Abstract
The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.
Highlights
Autoimmune liver diseases (AILDs), such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), are immune-mediated liver injuries that are characterized by lymphocyte infiltration into the liver, increases in circulating immunoglobulins, elevated liver enzymes, the generation of autoantibodies, and genetic risk factors, such as human leukocyte antigen (HLA) loci associations that predispose individuals to developing AILDs
Adoptively transferred induced pluripotent stem cell (iPSC)-mucosa-associated invariant T (MAIT) cells expressed the gut/liver homing receptors CXCR3 and CXCR6, demonstrating that the expression of these liver addressins was inducible. These findings impressively show that the adoptive transfer of iPSC-MAIT cells harbors the potential to restore MAIT cell function (Fig. 5A)
In the murine AIH model of concanavalin (Con) A-induced hepatitis, liver injury is mediated by TNFα, and iNKTmediated cytotoxicity is enhanced by the autocrine secretion of IL4, leading to the subsequent release of perforin and granzyme B (GzmB), as well as FasL-mediated HC death.[214,215,216]
Summary
Autoimmune liver diseases (AILDs), such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), are immune-mediated liver injuries that are characterized by lymphocyte infiltration into the liver, increases in circulating immunoglobulins, elevated liver enzymes, the generation of autoantibodies, and genetic risk factors, such as HLA loci associations that predispose individuals to developing AILDs. SOLUBLE MHCS IN TOLERANCE AND THE DIAGNOSTIC AND THERAPEUTIC EXPLOITATION OF CROSS-DRESSING AND TROGOCYTOSIS In addition to membrane-bound peptide-loaded MHCs, soluble pMHCs play an important role in regulating tolerance induction; liver allografts are the source of significant amounts of soluble donor MHC class I molecules that remain detectable in the recipients circulation for extended periods of time.[61] The fact that the liver is the largest solid organ leads to the hypothesis that the massive release of allogenic MHC-I molecules supports tolerance, since soluble MHC-I interacts with potentially alloreactive T cells in the absence of a costimulatory signal. EVs are attractive biocompatible tools to deliver therapeutics to the liver, since they can be “transfected” to carry therapeutic miRNAs and RNAi or can be alternatively loaded with chemotherapeutics, given that they are able to present specific addressins on their surface, such as CXCR3 or CCR6, that could be used to enhance liver targeting.[34]
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