Understanding Organ Damage in Systemic Sclerosis via scRNA-Seq Techniques

In a groundbreaking study published on June 17, 2025, researchers from Osaka University unveiled critical insights into systemic sclerosis (SSc), a rare autoimmune disease characterized by tissue fibrosis and vascular damage. Utilizing high-dimensional single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, the team identified unique immune cell subsets that are instrumental in the organ-specific complications associated with SSc, particularly in the kidneys and lungs.

Systemic sclerosis affects patients differently; while some remain stable, others face severe complications such as scleroderma renal crisis (SRC) and interstitial lung disease (ILD). The unpredictability of these manifestations has long been a challenge for clinicians. Dr. Hiroshi Shimagami, the lead author of the study, noted, "We know that immune dysregulation causes vascular damage and tissue fibrosis in systemic sclerosis; however, it remains unclear why skin symptoms and the level of organ involvement differ from patient to patient."

The study, titled "Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of patients with systemic sclerosis," highlighted two distinct immune cell subsets as potential biomarkers and drivers of disease: EGR1+ CD14+ monocytes and CD8+ effector memory T cells. EGR1+ monocytes, identified in the blood and kidneys of SRC patients, exhibited activation of inflammatory pathways linked to tissue damage. In contrast, CD8+ T cells were found to have a type II interferon signature in patients suffering from ILD, indicating their crucial role in pulmonary complications.

The research team conducted single-cell profiling of peripheral blood mononuclear cells (PBMC) from 21 immunosuppressant-naïve SSc patients, employing Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) to integrate transcriptome and surface protein data. Their findings revealed that EGR1+ monocytes express proteins associated with migration and tissue damage, implicating them in the progression of kidney injury in SRC patients. The study also demonstrated that these monocytes differentiate into macrophages expressing THBS1 within the kidney, contributing to vascular damage and fibrosis.

Additionally, the presence of CD8+ effector memory T cells with elevated levels of chemokine receptors CXCR3 and CCR5 in the lung samples from SSc-ILD patients suggests that these T cells play a significant role in driving pulmonary inflammation and fibrosis. Dr. Masayuki Nishide, senior author of the study, remarked, "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."

The implications of these findings extend beyond understanding the pathophysiology of systemic sclerosis. The identification of immune signatures unique to SRC and ILD could facilitate early intervention strategies and the development of targeted therapies, addressing one of the most challenging manifestations of autoimmunity. Given the limited treatment options currently available for SSc, these cellular subsets may pave the way for innovative therapeutic approaches.

As research in this area continues to evolve, the potential for improved patient outcomes through early diagnosis and intervention remains a hopeful prospect for those affected by systemic sclerosis. The findings underscore the need for ongoing exploration into the immune mechanisms underpinning this complex disease, with a focus on developing specific and effective treatments for its diverse manifestations.