Epigenetic basis for monocyte dysfunction in patients with severe alcoholic hepatitis

Area of Science:

• Immunology
• Hepatology
• Genomics

Background:

• Severe alcoholic hepatitis (sAH) increases susceptibility to infections, leading to poor outcomes.
• The underlying cellular and molecular mechanisms of impaired host defense in sAH are not fully understood.

Purpose of the Study:

• To investigate the immune cell dysfunction in patients with severe alcoholic hepatitis.
• To identify the molecular and epigenetic mechanisms contributing to increased infection susceptibility in sAH.

Main Methods:

• Phenotypic analysis and ex vivo stimulation of whole blood from sAH patients, healthy controls, and chronic alcohol consumers.
• Transcriptomic (RNA-seq) and epigenomic (ATAC-seq) profiling of CD14+ monocytes.
• Evaluation of monocyte and dendritic cell responses to pathogen-associated molecular patterns (PAMPs).

Main Results:

• Monocytes and dendritic cells in sAH patients showed altered expression of surface markers and impaired pro-inflammatory responses to PAMPs.
• Reduced cytokine polyfunctionality in sAH patients correlated with infection risk and mortality.
• CD14+ monocytes from sAH patients exhibited altered transcriptional and epigenomic profiles, with downregulated immune/metabolic pathways and upregulated immunomodulatory factors.

Conclusions:

• Altered monocyte transcriptional programs and functional properties in sAH are driven by epigenetic determinants.
• These epigenetic factors contribute to immune cell dysfunction and increased infection susceptibility in severe alcoholic hepatitis.