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Transcriptional Analysis of Liver Tissue Identifies Distinct Phenotypes of Indeterminate Pediatric Acute Liver
Catherine A Chapin1, Sarah A Taylor1, Padmini Malladi1
1Department of PediatricsNorthwestern UniversityFeinberg School of MedicineAnn & Robert H. Lurie Children's Hospital of ChicagoChicagoILUSA.
Insights
Pediatric acute liver failure (PALF) in indeterminate cases involves T-cell immune injury. Findings reveal a Th1-driven inflammatory response, suggesting immune-mediated mechanisms in PALF.
Area of Science:
- Hepatology
- Immunology
- Pediatric Gastroenterology
Background:
- Indeterminate pediatric acute liver failure (PALF) often shows T-cell immune injury, but inflammatory pathways are unclear.
- Understanding these pathways is crucial for identifying mechanisms of hepatic injury and potential therapeutic targets in PALF.
Purpose of the Study:
- To characterize the hepatic cytokine and transcriptional signatures in patients with indeterminate PALF.
- To elucidate the precise inflammatory pathways contributing to immune-driven liver injury in PALF.
Main Methods:
- Retrospective review of liver tissue from 22 children with PALF (17 indeterminate, 6 other diagnoses).
- Immunohistochemical staining for CD8 T cells, measurement of immune analytes, and RNA sequencing (RNA-seq) of liver tissue.
- Analysis included principal component analysis, hierarchical clustering, differential gene expression, and gene-set enrichment analysis.
Main Results:
- Most indeterminate PALF patients (94%) exhibited dense/moderate CD8 T-cell staining and Th1-associated cytokines (IFN-γ, TNF-α, IL-1β, IL-12).
- Transcriptional analysis identified two PALF phenotypes: Group 1 (mostly indeterminate PALF) showed heightened expression of genes related to innate inflammation, T-cell activation, and antigen stimulation.
- Group 1 demonstrated increased gene signatures for regulatory T cells, macrophages, Th1 cells, effector memory T cells, cytotoxic T cells, and activated dendritic cells.
Conclusions:
- Indeterminate PALF is characterized by a Th1-mediated inflammatory response, primarily driven by interferon-gamma (IFN-γ).
- Transcriptional data suggest a complex immune network underlies an immune-driven PALF phenotype, distinct from metabolic processes.
- These findings offer insights into PALF pathogenesis, guiding future research and potential therapeutic strategies targeting immune pathways.
Abstract:
Many patients with indeterminate pediatric acute liver failure (PALF) have evidence of T-cell driven immune injury; however, the precise inflammatory pathways are not well defined. We have characterized the hepatic cytokine and transcriptional signatures of patients with PALF. A retrospective review was performed on 22 children presenting with indeterminate (IND-PALF; n = 17) or other known diagnoses (DX-PALF; n = 6) with available archived liver tissue. Specimens were stained for clusters of differentiation 8 (CD8) T cells and scored as dense, moderate, or minimal. Measurement of immune analytes and RNA sequencing (RNA-seq) was performed on whole-liver tissue. Immune analyte data were analyzed by principal component analysis, and RNA-seq was analyzed by unsupervised hierarchical clustering, differential gene expression, and gene-set enrichment analysis. Most patients with IND-PALF (94%) had dense/moderate CD8 staining and were characterized by Th1 immune analytes including tumor necrosis factor α, interferon γ (IFN-γ), interleukin (IL) 1β, IL-12, C-X-C motif chemokine ligand (CXCL) 9, and CXCL12. Transcriptional analyses identified two transcriptional PALF phenotypes. Most patients in group 1 (91%) had IND-PALF and dense/moderate CD8 staining. This group was characterized by increased expression of genes and cell subset-specific signatures related to innate inflammation, T-cell activation, and antigen stimulation. Group 1 expressed significantly higher levels of gene signatures for regulatory T cells, macrophages, Th1 cells, T effector memory cells, cytotoxic T cells, and activated dendritic cells (adjusted P < 0.05). In contrast, patients in group 2 exhibited increased expression for genes involved in metabolic processes. Conclusion: Patients with IND-PALF have evidence of a Th1-mediated inflammatory response driven by IFN-γ. Transcriptional analyses suggest that a complex immune network may regulate an immune-driven PALF phenotype with less evidence of metabolic processes. These findings provide insight into mechanisms of hepatic injury in PALF, areas for future research, and potential therapeutic targets.
