Characteristics of immune checkpoint regulators and potential role of soluble TIM-3 and LAG-3 in male patients with alcohol-associated liver disease.

The involvement of immune checkpoint regulators (ICs) in alcohol-associated liver diseases (ALDs) is still largely unknown. Here, we analyzed the levels of 16 soluble ICs (sICs) in male patients with ALD to determine their clinical significance. The 16 sICs were measured using a luminex-based multiplex assay in 115 patients with ALD and 47 healthy controls (HCs). The expressions of membrane-type (m) PD-1 and mCTLA-4 on CD4+ and CD8+ T lymphocytes and NK cells of 28 patients with ALD and 8 HCs were also measured. Correlation test and risk assessment were also conducted to evaluate biomarkers of ALD in clinical practice. Our results show that four sICs were upregulated (sCTLA-4, sTIM-3, sCD27, and sGITR) and two sICs were downregulated (sLAG-3 and sHVEM) in ALD. mPD-1 expression was significantly more greatly increased on CD4+T lymphocytes in the ALD group than in the HC group (p = 0.009). sTIM-3 was positively correlated, while sLAG-3 was negatively correlated with non-invasive liver fibrosis markers (AST/ALT, APRI, GPR, and FIB-4) and Maddrey discriminant function score. Risk factor analysis showed that sTIM-3 was consistently associated with ALD severity in both MDF and FIB-4 scores, and sLAG-3 was associated with FIB-4 scores. This study revealed the involvement of sCTLA-4, sTIM-3, sCD27, sGITRL, sLAG-3, and sHVEM in discriminating male patients with ALD. Expressions of sTIM-3 and sLAG-3 were correlated with liver fibrosis markers and significantly associated with ALD severity, which can be further studied as diagnostic markers and therapeutic targets in ALD.