The liver is a tolerogenic organ with exquisite mechanisms of immune regulation that ensure upkeep of local and systemic immune tolerance to self and foreign antigens, but that is also able to mount ...effective immune responses against pathogens. The immune privilege of liver allografts was recognized first in pigs in spite of major histo-compatibility complex mismatch, and termed the ＂liver tolerance effect＂. Furthermore, liver transplants are spontaneously accepted with only low-dose immunosuppression, and induce tolerance for non-hepatic co-transplanted allografts of the same donor. Although this immunotolerogenic environment is favorable in the setting of organ transplantation, it is detrimental in chronic infectious liver diseases like hepatitis B or C, malaria, schistosomiasis or tumorigenesis, leading to pathogen persistence and weak anti-tumor effects. The liver is a primary site of T-cell activation, but it elicits poor or incomplete activation of T cells, leading to their abortive activation, exhaustion, suppression of their effector function and early death. This is exploited by pathogens and can impair pathogen control and clearance or allow tumor growth. Hepatic priming of T cells is mediated by a number of local conventional and nonconventional antigen-presenting cells （APCs）, which promote tolerance by immune deviation, induction of T-cell anergy or apoptosis, and generating and expanding regulatory T cells. This review will focus on the communication between classical and nonclassical APCs and lymphocytes in the liver in tolerance induction and will discuss recent insights into the role of innate lymphocytes in this process.
Renal inflammation, induced by autoantigen recognition or toxic drugs, leads to renal tissue injury and decline in kidney function. Recent studies have demonstrated the crucial role for regulatory T ...cells in suppressing pathogenic adaptive but also innate immune responses in the inflamed kidney. However, there is also evidence for other immune cell populations with immunosuppressive function in renal inflammation. This review summarizes mechanisms of immune cell regulation in immune-mediated glomerulonephritis and acute and chronic nephrotoxicity.
In sterile liver inflammation, danger signals are released in response to tissue injury to alert the immune system; e.g., by activation of the NLRP3 inflammasome. Recently, IL-33 has been identified ...as a novel type of danger signal or "alarmin", which is released from damaged and necrotic cells. IL-33 is a pleiotropic cytokine that targets a broad range of immune cells and exhibits pro- and anti-inflammatory properties dependent on the disease. This review summarizes the immunomodulatory roles of the NLRP3 inflammasome and IL-33 in sterile liver inflammation and highlights potential therapeutic strategies targeting these pathways in liver disease.
The clearance of apoptotic cells is pivotal for both maintaining tissue homeostasis and returning to homeostasis after tissue injury as part of the regenerative resolution response. The liver is ...known for its capacity to remove aged and damaged cells from the circulation and can serve as a graveyard for effector T cells. In particular Kupffer cells are active phagocytic cells, but during hepatic inflammatory responses incoming neutrophils and monocytes may contribute to pro-inflammatory damage. To stimulate resolution of such inflammation, myeloid cell function can change, via sensing of environmental changes in the inflammatory milieu. Also, the removal of apoptotic cells via efferocytosis and the signaling pathways that are activated in macrophages/phagocytes upon their engulfment of apoptotic cells are important for a return to tissue homeostasis. Here, we will discuss, how efferocytosis mechanisms in hepatic macrophages/phagocytes may regulate tissue homeostasis and be involved in tissue regeneration in liver disease.
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.
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein that is expressed on epithelial, endothelial and immune cells. CEACAM1 is a differentiation antigen ...involved in the maintenance of epithelial polarity that is induced during hepatocyte differentiation and liver regeneration. CEACAM1 regulates insulin sensitivity by promoting hepatic insulin clearance, and controls liver tolerance and mucosal immunity. Obese insulin-resistant humans with non-alcoholic fatty liver disease manifest loss of hepatic CEACAM1. In mice, deletion or functional inactivation of CEACAM1 impairs insulin clearance and compromises metabolic homeostasis which initiates the development of obesity and hepatic steatosis and fibrosis with other features of non-alcoholic steatohepatitis, and adipogenesis in white adipose depot. This is followed by inflammation and endothelial and cardiovascular dysfunctions. In obstructive and inflammatory liver diseases, soluble CEACAM1 is shed into human bile where it can serve as an indicator of liver disease. On immune cells, CEACAM1 acts as an immune checkpoint regulator, and deletion of
gene in mice causes exacerbation of inflammation and hyperactivation of myeloid cells and lymphocytes. Hence, hepatic CEACAM1 resides at the central hub of immune and metabolic homeostasis in both humans and mice. This review focuses on the regulatory role of CEACAM1 in liver and biliary tract architecture in health and disease, and on its metabolic role and function as an immune checkpoint regulator of hepatic inflammation.
Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of ...severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated GN, a severe form of ANCA-associated vasculitis, lupus nephritis associated with systemic lupus erythematosus, Goodpasture's disease, and IgA nephropathy. The immunopathogenesis of cGN is associated with activation of CD4
and CD8
T cells, which particularly accumulate in the periglomerular and tubulointerstitial space but also infiltrate glomeruli. Clinical observations and functional studies in pre-clinical animal models provide evidence for a pathogenic role of Th1 and Th17 cell-mediated immune responses in cGN. Emerging evidence further argues that CD8
T cells have a role in disease pathology and the mechanisms of activation and function of recently identified tissue-resident CD4
and CD8
T cells in cGN are currently under investigation. This review summarizes the mechanisms of pathogenic T-cell responses leading to glomerular damage and renal inflammation in cGN. Advanced knowledge of the underlying immune mechanisms involved with cGN will enable the identification of novel therapeutic targets for the replacement or reduction in standard immunosuppressive therapy or the treatment of refractory disease.
Innate lymphoid cells (ILCs) represent a heterogeneous population of recently discovered immune cells that mirror the functions of adaptive T lymphocytes. However, ILCs are devoid of specific antigen ...receptors and cellular activation depends on environmental cytokines, rendering them as early regulators of immune responses. Type 2 innate lymphoid cells (ILC2s) respond to alarmins, such as interleukin-25 and -33 and shape Th2-associated immunity by expressing IL-5 and IL-13 in a GATA3-dependent manner. In addition, ILC2s express the epidermal growth factor-like molecule Amphiregulin thereby promoting regeneration of injured tissue during inflammation. The gut and liver confer nutrient metabolism and bidirectional exchange of products, known as the gut-liver axis. Accordingly, both organs are continuously exposed to a large variety of harmless antigens. This requires avoidance of immunity, which is established by a tolerogenic environment in the gut and liver. However, dysregulations within the one organ are assumed to influence vitality of the other and frequently promote chronic inflammatory settings with poor prognosis. Intensive research within the last years has revealed that ILC2s are involved in acute and chronic inflammatory settings of gut and liver. Here, we highlight the roles of ILC2s in intestinal and hepatic inflammation and discuss a regulatory potential.
In immune-mediated hepatitis, type 2 innate lymphoid cells (ILC2) as well as effector CD4
T cells have been shown to drive disease pathology. However, less is known about mechanisms involved in the ...regulation of ILC2 function during liver inflammation. We showed that in homeostasis, hepatic ILC2 constituted a very small population with a naive, inactive phenotype. During immune-mediated hepatitis, the cytokines IL-33 and IFNγ were expressed in liver tissue. IL-33 induced strong activation and expression of type 2 cytokines as well as IL-6 by hepatic ILC2 while IFNγ suppressed cytokine production. Interestingly, this inhibitory effect was overcome by IL-33. The phenotype of activated hepatic ILC2 were stable since they did not show functional plasticity in response to liver inflammation-induced cytokines. Moreover, hepatic ILC2 induced a Th2 phenotype in activated CD4
T cells, which increased ILC2-derived cytokine expression via IL-2. In contrast, Th1 cells inhibited survival of ILC2 by production of IFNγ. Thus, hepatic ILC2 function is regulated by IL-33, IL-2, and IFNγ. While IL-33 and IL-2 support hepatic ILC2 activation, their inflammatory activity in immune-mediated hepatitis might be limited by infiltrating IFNγ-expressing Th1 cells.
Clinical observations show that patients with anorexia nervosa (AN) are surprisingly free from infectious diseases. There is evidence from studies in Drosophila melanogaster that starvation leads to ...an increased expression of antimicrobial peptides (AMPs). AMPs are part of the innate immune system and protect human surfaces from colonization with pathogenic bacteria, viruses and fungi. We compared the expression of AMPs between patients with AN and healthy controls (HC) and investigated the influence of weight gain. Using a standardized skin rinsing method, quantitative determination of the AMPs psoriasin and RNase 7 was carried out by ELISA. Even though non-significant, effect sizes revealed slightly higher AMP concentrations in HC. After a mean weight gain of 2.0 body mass index points, the concentration of psoriasin on the forehead of patients with AN increased significantly. We could not confirm our hypotheses of higher AMP concentrations in patients with AN that decrease after weight gain. On the contrary, weight gain seems to be associated with increasing AMP concentrations.
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