Cellular and molecular fine mapping pinpoints new immunopathology of lupus

Nakano, M.; Kono, M.; Asahara, K.; Katsuyama, T.; Kubo, S.; Katsuyama, E.; Fujita, Y.; Inokuchi, H.; Nishino, T.; Arakawa, T.; Kawashima, T.; Noma, S.; Bagherzadeh, R.; Matsumoto, Y.; Inamo, J.; Takahashi, H.; Natsumoto, B.; Zhang, X.; Bae, S.-C.; Suzuki, A.; Hatano, H.; Terao, C.; Tanaka, Y.; Yamamoto, K.; Ishigaki, K.

doi:10.64898/2025.12.08.693110

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bioRxiv · 10.64898/2025.12.08.693110

Cellular and molecular fine mapping pinpoints new immunopathology of lupus

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Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with an unknown etiology. To pinpoint new disease-relevant cell states and their molecular profiles, we performed an in-depth investigation of multimodal single-cell datasets comprising [~]2.1 million peripheral blood mononuclear cells from 346 donors. By resolving 123 fine-grained cell states across 27 cell types, we identified previously uncharacterized populations distinctively associated with clinical severity and treatment status, including GZMK+GZMH+HLA-DR+ effector memory CD8+ T cells (double-positive [DP] EMCD8) and FOXO1+ARHGAP15+ T cells. Through extensive statistical frameworks and multimodal approaches, we delineated their aberrant immune signaling networks, transcriptional regulators, key surface proteins, T cell receptor repertoires, and genetic/epigenetic landscapes, underscoring them as candidate drivers of SLE immunopathology. These findings provide new insights into therapeutic target discovery in SLE.

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Nakano, M., Kono, M., Asahara, K., Katsuyama, T., Kubo, S., Katsuyama, E., Fujita, Y., Inokuchi, H., Nishino, T., Arakawa, T., Kawashima, T., Noma, S., Bagherzadeh, R., Matsumoto, Y., Inamo, J., Takahashi, H., Natsumoto, B., Zhang, X., Bae, S.-C., Suzuki, A., Hatano, H., Terao, C., Tanaka, Y., Yamamoto, K., Ishigaki, K.. 2025-12-11. Cellular and molecular fine mapping pinpoints new immunopathology of lupus. https://doi.org/10.64898/2025.12.08.693110

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