Year: 2022
Type: article
Study design: Observational Study
Abstract: Aim: Metabolic liver diseases, including alcohol- and non-alcoholic fatty liver diseases (ALD/NAFLD), are characterized by inflammation and decreased ability to prevent infections. Patients with severe alcohol-associated hepatitis (sAH) are particularly susceptible to infections while undergoing treatment with steroids. Understanding the immunological mechanisms for these responses is critical to managing the treatment of patients with metabolic liver diseases. Cytotoxic NK cells and CD8 T cells, using cytolytic granules, serve an important immunological role by killing infected cells, including monocytes. However, patients with sAH have dysfunctional NK cells, which cannot kill target cells, though the mechanism is unknown. Method: = 7-8 for all patient groups) on PBMCs isolated from patients with sAH and healthy controls (HC). Results: ScRNA-seq revealed receptors in NK cells and CD8 T cells required for cytotoxic cell recognition of activated monocytes were downregulated in patients with sAH compared to healthy controls. Granulysin was the most downregulated gene in both NK cells and effector CD8 T cells. In NK cells from HC, expression of granulysin, perforin, and granzymes A and B was highly correlated; however, in sAH, these genes lost coordinate expression, indicative of dysfunctional cytolytic granule formation. Finally, the expression of cytolytic granule proteins in NK cells was decreased from sAH, indicating reduced cytolytic granules. Conclusion: Together, these results suggest a loss of cytotoxic cell function in PBMCs from sAH that may contribute to a decreased ability to communicate with other immune cells, such as monocytes, and prevent the killing of infected cells, thus increasing the risk of infection.
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Funders: Cleveland Clinic, American College of Gastroenterology, Case Western Reserve University, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Novel therapeutics for alcoholic hepatitis - Cleveland Translational Component, Hyperammonemia reduces skeletal muscle protein synthesis via a beta-catenin-cMyc mediated impaired ribosomal biogenesis, Sarcopenia in cirrhosis is mediated by a hyperammonemic stress response, Immersive Training in Glycosciences, IRF3 activation promotes fibrotic liver injury in alcohol-associated-liver disease, Mechanisms of Malnutrition in Cirrhosis with Portosystemic Shunting, Nutritional modulation to minimize resistance exercise induced metabolic deregulations and improve training responsiveness in Chronic Obstructive Pulmonary Disease, C-Type Lectins and Immune Surveillance in ALD, Alcoholic Hepatitis Consortia: an intramural/extramural collaboration to unravel genetic determinants, IRAKM and Mincle in ALD, VCU-Atlanta Center for the Childhood Liver Disease Research Network (ChiLDReN), Alcohol and tissue injury, from mechanisms to treatments, Continuation of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Clinical Center-Cleveland site, Integrated Therapies for Alcohol use in Alcohol-associated Liver Disease (ITAALD)- Cleveland Clinic Clinical Center, Mechanisms of HIF1 alpha mediated dysregulated skeletal muscle proteostasis in alcoholic liver disease, Transcriptional and non-transcriptional function of IRF3 in ALD
OpenAlex ID: W4312898427