New Cellular Biomarkers Correlate with Disease Severity in Sjögren Disease

Autoimmune disorders arise when immune responses target self-antigens, driving chronic inflammation and long-term morbidity. In primary Sjögren disease, inflammation of salivary and lacrimal glands leads to dry mouth and dry eyes alongside systemic complications, underscoring an unmet need for disease-modifying strategies. CD4+ T cells are key orchestrators, but contributions from tissue-resident cells remain poorly defined. A new study reveals a disease-driving interaction between immune cells and fibroblasts in primary Sjögren disease.

Researchers at Tokushima University (Tokushima, Japan) describe a pathogenic axis between CD153+ CD4+ T cells and CD30+ fibroblasts in primary Sjögren disease (pSjD). The work identifies nonimmune fibroblasts, the structural cells that form tissue architecture, as active contributors to disease propagation rather than passive bystanders. The authors present this immune–stromal crosstalk as a central driver of glandular inflammation.

Using a mouse model of pSjD, the team performed high-resolution single-cell RNA sequencing and T cell receptor sequencing of salivary gland cells to map cellular interactions. The analysis showed that CD153+ CD4+ T cells directly engage CD30+ fibroblasts, triggering fibroblast activation, proliferation, and secretion of inflammatory chemokines. These signals recruit additional immune cells and sustain tertiary lymphoid structure–like tissues within the glands, creating a self-reinforcing pathogenic microenvironment.

Functional experiments further supported the role of this pathway. Removing CD153 from CD4+ T cells or neutralizing fibroblast-derived chemokines reduced immune-cell infiltration and significantly halted autoimmune-like pathology in the mouse model. Analyses of patient samples similarly showed increased CD153+ CD4+ T cells and CD30+ fibroblasts that preferentially interact, with CD153–CD30 axis activity positively correlating with disease severity. The expansion of these cells in affected tissues may therefore serve as a novel biomarker for diagnosis and/or monitoring of disease progression.

The findings were published in Nature Communications. Participating institutions include the Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, and the Department of Oral and Maxillofacial Surgery, Tokushima University Hospital. 

“Our study provides a new perspective on autoimmune diseases and demonstrates that chronic inflammation is maintained not only by abnormal immune cells but also through interactions between immune cells and tissue-resident fibroblasts,” said Kunihiro Otsuka, Assistant Professor, Department of Oral and Maxillofacial Surgery, Tokushima University Hospital, Japan.

“Importantly, it highlights that fibroblasts create a pathological microenvironment that worsens the diseased condition through direct interaction with abnormal immune cells. This concept has significant implications in therapeutics for rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and chronic inflammatory disorders associated with fibrosis,” added Otsuka.

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