Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20251, Hamburg, Germany.
Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20251, Hamburg, Germany.
Cell Mol Immunol. 2021 Jan;18(1):92-111. doi: 10.1038/s41423-020-00568-6. Epub 2020 Oct 27.
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.
肝脏是一个重要的免疫器官，控制着全身的耐受性。肝脏内存在专业的和非常规的抗原提呈细胞，对于诱导和维持耐受至关重要。在稳态下协调免疫反应依赖于健康和良好的免疫性肝微环境，这是由肝内抗原提呈细胞与肝内和肝浸润的白细胞之间的相互作用维持的。在病原体或自身抗原的作用下，耐受被未知机制所破坏。肝内实质细胞和非实质细胞表现出独特的抗原提呈特性。通过传统和非传统机制从肠道呈递微生物和内源性脂质、代谢物和肽衍生抗原，可以教育肝内免疫细胞并引发效应应答或耐受。这种平衡的破坏会导致自身免疫性肝病，如自身免疫性肝炎、原发性胆汁性胆管炎和原发性硬化性胆管炎。尽管这些自身免疫性肝病的确切病因尚不清楚，但人们认为，对自身抗原和微生物代谢物和脂质的耐受性的破坏，以及胆汁酸组成的改变，可能导致效应细胞激活和极化的改变，并可能减少或损害保护性抗炎性调节性 T 和 B 细胞应答。此外，抗原和抗原：MHC 复合物通过细胞间的 trogocytosis 或细胞外囊泡在不同（非）免疫细胞之间的经典和非经典传递，可能在肝内炎症和耐受的诱导中发挥作用。在这里，我们总结了抗原呈递、自身抗体产生的新进展，以及在自身免疫性肝病的特征和治疗中应用新型治疗方法的新进展。
