Comparative single-cell and spatial profiling of anti-SSA-positive and anti-centromere-positive Sjögren’s disease reveals common and distinct immune activation and fibroblast-mediated inflammation

Jun Inamo (), Masaru Takeshita (), Katsuya Suzuki, Kazuyuki Tsunoda, Satoshi Usuda, Junko Kuramoto, Jonathan Moody, Chung-Chau Hon, Yoshinari Ando, Takashi Sasaki, Kazutoshi Yoshitake, Susumu Mitsuyama, Shuichi Asakawa, Yae Kanai, Tsutomu Takeuchi and Yuko Kaneko
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Jun Inamo: Keio University School of Medicine
Masaru Takeshita: Keio University School of Medicine
Katsuya Suzuki: Keio University School of Medicine
Kazuyuki Tsunoda: Keio University School of Medicine
Satoshi Usuda: Keio University School of Medicine
Junko Kuramoto: Keio University School of Medicine
Jonathan Moody: RIKEN Center for Integrative Medical Sciences
Chung-Chau Hon: RIKEN Center for Integrative Medical Sciences
Yoshinari Ando: RIKEN Center for Integrative Medical Sciences
Takashi Sasaki: Keio University School of Medicine
Kazutoshi Yoshitake: University of Tokyo
Susumu Mitsuyama: University of Tokyo
Shuichi Asakawa: University of Tokyo
Yae Kanai: Keio University School of Medicine
Tsutomu Takeuchi: Keio University School of Medicine
Yuko Kaneko: Keio University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Sjögren’s disease (SjD) is an autoimmune disease that causes salivary gland dysfunction due to immune-mediated destruction. While autoantibodies such as anti-SSA and anti-centromere (CENT) are associated with distinct clinical manifestations, the molecular features remain to be elucidated. In this study, we apply multi-modal single-cell technologies: single-cell RNA sequencing, T cell and B cell receptor sequencing and spatial transcriptomics to salivary gland lesions, aiming to elucidate common and unique cellular and transcriptional signatures linked to different autoantibody profiles. Our analysis demonstrates that GZMB+GNLY+ CD8+ T cells are the main expanded subset across different autoantibody statuses, highlighting their central role in SjD pathogenesis, while the enrichment of memory B cells is more prominent in anti-CENT-positive patients. Cytokine signaling also differs by autoantibody profile, with an activated interferon signature in anti-SSA-positive patients, whereas TGFβ signaling is enhanced in anti-CENT-positive patients. Furthermore, spatial profiling reveals THY1+ fibroblasts, expressing complement genes and chemokines, as key hubs orchestrating inflammation within the salivary glands. These findings deepen our understanding of the pathogenesis of SjD, and may inform the development of targeted and personalized therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-63935-9

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