Transcriptional Analysis of Liver Tissue Identifies Distinct Phenotypes of Indeterminate Pediatric Acute Liver Failure.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
received:
24
02
2021
accepted:
01
03
2021
entrez:
25
8
2021
pubmed:
26
8
2021
medline:
26
8
2021
Statut:
epublish
Résumé
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
Identifiants
pubmed: 34430782
doi: 10.1002/hep4.1726
pii: 02009842-202108000-00005
pmc: PMC8369940
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1373-1384Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001422
Pays : United States
Informations de copyright
© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.
Références
Squires RH, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006;148:652‐658.
Narkewicz MR, Dell Olio D, Karpen SJ, Murray KF, Schwarz K, Yazigi N, et al. Pattern of diagnostic evaluation for the causes of pediatric acute liver failure: an opportunity for quality improvement. J Pediatr 2009;155:801‐806 e801.
Narkewicz MR, Horslen S, Hardison RM, Shneider BL, Rodriguez‐Baez N, Alonso EM, et al. A learning collaborative approach increases specificity of diagnosis of acute liver failure in pediatric patients. Clin Gastroenterol Hepatol 2018;16:1801‐1810.
Schwarz KB, Olio DD, Lobritto SJ, Lopez MJ, Rodriguez‐Baez N, Yazigi NA, et al. Analysis of viral testing in nonacetaminophen pediatric acute liver failure. J Pediatr Gastroenterol Nutr 2014;59:616‐623.
James LP, Alonso EM, Hynan LS, Hinson JA, Davern TJ, Lee WM, et al. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics 2006;118:e676‐e681.
Bucuvalas J, Filipovich L, Yazigi N, Narkewicz MR, Ng V, Belle SH, et al. Immunophenotype predicts outcome in pediatric acute liver failure. J Pediatr Gastroenterol Nutr 2013;56:311‐315.
DiPaola F, Grimley M, Bucuvalas J. Pediatric acute liver failure and immune dysregulation. J Pediatr 2014;164:407‐409.
McKenzie RB, Berquist WE, Nadeau KC, Louie CY, Chen SF, Sibley RK, et al. Novel protocol including liver biopsy to identify and treat CD8+ T‐cell predominant acute hepatitis and liver failure. Pediatr Transplant 2014;18:503‐509.
Molina RA, Katzir L, Rhee C, Ingram‐Drake L, Moore T, Krogstad P, et al. Early evidence of bone marrow dysfunction in children with indeterminate fulminant hepatic failure who ultimately develop aplastic anemia. Am J Transplant 2004;4:1656‐1661.
Gonzalez‐Casas R, Garcia‐Buey L, Jones EA, Gisbert JP, Moreno‐Otero R. Systematic review: hepatitis‐associated aplastic anaemia—a syndrome associated with abnormal immunological function. Aliment Pharmacol Ther 2009;30:436‐443.
Chapin CA, Burn T, Meijome T, Loomes KM, Melin‐Aldana H, Kreiger PA, et al. Indeterminate pediatric acute liver failure is uniquely characterized by a CD103(+) CD8(+) T‐cell infiltrate. Hepatology 2018;68:1087‐1100.
Leonis MA, Miethke AG, Fei L, Maynor S, Chapin CA, Bleesing JJH, et al. Four biomarkers linked to activation of CD8+ lymphocytes predict clinical outcomes in pediatric acute liver failure. Hepatology 2020 Apr 15. https://doi.org/10.1002/hep.31271 . [Epub ahead of print]
doi: 10.1002/hep.31271
Chapin CA, Melin‐Aldana H, Kreiger PA, Burn T, Neighbors K, Taylor SA, et al. Activated CD8 T‐cell hepatitis in children with indeterminate acute liver failure: results from a multicenter cohort. J Pediatr Gastroenterol Nutr 2020;71:713‐719.
Azhar N, Ziraldo C, Barclay D, Rudnick DA, Squires RH, Vodovotz Y. Analysis of serum inflammatory mediators identifies unique dynamic networks associated with death and spontaneous survival in pediatric acute liver failure. PLoS One 2013;8:e78202.
Zamora R, Vodovotz Y, Mi QI, Barclay D, Yin J, Horslen S, et al. Data‐driven modeling for precision medicine in pediatric acute liver failure. Mol Med 2017;22:821‐829.
Simonian MH. Spectrophotometric determination of protein concentration. Curr Protoc Cell Biol 2002;Appendix 3:Appendix 3B.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA‐seq data with DESeq2. Genome Biol 2014;15:550.
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000;25:25‐29.
Resource TGO. 20 years and still GOing strong. Nucleic Acids Res 2019;47:D330‐D338.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge‐based approach for interpreting genome‐wide expression profiles. Proc Natl Acad Sci U S A 2005;102:15545‐15550.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13:2498‐2504.
Merico D, Isserlin R, Stueker O, Emili A, Bader GD. Enrichment map: a network‐based method for gene‐set enrichment visualization and interpretation. PLoS One 2010;5:e13984.
Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA‐seq data. BMC Bioinformatics 2013;14:7.
Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan‐cancer immunogenomic analyses reveal genotype‐immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep 2017;18:248‐262.
Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf A, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 2013;39:782‐795.
Salehi S, Tavabie OD, Verma S, McPhail MJW, Farzaneh F, Bernal W, et al. Serum microRNA signatures in recovery from acute and chronic liver injury and selection for liver transplantation. Liver Transpl 2020;26:811‐822.
Chalin A, Lefevre B, Devisme C, Pronier C, Carrière V, Thibault V, et al. Serum CXCL10, CXCL11, CXCL12, and CXCL14 chemokine patterns in patients with acute liver injury. Cytokine 2018;111:500‐504.
Basset L, Chevalier S, Danger Y, Arshad MI, Piquet‐Pellorce C, Gascan H, et al. Interleukin‐27 and IFNγ regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis. J Mol Med (Berl) 2015;93:1355‐1367.
Cruikshank WW, Kornfeld H, Center DM. Interleukin‐16. J Leukoc Biol 2000;67:757‐766.
Joffre OP, Segura E, Savina A, Amigorena S. Cross‐presentation by dendritic cells. Nat Rev Immunol 2012;12:557‐569.
Liepelt A, Tacke F. Stromal cell‐derived factor‐1 (SDF‐1) as a target in liver diseases. Am J Physiol Gastrointest Liver Physiol 2016;311:G203‐G209.
DeLeve LD, Wang X, Wang L. VEGF‐sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration. Am J Physiol Gastrointest Liver Physiol 2016;310:G739‐G746.
Patel KR, Bertuch A, Sasa GS, Himes RW, Wu H. Features of hepatitis in hepatitis‐associated aplastic anemia: clinical and histopathologic study. J Pediatr Gastroenterol Nutr 2017;64:e7‐e12.