Autoantibody landscape and functional role of anti-C-C motif chemokine receptor 8 autoantibodies in systemic sclerosis: post-hoc analysis of a B-cell depletion trial

Kazuki M. Matsuda (), Yang-Yi Chen, Satoshi Ebata, Kazuhiro Iwadoh, Hirohito Kotani, Ai Kuzumi, Asako Yoshizaki-Ogawa, Cheng-Che E. Lan, Hsin-Su Yu, Hayakazu Sumida and Shinichi Sato ()
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Kazuki M. Matsuda: The University of Tokyo Hospital, Department of Dermatology
Yang-Yi Chen: Kaohsiung Medical University, Department of Dermatology, Kaohsiung Medical University Hospital
Satoshi Ebata: The University of Tokyo Hospital, Department of Dermatology
Kazuhiro Iwadoh: The University of Tokyo Hospital, Department of Dermatology
Hirohito Kotani: The University of Tokyo Hospital, Department of Dermatology
Ai Kuzumi: The University of Tokyo Hospital, Department of Dermatology
Asako Yoshizaki-Ogawa: The University of Tokyo Hospital, Department of Dermatology
Cheng-Che E. Lan: Kaohsiung Medical University, Department of Dermatology, Kaohsiung Medical University Hospital
Hsin-Su Yu: Kaohsiung Medical University, Department of Dermatology, Kaohsiung Medical University Hospital
Hayakazu Sumida: The University of Tokyo Hospital, Department of Dermatology
Shinichi Sato: The University of Tokyo Hospital, Department of Dermatology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Systemic sclerosis (SSc) is an autoimmune disease marked by fibrosis and extensive autoantibody production. Although B-cell depletion with rituximab (RTX) has shown clinical benefit, predictive biomarkers of response remain elusive. Here, we apply proteome-wide autoantibody screening using wet protein arrays covering 13,455 human antigens in serum samples from participants of the randomized trial of RTX. We identify a significant elevation in the total autoantibody levels in SSc compared to healthy controls, with greater reductions post-treatment observed in RTX high responders than in low responders. A stepwise selection highlights 88 clinically relevant autoantibodies, including those targeting G protein-coupled receptors. Among them, anti-C-C motif chemokine receptor 8 (CCR8) autoantibodies are functionally validated by cell-based assays using CCR8-overexpressing HEK293 cells. Furthermore, in a bleomycin-induced mouse model, anti-CCR8 antibody administration exacerbates dermal fibrosis and modifies immune cell infiltration. Although external validation with multiple comparison adjustment is further required, these findings reveal an autoantibody signature associated with therapeutic response and pathogenic potential in SSc, providing a foundation for precision immunotherapy and mechanistic insights into disease progression.

Date: 2025
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DOI: 10.1038/s41467-025-66974-4

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