Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological features of interface hepatitis. AIH therapeutic management still relies on the administration of corticosteroids, azathioprine and other immunosuppressants like calcineurin inhibitors and mycophenolate mofetil. Withdrawal of immunosuppression often results in disease relapse, and, in some cases, therapy is ineffective or associated with serious side effects. Understanding the mechanisms underlying AIH pathogenesis is therefore of paramount importance to develop more effective and well tolerated agents capable of restoring immunotolerance to liver autoantigens. Imbalance between effector and regulatory cells permits liver damage perpetuation and progression in AIH. Impaired expression and regulation of CD39, an ectoenzyme key to immunotolerance maintenance, have been reported in Tregs and effector Th17-cells derived from AIH patients. Interference with these altered immunoregulatory pathways may open new therapeutic avenues that, in addition to limiting aberrant inflammatory responses, would also reconstitute immune homeostasis. In this review, we highlight the most recent findings in AIH immunopathogenesis and discuss how these could inform and direct the development of novel therapeutic tools.
Highlights
Autoimmune hepatitis (AIH) was initially described as a severe form of fluctuating persistent hepatitis, associated with acneiform rashes, spider angiomas, amenorrhea and marked elevation of serum immunoglobulins [1]
We have shown that CD4+CD25high Tregs from AIH patients display low levels of Galectin-9, contain higher frequencies of IFNg+ and IL-17+-cells, while displaying lower proportions of FOXP3+, IL-10+ and TGF-b+-cells
In a subsequent study we have reported that AIH Tregs display reduced ability to produce IL-10, this resulting in low responsiveness to low dose IL-2, as demonstrated by inability to upregulate the phosphorsignal-transducer-and-activator-of-transcription-5 [73]
Summary
Autoimmune hepatitis (AIH) was initially described as a severe form of fluctuating persistent hepatitis, associated with acneiform rashes, spider angiomas, amenorrhea and marked elevation of serum immunoglobulins [1]. Subsequent studies showed that AIH occurs in individuals of all ages and, present in both sexes, is prevalent in females [2]. AIH is diagnosed based on the presence of hypergammaglobulinemia, serum autoantibodies and histological features of interface hepatitis [3]. While positivity for anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA) identifies type-1 AIH (AIH-1), liver-kidney-microsomal-type-1 (LKM-1) antibodies, which target the cytochrome P4502D6 (CYP2D6) liver enzyme [4], are the serological hallmarks of type-2 AIH (AIH-2) [5].
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