T cell hyporesponsiveness distinguishes Autoimmune Hepatitis from Drug-Induced Liver Injury

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Autoimmune hepatitis (AIH) and drug-induced liver-injury (DILI) have overlapping features and are difficult to distinguish. Both conditions are presumably driven by a T cell response to hepatocyte antigens – autoantigens in AIH and neoantigens in DILI. Since AIH and DILI require different management, improved understanding of common and distinctive immune features is needed. We analysed clinical and histological features of untreated AIH (n=11) and DILI (n=9) patients and immune cells in blood and liver by flow cytometry. Immune profiling was repeated after disease remission. Untreated AIH and DILI patients manifested similar serum ALT levels (AIH: 779 U/l, DILI: 839 U/l), mHAI scores (AIH: 8, DILI: 9), and numbers of liver-infiltrating CD3+T cells. Both conditions showed a marked increase in hepatic CD8+T cells with an activated phenotype (CD38, ICOS, PD-1), as compared to MASLD (n=5). However, AIH showed distinctively lower levels of effector molecules (IFNg, FASL, IL-2) in hepatic T cells or in blood T cells. Moreover, the numbers of migrating CCR7+Foxp3+CD25+Tregs was significantly increased in AIH blood (AIH=4,28; DILI: 2,55%; p=0,01). After disease remission, the T cell phenotype persisted in treated AIH, whereas the activated T cell phenotype normalised in DILI. Conclusion: Clinically and histologically AIH and DILI were indistinguishable. However, AIH was characterised by distinctive markers of hypo-responsiveness in effector T cells and increased migratory capacity of Tregs. Although both AIH and DILI patients presented with acute clinical disease, the observed immune adaptations in AIH suggest a more long-standing immune response with extended preclinical phase. Publication History Article published online: 20 January 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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