Differential iNKT and T Cells Activation in Non-Alcoholic Fatty Liver Disease and Drug-Induced Liver Injury

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) and idiosyncratic drug-induced liver injury (DILI) could share molecular mechanisms involving the immune system. We aimed to identify activation immunological biomarkers in invariant natural killer T (iNKT) and CD4/CD8+ T cells in NAFLD and DILI. Methods: We analyzed the activation profile (CD69, CD25, and HLA-DR) and natural killer group 2 member D (NKG2D) on iNKT cells, and CD4/CD8 T cells in peripheral blood mononuclear cells from NAFLD, with or without significant liver fibrosis, and DILI patients. Results: There was an increase in iNKT cells in NAFLD patients compared to DILI or control subjects. Regarding the cellular activation profile, NAFLD with significant liver fibrosis (F ≥ 2) displayed higher levels of CD69+iNKT cells compared to NAFLD with none or mild liver fibrosis (F ≤ 1) and control patients. CD69+iNKT positively correlated with insulin resistance, aspartate aminotransferase (AST) level, liver fibrosis-4 index (FIB4) and AST to Platelet Ratio Index (APRI). DILI patients showed an increase in CD69+ and HLA-DR+ in both CD4+ and CD8+ T cells, detecting the most relevant difference in the case of CD69+CD8+ T cells. Conclusions: CD69+iNKT may be a biomarker to assess liver fibrosis progression in NAFLD. CD69+CD8+ T cells were identified as a potential distinctive biomarker for distinguishing DILI from NAFLD.

Analysis of traditional Chinese medicine syndrome types and frequency changes of CD8+ and CD25+ T cells in metabolic-related fatty liver disease

“…Scholars have analyzed the activation profiles of iNKT cells, natural killer gene 2 members, and CD 4 /CD 8 T cells in peripheral blood mononuclear cells of NAFLD patients and DILI patients with or without significant liver fibrosis. CD 8 T cells were identified as a potential biomarker for distinguishing between liver fibrosis and MAFLD (13). In addition, animal experiments have found that CD 8 T lymphocytes exhibit a decrease in CD 25 activation markers under the action of co-stimulatory molecules expressed in dendritic cells (14).…”

Deciphering the liver enigma: distinguishing drug-induced liver injury and metabolic dysfunction-associated steatotic liver disease—a comprehensive narrative review

“…Other potential biomarkers for DILI are glutamate dehydrogenase, high mobility group protein B1, and macrophage colony-stimulating factor receptor; however further studies are needed for the validation of these markers [3]. Finally, a recent prospective cohort study has identified several protein biomarkers that could be useful to diagnose and distinguish DILI from any other acute liver injury in clinical practice, with fructose-1,6-bisphosphatase 1 being of particular interest [78].…”

Immunophenotyping to improve the mechanistic understanding of idiosyncratic drug-induced liver injury: clinical implications and future directions

“…Therefore, immunophenotyping of patients at the time of liver injury would be useful to unravel the pathogenetic details of liver toxicity and to stop using empiric aggressive therapies (such as corticosteroids or alternative immune regulatory agents, when hepatotoxicity is unresponsive to oral steroids) to mitigate these adverse events. Subsequently, our group published another study [32] on extended immunophenotyping of DILI and MAFLD, focusing particularly on the iNK-T population. The highest level of iNK-T was found in PBMCs from MAFLD patients with significant liver fibrosis, suggesting a role for iNK-T in MAFLD progression.…”