Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease

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.

Immune Equilibrium Depends on the Interaction Between Recognition and Presentation Landscapes

“…Bregs exert their functions due to the production of anti-inflammatory cytokines, inhibit different populations of immune cells, and can induce the formation of Tregs from effector T cells acting as tolerogenic antigenpresenting cells, which do not exclude the Ag-specific effect of Bregs (91,95,96). Similar to T cells, irrelevant induction of Bregs and an imbalance between effector and regulatory B cells play a significant role in the pathogenesis of different autoimmune and oncologic processes, in patients with chronic infections and graft rejections (97)(98)(99)(100)(101). However, in this case, a transition Beff ↔ Breg could be primarily associated with the peculiarities of the microenvironment and only indirectly mediated by the shifts of spectra of the presented antigens and the conditions of their presentations via T cells (91,(102)(103)(104).…”

Features of the immunoreactivity T and B lymphocytes subpopulations and cytokine imbalance in patients with hepatosplenomegaly of different etiology

“…In group I a low level of IL-1β against the background of a high concentration of IL-6 indicates the resolution of an acute inflammatory reaction, since one of the main functions of IL-6 is self-limitation of the inflammatory response by suppressing the production of TNF-α and IL-1β, and stimulation synthesis of an antagonist of the IL-1 receptor and the soluble TNF-p55 receptor [15]. Through stimulating B lymphocytes, IL-6 induces the synthesis of immunoglobulins and also participates in the differentiation of cytotoxic T lymphocytes [16].…”

“…An increase in the synthesis of IL-10 was observed in all groups, but most pronounced in groups I and II. This led to a decrease in anti-infectious protection, the development of immunosuppression, disruption of reparative processes due to a shift in the balance towards Th2 [16]. The high production of IL-10 is probably associated with a high level of immunoglobulins in these groups and as a consequence a high immune complexes concentration which acting on macrophages induces the secretion of many cytokines, including IL-10.…”

Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities

“…Indeed, although results have yet to be released, a clinical trial is underway examining the therapeutic effect of MSC-derived EVs in the autoimmune disease Type I diabetes (NCT02138331). Pre-clinical success in the treatment of sepsis ( Song et al, 2017 ), inflammatory bowel disease ( Yang et al, 2015 ; Mao et al, 2017 ), and multiple sclerosis ( Casella et al, 2018 ; Laso-Garcia et al, 2018 ) suggests EV-mediated treatment of inflammatory and autoimmune disorders ( Coakley et al, 2017 ; Sharma et al, 2017 ; Fujita et al, 2018 ; Xu H. et al, 2019 ; Goodman and Davies, 2020 ; Kahmini and Shahgaldi, 2020 ; Xu et al, 2020 ; Horst et al, 2021 ) may soon expand further into patient trials.…”