Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts
Franco B. Mueller, Hua Yang, Michelle Lubetzky, Akanksha Verma, John R. Lee, Darshana M. Dadhania, Jenny Z. Xiang, Steven P. Salvatore, Surya V. Seshan, Vijay K. Sharma, Olivier Elemento, Manikkam Suthanthiran, Thangamani Muthukumar
Franco B. Mueller, Hua Yang, Michelle Lubetzky, Akanksha Verma, John R. Lee, Darshana M. Dadhania, Jenny Z. Xiang, Steven P. Salvatore, Surya V. Seshan, Vijay K. Sharma, Olivier Elemento, Manikkam Suthanthiran, Thangamani Muthukumar
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Research Article Immunology Transplantation

Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Abstract

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell–mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.

Authors

Franco B. Mueller, Hua Yang, Michelle Lubetzky, Akanksha Verma, John R. Lee, Darshana M. Dadhania, Jenny Z. Xiang, Steven P. Salvatore, Surya V. Seshan, Vijay K. Sharma, Olivier Elemento, Manikkam Suthanthiran, Thangamani Muthukumar

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Figure 9

Correlation clustering of enriched energy metabolism and immune response pathways in TCMR.

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Correlation clustering of enriched energy metabolism and immune response...
Hierarchical correlation clustering of 41 statistically significant enriched immune response and energy metabolism pathways in TCMR. Pathway names (red, immune response pathways; green, energy metabolism pathways) and numbers correspond to the KEGG pathway database. We used GAGE for pathway enrichment analysis. For a given pathway, the GAGE algorithm tests whether specific gene sets are significantly differentially expressed (each TCMR vs. all Normal) relative to the background whole gene set of 16,381 genes (each TCMR vs. all Normal) that we identified, using a rank-based 2-sample t test. For each gene set, a global P value is derived in a meta-test on the negative log sum of all P values from the individual TCMR vs. Normal comparisons. The stat mean is the mean of the individual statistics from multiple gene-set tests. Among the TCMR samples, the relationship of the stat mean between any 2 pathways is represented by the correlation coefficient (r) value. In the heatmap above, each square is the correlation coefficient, adjusted for multiple comparisons, of the 2 pathways. If the correlation coefficient is positive (blue), then both pathways are concordant (both are either up- or downregulated). If the correlation coefficient is negative (red), then both pathways are discordant (one is up- and the other is downregulated).