| Antigen presentation |
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Genetic associations with HLA-(human leucocyte antigen) variants hint at a relevant role of antigen presentation for both DILI/HDS and AIH (e.g., HLA-DRB1*03:01 and DRB1*04:01 are associated with the risk for AIH and HLA-B*57:01 is associated with the risk for flucloxacillin-induced DILI)
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In DILI/HDS, neoantigen formation and haptenization seem to be involved, but have been investigated in only few cases (e.g., in flucloxacillin-induced DILI)
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The hepatic microenvironment has not been characterized thoroughly for DILI/HDS yet (different kinds of antigen presenting cells, costimulatory molecules, etc.)
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For the majority of AIH patients, the main antigen is unknown. In 5-10% of AIH patients, disease-specific antibodies (anti-SLPA/LP, anti-LKM and anti-LC1) are detected for which the respective antigens have been characterized (SEPSECS, CYP, 2D6 and FTCD). These antigens could be involved in the pathogenesis of AIH.
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| Metabolism |
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Drug- and host-specific factors influence metabolism and susceptibility to DILI/HDS (lipophilicity, dosage, age, sex, ongoing inflammation etc.).
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Genetic variants of checkpoints of phase I and II biotransformation increase the risk for DILI/HDS (e.g., polymorphisms of NAT2 have been associated with the risk for isoniazide-induced DILI)
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New treatments for cholestatic liver diseases like PBC might offer therapeutic options for impaired hepatobiliary excretion of drugs in DILI/HDS
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| Pro-inflammatory mechanisms |
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In flucloxacillin- and amoxicillin-clavulanate-induced DILI, peripheral effector cells have been characterized and IFNγ has been identified as a relevant proinflammatory cytokine.
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In AIH, conflicting results exist about the main proinflammatory cell type (CD4+, Th1, Th2, CD8+, Th17 or γδT cells)
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A full characterization of the composition of pro-inflammatory immune competent cells and effector cytokines is pending, both for DILI/HDS and AIH. Intrahepatic analyses are required, since peripheral blood cells probably not reflect the situation in the liver
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Identification of relevant pro-inflammatory pathways can offer specific treatment options for both DILI/HDS and AIH
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| Regulatory mechanisms |
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An impairment of regulatory mechanisms has been proposed for several inflammatory liver diseases
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Mediators of tolerance are, among others, regulatory T cells (Treg) and anti-inflammatory cytokines like IL-10 or TGFβ
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Restoration of tolerance could be a therapeutic aim for both DILI/HDS and AIH
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In mild forms of DILI, transient elevation of liver enzymes returning to normal levels spontaneously might represent restoration of tolerance. The molecular mechanisms for these clinical observations have not yet been analyzed
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