Scientists Identify Immune Cells That Unlock Scleroderma Mysteries

AsianScientist (Aug. 22, 2025) – Systemic sclerosis, commonly referred to as scleroderma, is a rare connective tissue disorder with a complex and unknown cause. This autoimmune disease is characterized by skin hardening and Raynaud’s phenomenon, where the fingers and toes change color and lose sensation in response to cold temperatures. In addition, systemic sclerosis can have serious implications for internal organs like the lungs and kidneys.

However, it remains unclear why skin symptoms and the extent of organ involvement varied between patients. To investigate this, researchers at the University of Osaka studied 21 patients and identified a cellular pattern that could help explain why some individuals with autoimmune disease remain stable while others develop severe, life-threatening complications. Their findings were published in the journal Nature Communications. 

To understand how immune cells vary and how that relates to different symptoms, researchers studied blood immune cells from the patients who hadn’t taken immune-suppressing drugs and analyzed them cell by cell, looking for differences in gene expression.

Additionally, proteins on the cell surface were examined to identify biomarkers of disease, which are useful for identifying and treating diseases in earlier stages.

Researchers discovered a specific type of monocyte (EGR1+ CD14+) that is linked to kidney issues. These monocytes activate inflammatory pathways and can transform into harmful macrophages – innate immune cells that usually engulf and digest pathogens – at sites of tissue injury.

While immune cells generally protect the body, they can become detrimental when incorrectly activated due to changes in gene expression. In this instance, CD14+ monocytes differentiated into destructive macrophages, leading to increased inflammation around the kidneys, which contributed to scarring of internal organs.

The researchers also found that a type of CD8+ T cell, lymphocytes involved in immune defense, makes them more aggressive and inflammatory. This was linked to worsening lung disease. These CD8+ T cells and EGR1+ CD14+ monocytes likely build up in the lungs and kidneys, where they trigger or attract other factors that drive disease progression.

“The results were intriguing,” explained senior author Masayuki Nishide, from the Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka. “We identified a specific subset of immune cells, the EGR1-expressing subpopulation of CD14+ monocytes, that were clearly associated with scleroderma renal crisis, a serious kidney complication in patients with systemic sclerosis,” he added.

“Taken together, our single-cell analysis of patient samples show that specific abnormalities in distinct subsets of immune cell are associated with different clinical symptoms of systemic sclerosis, particularly organ manifestations,” said lead author Hiroshi Shimagami from the Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka.

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Source:  The University of Osaka ; Image: Shutterstock

You can find the article at Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of patients with systemic sclerosis

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