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Differential blood transcriptome modules predict response to corticosteroid therapy in alcoholic hepatitis
Shvetank Sharma1, Sukriti Baweja1, Jaswinder S Maras1
1Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
JHEP Reports : Innovation in Hepatology
|June 7, 2021
Summary
Peripheral blood mononuclear cells (PBMCs) in severe alcoholic hepatitis (SAH) show distinct gene expression profiles. Non-responders to corticosteroids exhibit higher activity in T and B cell, NK cell, and mitochondrial pathways, indicating potential for early treatment assessment.
Area of Science:
- Immunology
- Genomics
- Hepatology
Background:
- Severe alcoholic hepatitis (SAH) treatment with corticosteroids is ineffective for some patients, with response only evident after 7 days.
- Understanding peripheral blood mononuclear cell (PBMC) profiles in SAH patients is crucial for predicting treatment outcomes.
- Steroid non-responders (NR) and responders (R) in SAH have distinct clinical trajectories.
Purpose of the Study:
- To investigate the gene expression profiles of PBMCs in SAH patients at baseline and during corticosteroid therapy.
- To identify molecular differences between steroid-responders (R) and steroid-non-responders (NR) in SAH.
- To explore the potential for early prediction of corticosteroid response in SAH using blood transcription modules (BTMs).
Main Methods:
- RNA-sequencing analysis of PBMCs from 32 SAH patients at baseline and after 7 days of corticosteroid treatment.
- Classification of patients into R and NR groups (n=16 each) using the Lille model.
- Identification and activity assessment of 346 blood transcription modules (BTMs) representing immune cell types and functions.
Main Results:
- At baseline, 345 BTMs were upregulated in NR compared to R, with prominent modules related to lymphoid cells (T, B, NK), cell division, and mitochondrial electron transport chain (ETC).
- NR group showed significantly greater T and B cell activation/proliferation and differentiation compared to R.
- After 7 days of corticosteroids, NR showed no significant BTM changes, while R exhibited downregulation of innate and adaptive immunity BTMs.
Conclusions:
- Upregulated PBMCs gene modules associated with T and B cell activation/proliferation, NK cells, and mitochondrial ETC are characteristic of SAH patients who do not respond to steroids.
- These findings suggest a potential biomarker for predicting corticosteroid response in SAH.
- Early identification of non-responders could facilitate timely alternative treatment strategies.
Keywords:
Alcoholic liver diseaseBTM, blood transcription moduleCTP score, Child-Turcott-Pugh scoreDEGs, differentially expressed genesETC, electron transport chainGlucocorticoid receptorMDF, Maddrey’s discriminant functionMELD, model for end-stage liver diseaseNK cells, natural killer cellsNR, non-respondersNR3C1NR3C1, nuclear receptor subfamily 3 group c gene member 1OxPhos, oxidative phosphorylationPBMCs, peripheral blood mononuclear cellsR, respondersRNA-seq, RNA sequencingSAH, severe alcoholic hepatitisSteroidTranscriptome
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