August 2026

RHEUMATOLOGY

EPITHELIAL ABNORMALITIES IN SCLERODERMA LIKELY FROM CHRONIC ACID EXPOSURE

A recent study suggests that many epithelial abnormalities in systemic sclerosis are likely from chronic acid exposure. Published in JCI Insight, the study was led by Northwestern Medicine scientists, including Matthew Dapas, PhD.

Analyzing cells from esophageal tissue samples collected from patients with systemic sclerosis, those with GERD and healthy individuals, the investigators also found that the reflux-associated changes were more pronounced in the upper section of the esophagus among patients with systemic sclerosis. “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,” Dr. Dapas says.

A Detailed Data Dive
Dr. 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 GERD and healthy controls. The findings provide the most detailed view to date of cellular changes in the esophagus of patients with scleroderma.

Using single-cell and spatial transcriptomic technologies, the team examined the stratified squamous epithelium and found that patients with systemic sclerosis had fewer mature cells in the outermost layer of the esophagus than 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,” says Dr. Dapas.

Although the epithelial changes appeared largely reflux-driven, the study also identified biological signals unique to systemic sclerosis. “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,” Dr. Dapas adds.

Looking Forward
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 tissue, like smooth muscle, Dapas said.

“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,” Dr. Dapas. “It’s just amazing how we have these technologies that can help us deduce what’s actually happening in patients at the cellular level.” He and his collaborators are now investigating genetic factors that may help explain why some patients develop more severe disease symptoms than others.
 
Northwestern Medicine co-authors included Hadijat-Kubura M. Makinde, PhD; Dustin Carlson, MD; Parambir Dulai, MD; John Pandolfino, MD; Harris R. Perlman, PhD; Carrie Richardson, MD; and Deborah Winter, PhD.
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The study was supported by NIH grants P01DK117824, U01DK134321, R01AI163742, U19AI181102, R01AR080513, R01AR075423 and R01AR073270. Additional funding came from the Digestive Health Foundation.
Matthew Dapas, PhD, first author of the study and Research Assistant Professor of Rheumatology at Northwestern Medicine
Dustin Carlson, MD, Associate Professor of Gastroenterology and Hepatology at Northwestern Medicine
Parambir Dulai, MD, Associate Professor of Gastroenterology and Hepatology and Director of Research in the Center for Human Immunobiology at Northwestern Medicine 
Hadijat-Kubura M. Makinde, PhD, Research Assistant Professor of Rheumatology at Northwestern Medicine
John Pandolfino, MD, the Hans Popper Professor of Medicine and Chief of Gastroenterology and Hepatology at Northwestern Medicine
Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and Professor of Rheumatology at Northwestern Medicine
Carrie Richardson, MD, Associate Professor of Rheumatology at Northwestern Medicine
Deborah Winter, PhD, the Solovy/Arthritis Research Society Research Professor and Associate Professor of Rheumatology at Northwestern Medicine

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