The FGL-1/LAG-3 Axis is Associated With Disease Course in Alcohol-associated Hepatitis: A Preliminary Report

Alcohol-associated hepatitis (AH) has a short-term mortality rate of up to 40% primarily related to impaired hepatocyte regeneration and uncontrolled liver inflammation. The acute phase protein fibrinogen-like protein 1 (FGL-1) produced by hepatocytes stimulates hepatocyte proliferation by autocrine signaling. FGL-1 also is a ligand for the inhibitory T cell receptor lymphocyte activation gene 3 (LAG-3). In these ways, FGL-1 and LAG-3 have beneficial interactions that could be interrupted in AH.

We aimed to characterize FGL-1 and LAG-3 in patients with AH and describe their relationship with the disease state and course.

Thirty-two patients with AH were included at diagnosis and followed up for 3 years. We measured the hepatic gene expression of FGL-1 and LAG-3 using RNA sequencing, plasma FGL-1 and soluble (s)LAG-3 using ELISA, and LAG-3⁺CD8⁺ T cells using flow cytometry. Healthy persons (HC) and patients with stable alcohol-associated cirrhosis served as controls.

At diagnosis of AH, liver FGL-1 mRNA was increased when compared to HC, whereas plasma FGL-1 was unchanged. In contrast, liver LAG-3 mRNA was reduced in AH. Plasma sLAG-3 levels and the frequency of LAG-3⁺CD8⁺ T cells were as in HC. However, those patients who had the lowest plasma FGL-1 and the lowest frequency of LAG-3⁺CD8⁺ T cells at diagnosis had the highest disease severity and mortality.

Our data suggest that an impaired FGL-1/LAG-3 axis may be involved in the pathogenesis and course of AH.