Restoring Balance in Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic, immune-mediated inflammatory liver disease leading to progressive hepatocyte destruction. Histologically, it is characterized by interface hepatitis with piecemeal necrosis and plasmacytosis. Most patients display hypergammaglobulinemia and liver autoantigen–specific autoantibodies. Furthermore, serum aminotransferases are often elevated. If untreated, AIH typically progresses to fibrosis and cirrhosis, resulting in complications such as portal hypertension and hepatic decompensation. Acute severe AIH may present with fulminant liver failure requiring transplantation. For a more comprehensive overview of AIH, please refer to a recent report of the International Autoimmune Hepatitis Group.¹

Currently, the standard of care mainly consists of traditional immunosuppression with corticosteroids and cytostatic drugs, such as prednisone or prednisolone alone or in combination with azathioprine. Only very few alternatives, like a B cell depletion therapy with rituximab or blockade of interleukin (IL)-2 synthesis by calcineurin inhibitors (tacrolimus, cyclosporine), have been considered. This stands in contrast to many other autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, or psoriasis, for which novel more specific therapeutics, including biopharmaceuticals, have been successfully introduced into clinical practice. Considering that the immunopathologic mechanisms of AIH have been investigated for many decades, resulting in the identification of cellular and soluble drives of the diseases, it comes to somewhat of a surprise that more specific treatments are not being used on a regular basis.

Now, a new player has been identified that might offer novel possibilities for restoring immune balance in AIH. The research team around Dean Tian identified the ubiquitin-conjugating enzyme E2O (UBE2O) as a protective factor in AIH.² UBE2O is an atypical ubiquitin-conjugating enzyme that combines the activities of the ubiquitin-conjugating enzyme E2 and the ubiquitin–protein ligase E3 and can directly bind and mono- or polyubiquitinate proteins. Lei et al found that UBE2O expression is significantly reduced in both patients with AIH and murine models of AIH, correlating with disease severity.

As a murine model for chronic AIH, they injected plasmids expressing human CYP2D6, one of the major autoantigens in human AIH.³ They further administered an additional plasmid containing the UBE2O gene using the high-volume rapid injection method. The injection of large volumes of DNA via the tail vein causes cardiac congestion and backflow into the liver, generating temporary pores in the membranes of hepatocytes.⁴ Hepatocyte-specific overexpression of UBE2O alleviated liver inflammation and fibrosis while restoring the regulatory T cell (Treg)/Th17 equilibrium. Mechanistically, the authors could convincingly demonstrate that high levels of UBE2O promote ubiquitination and subsequent proteasome-mediated degradation of Y-box binding protein 1 (YBX1), a transcription factor for genes such as IL-6. The observed reduction in IL-6 secretion went along with a differentiation of naïve CD4 T cells toward Tregs rather than Th17 cells (Figure 1). Thus, UBE2O, via YBX1 degradation and IL-6 reduction, restored a healthy immune balance. This protective effect of UBE2O was reversed when YBX1 was also overexpressed. In summary, the findings of Lei et al implicate the UBE2O–YBX1–IL-6 pathway as a potential therapeutic target for AIH.

Figure 1.

The UBE2O–YBX1–IL-6 pathway determines the outcome of murine AIH. AIH, autoimmune hepatitis; IL, interleukin; Tregs, regulatory T cells; UBE20, ubiquitin-conjugating enzyme E2O; YBX1, Y-box binding protein 1.

Although Lei et al demonstrated UBE2O to be not just a biomarker for AIH, but also a credible driver-level intervention point, UBE2O overexpression in patients might be problematic. First, from a technical point of view, a delivery of UBE2O plasmid via hydrodynamic gene delivery is not clinically translatable. However, other means of liver-specific delivery, including adeno-associated viruses or messenger RNA delivery via lipid nanoparticles, could be considered. Second, UBE2O is a pleiotropic enzyme involved in many vital mechanisms, such as protein homeostasis, metabolism, and DNA repair. Thus, UBE2O overexpression might result in unfavorable off-target ubiquitination. Rather than targeting UBE2O directly, an inhibition of the downstream elements YBX1 or IL-6 might be more feasible. For example, the use of proteolysis-targeting chimera might allow targeting YBX1 specifically, causing its degradation through engagement of the E3 ubiquitin ligase.⁵ Another possibility would be the use of anti–IL-6 antibodies, such as tocilizumab. Although anti–IL-6 antibodies have been introduced into clinical practice for many autoimmune diseases, including rheumatoid arthritis and treatment of the cytokine release syndrome, they have not yet been widely considered as a treatment for AIH. The beneficial use of tocilizumab has been reported in a patient with refractory checkpoint inhibitor hepatitis, an autoimmune-mediated liver disease that is associated with checkpoint inhibitor therapies and shares some similarities with AIH.⁶ In contrast, another case report describes the de novo appearance of AIH after tocilizumab therapy in a patient with adult-onset Still’s disease, a systemic inflammatory disease.⁷ Further, IL-6 is not purely pathogenic because it also contributes to liver regeneration.⁸ Thus, treatment of AIH with anti–IL-6 antibodies might result in somewhat paradoxical outcomes.

AIH remains a challenging disease with limited therapeutic options, despite well-characterized immunopathology. The identification of the UBE2O–YBX1–IL-6 axis as a regulator of immune balance provides a promising new avenue for intervention, highlighting mechanisms that could be leveraged to restore Treg/Th17 equilibrium. However, translational challenges and the pleiotropic roles of these molecules suggest that indirect targeting strategies may be more feasible and warrant further investigation.