Cellular interactions in self-directed immune mediated liver diseases

Abstract

The lymphocyte population must traverse a complex path throughout their journey to the liver. The signals which these cells must detect, including cytokines, chemokines and other soluble factors, steer their course towards further crosstalk with other hepatic immune cells, hepatocytes and biliary epithelial cells. A series of specific chemokine receptors and adhesion molecules drive not only the recruitment, migration, and retention of these cells within the liver, but also their localisation. Perturbation of these interactions and failure of self-recognition drives the development of several autoimmune liver diseases. Understanding the nature of these interactions develops our understanding of immune mediated liver disease pathogenesis, providing new opportunities for intervention to resolve uncontrolled inflammation.In this review, we provide an overview of the complex recruitment pathways and cellular interactions which position lymphocyte populations in the liver. We discuss how these are disrupted in autoimmune diseases and highlight the mechanism of immune cells inside hepatocytes (emperipolesis) in autoimmune hepatitis and immune cells inside biliary epithelial cells (intra-epithelial lymphocyte) in primary biliary cholangitis as well as avenues to manipulate these pathways for therapy. We also cover the immune mediated tissue injury mechanisms impacted by checkpoint inhibitors, leading to checkpoint inhibitor-induced liver injury (CHILI). Finally, we describe emerging immune-based therapies, including regulatory T cell, anti-cytokine and anti-chemokine therapies, cytokine supplementation such as interleukin-2 as well as numerous modalities of co-inhibitory molecule manipulation, including bispecific T cell engagers (BiTEs) and checkpoint inhibitor bispecific T cell engagers (CiTEs) and discuss their potential application in the treatment of autoimmune liver diseases.Immune-mediated liver disease encompasses two broad categories: autoimmune and inflammatory liver injury, the former resulting from a breakdown in immunological self-tolerance. These share common features, namely histologically dense immune infiltrates, autoantibody positivity and immunoglobulin elevation. Whilst well defined in their epidemiology, presentation and diagnostic evaluation, their treatment remains an unmet clinical need. Our incomplete understanding of the mechanisms leading to breakdown in immunological self-tolerance and our inability to restore immune homeostasis hampers present progress in treatment. This review summarises recent advances in our understanding of the loss of hepatic tolerance and the cellular interactions leading to this, including immune cell invasion towards hepatocytes and biliary epithelial cells, checkpoint-induced immune-mediated liver injury (CHILI) and concludes with current progress in treatment strategies.