Background and aim Dermatomyositis (DM) is an immune-mediated myopathy marked by chronic inflammation and heterogeneous clinical trajectories. The molecular determinants driving disease onset and progression remain poorly defined. This study aimed to construct a high-accuracy diagnostic risk model, identify causally relevant genes, and uncover cell-type-specific immune circuits contributing to DM pathogenesis, with emphasis on BTN3A2. Methods We integrated three bulk transcriptomic datasets to identify dysregulated genes and performed functional enrichment analyses. An 18-gene diagnostic risk score was generated using LASSO and validated externally. Summary-based Mendelian randomization with tissue-specific eQTLs was applied to identify causal genes. Single-cell RNA sequencing (GSE190684) was analyzed to map cellular heterogeneity, quantify risk-score and BTN3A2 distributions, and evaluate ligand–receptor communication across clinical states and expression subgroups. Results Bulk analyses identified 2,051 dysregulated genes enriched in antiviral responses, antigen presentation, and immune activation. Summary-data based Mendelian Randomization (SMR) uncovered 85 causal genes shared across skin and muscle, converging on MHC-related and autoimmune pathways. Integrating causal and transcriptional evidence yielded 16 core DM genes, highlighting BTN3A2 for its potential dual diagnostic and suggestive causal relevance. The 18-gene risk score demonstrated excellent predictive performance (AUC 0.957/0.724). Single-cell profiling revealed that both the risk score and BTN3A2 were predominantly enriched in CD14⁺/CD16⁺ monocytes and T-cell subsets. Cell–cell communication analysis identified a monocyte-derived LGALS9-CD44/CD45 signaling axis as the key interaction pathway distinguishing clinical states and risk groups. Conclusion This multi-omics study establishes a precise diagnostic risk score and suggests that BTN3A2 may serve as a mechanistically relevant biomarker in DM. The discovery of an LGALS9-CD44/CD45 monocyte-T cell circuit provides new insight into DM immunopathology and highlights actionable targets for precision diagnosis and therapy.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> Key points </entry> </row> <row> <entry align="left" nameend="c2" namest="c1"> • An externally validated, high-accuracy 18-gene diagnostic risk score was established, providing a robust molecular tool for precision risk stratification in dermatomyositis. </entry> </row> <row> <entry align="left" nameend="c2" namest="c1"> • BTN3A2 emerged as a gene with both diagnostic significance and genetic causal relevance, positioning it as a pivotal regulator of dermatomyositis immunopathology. </entry> </row> <row> <entry align="left" nameend="c2" namest="c1"> • Single-cell RNA sequencing identified CD14⁺/CD16⁺ monocytes and T-cell subsets as the major cellular sources driving elevated risk and BTN3A2 overexpression, while intercellular communication analysis uncovered a monocyte-derived LGALS9–CD44/CD45 axis that mechanistically links genetic risk, transcriptional activation, and immune dysfunction. </entry> </row> <row> <entry align="left" nameend="c2" namest="c1"> • These findings delineate a mechanistic, multi-dimensional framework that integrates diagnostic markers, genetic susceptibility, and cell–cell signaling, offering translational insights for precision diagnostics and targeted immunotherapies in dermatomyositis. </entry> </row> </tbody> </tgroup> </Table>

Integrated multi-dimensional analyses reveal a BTN3A2-centered diagnostic risk score and a monocyte-T cell axis as central drivers of dermatomyositis

期刊论文
发表日期：

2026年4月30日

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Jing Yang,
Long-Kuan Yin,
Jin Tang

摘要

Background and aim

Dermatomyositis (DM) is an immune-mediated myopathy marked by chronic inflammation and heterogeneous clinical trajectories. The molecular determinants driving disease onset and progression remain poorly defined. This study aimed to construct a high-accuracy diagnostic risk model, identify causally relevant genes, and uncover cell-type-specific immune circuits contributing to DM pathogenesis, with emphasis on BTN3A2.

Methods

We integrated three bulk transcriptomic datasets to identify dysregulated genes and performed functional enrichment analyses. An 18-gene diagnostic risk score was generated using LASSO and validated externally. Summary-based Mendelian randomization with tissue-specific eQTLs was applied to identify causal genes. Single-cell RNA sequencing (GSE190684) was analyzed to map cellular heterogeneity, quantify risk-score and BTN3A2 distributions, and evaluate ligand–receptor communication across clinical states and expression subgroups.

Results

Bulk analyses identified 2,051 dysregulated genes enriched in antiviral responses, antigen presentation, and immune activation. Summary-data based Mendelian Randomization (SMR) uncovered 85 causal genes shared across skin and muscle, converging on MHC-related and autoimmune pathways. Integrating causal and transcriptional evidence yielded 16 core DM genes, highlighting BTN3A2 for its potential dual diagnostic and suggestive causal relevance. The 18-gene risk score demonstrated excellent predictive performance (AUC 0.957/0.724). Single-cell profiling revealed that both the risk score and BTN3A2 were predominantly enriched in CD14⁺/CD16⁺ monocytes and T-cell subsets. Cell–cell communication analysis identified a monocyte-derived LGALS9-CD44/CD45 signaling axis as the key interaction pathway distinguishing clinical states and risk groups.

Conclusion

This multi-omics study establishes a precise diagnostic risk score and suggests that BTN3A2 may serve as a mechanistically relevant biomarker in DM. The discovery of an LGALS9-CD44/CD45 monocyte-T cell circuit provides new insight into DM immunopathology and highlights actionable targets for precision diagnosis and therapy.

Key points

• An externally validated, high-accuracy 18-gene diagnostic risk score was established, providing a robust molecular tool for precision risk stratification in dermatomyositis.

• BTN3A2 emerged as a gene with both diagnostic significance and genetic causal relevance, positioning it as a pivotal regulator of dermatomyositis immunopathology.

• Single-cell RNA sequencing identified CD14⁺/CD16⁺ monocytes and T-cell subsets as the major cellular sources driving elevated risk and BTN3A2 overexpression, while intercellular communication analysis uncovered a monocyte-derived LGALS9–CD44/CD45 axis that mechanistically links genetic risk, transcriptional activation, and immune dysfunction.

• These findings delineate a mechanistic, multi-dimensional framework that integrates diagnostic markers, genetic susceptibility, and cell–cell signaling, offering translational insights for precision diagnostics and targeted immunotherapies in dermatomyositis.