Under-Evaluated or Unassessed Pathogenic Pathways in Autoimmune Hepatitis and Implications for Future Management.

Autoimmune hepatitis is a consequence of perturbations in homeostatic mechanisms that maintain self-tolerance but are incompletely understood. The goals of this review are to describe key pathogenic pathways that have been under-evaluated or unassessed in autoimmune hepatitis, describe insights that may shape future therapies, and encourage investigational efforts. The T cell immunoglobulin mucin proteins constitute a family that modulates immune tolerance by limiting the survival of immune effector cells, clearing apoptotic bodies, and expanding the population of granulocytic myeloid-derived suppressor cells. Galectins influence immune cell migration, activation, proliferation, and survival, and T cell exhaustion can be induced and exploited as a possible management strategy. The programmed cell death-1 protein and its ligands comprise an antigen-independent inhibitory axis that can limit the performance of activated T cells by altering their metabolism, and epigenetic changes can silence pro-inflammatory genes or de-repress anti-inflammatory genes that affect disease severity. Changes in the intestinal microbiota and permeability of the intestinal mucosal barrier can be causative or consequential events that affect the occurrence and phenotype of immune-mediated disease, and they may help explain the female propensity for autoimmune hepatitis. Perturbations within these homeostatic mechanisms have been implicated in experimental models and limited clinical experiences, and they have been favorably manipulated by monoclonal antibodies, recombinant molecules, pharmacological agents or dietary supplements. In conclusion, pathogenic mechanisms that have been implicated in other systemic immune-mediated and liver diseases but under-evaluated or unassessed in autoimmune hepatitis warrant consideration and rigorous evaluation.