Hiroshi Shimagami, Masayuki Nishide ≪Respiratory Medicine and Clinical Immunology≫, Masashi Narazaki ≪Advanced Clinical and Translational Immunology≫ Researchers unveil the immune cells responsible for systemic sclerosis’s deadliest complications
Nature Communications
A research team led by The University of Osaka finds that elevated levels of certain immune cells in patients with systemic sclerosis are associated with scleroderma renal crisis and interstitial lung disease.
Figure 1. Patients with scleroderma renal crisis demonstrated specific enrichment of CD14+ monocytes with increased EGR1 expression and activation of NF-κB–related pathways. Trajectory analysis indicated that they differentiated into macrophages and expressed high levels of THBS1 in the kidney. In patients with SSc-ILD, CD8+ effector memory T cells with increased type II ISG expression were enriched in peripheral blood. A similar cell population was also enriched in the lung tissue of patients with advanced SSc-ILD, suggesting migration of CD8+ T cells from peripheral blood to the lung.
SSc, systemic sclerosis; ILD, interstitial lung disease; WBC, white blood cells; ISG, interferon signature genes.
Treating rare diseases can be complicated at the best of times, and it gets even more complicated when different patients with the same disease exhibit different symptoms. Now, researchers from Japan have reported a cellular signature that might explain why some patients with autoimmune disease are stable while others face life-threatening complications.
In a study to be published in Nature Communications, a multi-institutional research team led by The University of Osaka has revealed that, for patients with systemic sclerosis, this variation in disease severity seems to be due to the proliferation of certain immune cells in key organs.
Systemic sclerosis is a rare autoimmune disease that is mainly characterized by hardening of the skin, as well as Raynaud’s phenomenon, in which the fingers and toes change color and lose sensation in cold temperatures. In addition to these symptoms, systemic sclerosis can affect internal organs, such as the lungs and kidneys, with serious consequences.
“We know that immune dysregulation causes vascular damage and tissue fibrosis in systemic sclerosis,” says lead author, Hiroshi Shimagami. “However, it remains unclear why skin symptoms and the level of organ involvement differ from patient to patient.”
To explore this, the researchers took blood and tissue samples from patients with systemic sclerosis 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.
“The results were intriguing,” explains Masayuki Nishide, senior author. “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.”
While immune cells usually help the body fight infection and disease, in certain cases they can be inappropriately activated through gene expression. In this instance, CD14+ monocytes differentiated – or transformed – into destructive macrophages, which can further promote inflammation near the kidneys and contribute to the thickening and scarring of internal organs.
In addition, the researchers found that CD8+ T cells with a type II interferon signature, which makes the immune cells particularly aggressive and inflammatory, were linked to progressive interstitial lung disease. EGR1-expressing CD14+ monocytes and these peculiar CD8+ T cells are likely to accumulate in the kidney or the lung, respectively, and produce or recruit other factors that contribute to disease progression.
“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,” says Dr Shimagami.
Given that few treatment options are currently available for patients with systemic sclerosis, this study suggests promising avenues for the development of new therapeutic strategies. Predicting disease through biomarkers and preventing severe organ involvement would have a significant, positive impact on these patients’ quality of life.
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The article, “Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of patients with systemic sclerosis,” is to be published in Nature Communications at DOI: https://doi.org/10.1038/s41467-025-60034-7.
Summary: Researchers from The University of Osaka found that EGR1-expressing CD14+ monocytes and CD8+ T cells with a type II interferon signature are associated with scleroderma renal crisis and interstitial lung disease, respectively, in patients with systemic sclerosis. Understanding the specific immune cell abnormalities underlying different clinical manifestations of the disease could help predict and prevent serious complications.
Tweet: Researchers from @UOsaka find abnormal proliferation of specific #immune cell subsets is linked to #scleroderma renal crisis and #interstitial lung disease in patients with systemic sclerosis @osaka_univ_e
Primary Keyword: Immunology
Additional Keyword: Immune cells, T lymphocytes, monocytes, immune disorders, autoimmune disorders, scleroderma, macrophages, gene expression, renal failure
Method of Research: Experimental study
Subject of Research: Human tissue samples
Title: “Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of patients with systemic sclerosis”
Journal: Nature Communications
Authors: Hiroshi Shimagami, Kei Nishimura, Hiroaki Matsushita, Shoichi Metsugi, Yasuhiro Kato, Takahiro Kawasaki, Kohei Tsujimoto, Ryuya Edahiro, Eri Itotagawa, Maiko Naito, Shoji Kawada, Daisuke Nakatsubo, Kazuki Matsukawa, Tomoko Namba-Hamano, Kazunori Inoue, Atsushi Takahashi, Masayuki Mizui, Seiya Kato, Hayato Hikita, Shigeaki Nakazawa, Yoichi Kakuta, Hachiro Konaka, Kensuke Mitsumoto, Nachi Ishikawa, Jun Fujimoto, Shinji Higa, Ryusuke Omiya, Yoshitaka Isaka, Tetsuo Takehara, Norio Nonomura, Yukinori Okada, Kunihiro Hattori, Masashi Narazaki, Atsushi Kumanogoh, Masayuki Nishide
DOI: 10.1038/s41467-025-60034-7.
Funded by: Japan Society for the Promotion of Science
Japan Agency for Medical Research and Development
Japan Science and Technology Agency
