happening in the esophagus, we’ll need to somehow explore deeper tissue beyond the epithelium, like the smooth muscle,” Dapas said.
Beyond improving understanding of gastrointestinal complications, the findings may ultimately support more personalized approaches to treating systemic sclerosis. Dapas and colleagues are now investigating genetic factors that may help explain why some patients develop more severe disease symptoms than others.
For Dapas, the study also demonstrates the power of emerging technologies to answer longstanding questions about complex autoimmune diseases.
“This work clears up a lot of questions raised from previous studies done in animal models and bulk tissue by looking at the cellular level,” he said. “It’s just amazing how we have these technologies that can help us deduce what’s actually happening in patients at the cellular level.”
Additional Feinberg co-authors included Hadijat-Kubura M. Makinde, PhD, research assistant professor of Medicine in the Division of Rheumatology; Dustin Carlson, MD, associate professor of Medicine in the Division of Gastroenterology and Hepatology; Parambir Dulai, MD, associate professor and director of research in the Center for Human Immunobiology; John Pandolfino, MD, the Hans Popper Professor of Medicine and chief of Gastroenterology and Hepatology; Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of Rheumatology; Carrie Richardson ‘12 MD, ‘GME, associate professor of Medicine in the Division of Rheumatology; and Deborah Winter, PhD, the Solovy/Arthritis Research Society Research Professor and associate professor of Rheumatology.
The study was supported by National Institutes of Health grants P01DK117824, U01DK134321, R01AI163742, U19AI181102, R01AR080513, R01AR075423 and R01AR073270. Additional funding came from the Digestive Health Foundation.
