Frontiers in cardiovascular medicine · 2026
Transcriptomic signatures and immune microenvironment of acute rejection after heart transplantation: an integrated bioinformatics analysis.
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Zhou Wenjun, Huang Langjing, Tang Wenwen
Аннотация
BACKGROUND: Histologic assessment of endomyocardial biopsy (EMB) remains the standard for diagnosing acute cardiac allograft rejection, yet molecular profiling may provide complementary quantitative insights.
METHODS: Microarray data (GSE2596; GPL1053) were obtained from the Gene Expression Omnibus. Acute rejection (R, n = 16) and non-rejection (N, n = 27) samples were analyzed after excluding infection-related groups. Probes were mapped to gene symbols and summarized per gene. Differential expression was assessed using Welch's t-test with Benjamini-Hochberg false discovery rate control. Reactome over-representation analysis was performed for significant genes. Immune cell scores were estimated using MCP-counter markers. An L1-penalized logistic regression model was evaluated by 5-fold cross-validation. Experimental validation was performed by quantitative PCR in a cervical heterotopic cardiac xenotransplantation model (BALB/c to C57), including normal control and sham groups.
RESULTS: Among 3,968 genes, 1,032 were differentially expressed (FDR<0.05), including 135 with |log2FC|>1. Upregulated genes included HLA-DMA, DEF6, TRB@, and CD74. Enrichment analysis highlighted interferon signaling, T-cell receptor signaling, chemokine pathways, and antigen presentation. Immune scoring indicated increased monocytic, B-lineage, and T/cytotoxic lymphocyte signals in rejection. The diagnostic model achieved strong discrimination (5-fold AUC=0.993). qPCR confirmed coordinated upregulation of interferon-related (Ifng, Stat1), chemokine (Cxcl10), and cytotoxic (Prf1) genes in transplanted grafts.
CONCLUSIONS: Acute rejection EMB transcriptomes demonstrate coordinated interferon-driven immune activation. A compact gene signature shows strong internal diagnostic performance, supported by experimental validation, warranting external confirmation.
METHODS: Microarray data (GSE2596; GPL1053) were obtained from the Gene Expression Omnibus. Acute rejection (R, n = 16) and non-rejection (N, n = 27) samples were analyzed after excluding infection-related groups. Probes were mapped to gene symbols and summarized per gene. Differential expression was assessed using Welch's t-test with Benjamini-Hochberg false discovery rate control. Reactome over-representation analysis was performed for significant genes. Immune cell scores were estimated using MCP-counter markers. An L1-penalized logistic regression model was evaluated by 5-fold cross-validation. Experimental validation was performed by quantitative PCR in a cervical heterotopic cardiac xenotransplantation model (BALB/c to C57), including normal control and sham groups.
RESULTS: Among 3,968 genes, 1,032 were differentially expressed (FDR<0.05), including 135 with |log2FC|>1. Upregulated genes included HLA-DMA, DEF6, TRB@, and CD74. Enrichment analysis highlighted interferon signaling, T-cell receptor signaling, chemokine pathways, and antigen presentation. Immune scoring indicated increased monocytic, B-lineage, and T/cytotoxic lymphocyte signals in rejection. The diagnostic model achieved strong discrimination (5-fold AUC=0.993). qPCR confirmed coordinated upregulation of interferon-related (Ifng, Stat1), chemokine (Cxcl10), and cytotoxic (Prf1) genes in transplanted grafts.
CONCLUSIONS: Acute rejection EMB transcriptomes demonstrate coordinated interferon-driven immune activation. A compact gene signature shows strong internal diagnostic performance, supported by experimental validation, warranting external confirmation.