ABSTRACT
CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.
Subject(s)
Endothelial Cells/drug effects , Hepatitis, Viral, Animal/drug therapy , Liver/drug effects , Pore Forming Cytotoxic Proteins/antagonists & inhibitors , Protective Agents/pharmacology , Sulfonamides/pharmacology , Adenoviridae/genetics , Adenoviridae/immunology , Adenoviridae/pathogenicity , Animals , Antibodies/administration & dosage , CD40 Antigens/antagonists & inhibitors , CD40 Antigens/genetics , CD40 Antigens/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Capillaries/drug effects , Capillaries/virology , Disease Models, Animal , Endothelial Cells/immunology , Endothelial Cells/virology , Gene Expression , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hepatitis, Viral, Animal/immunology , Hepatitis, Viral, Animal/virology , Hepatocytes/drug effects , Hepatocytes/immunology , Hepatocytes/virology , Humans , Liver/blood supply , Liver/pathology , Liver/virology , Luciferases/genetics , Luciferases/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/administration & dosage , Poly I-C/administration & dosage , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/immunologyABSTRACT
BACKGROUND AND OBJECTIVE: Orthodontic tooth movement is known to cause sterile inflammation of the periodontal ligament (PDL). It may also be accompanied by pathological effects of external apical root resorption, with interindividual differences in the incidence and extent of resorption. An involvement of autoimmunological mechanisms is currently under discussion. This study aimed to improve our understanding of similarities between the inflammatory mechanisms underlying the pathophysiology of periodontitis and root resorption. MATERIALS AND METHODS: Human PDL cells were stimulated with interleukin (IL)-1ß/IL-17A/IFN-γ, or left non-stimulated. Their potential for phagocytosis was then evaluated by incubation with dextran or E. coli or S. aureus particles, followed by flow cytometric and immunohistochemical analysis. Real-time polymerase chain reaction (PCR) was used to analyze receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) expression in PDL cells. Verification was obtained in vivo by studying IL-17A, RANKL, and OPG expression in biopsies of inflamed periodontal tissues and in biopsies of rat maxillae with mechanically induced root resorption. Statistical analysis included Wilcoxon's rank sum test to analyze gene expression data and one-way ANOVA in conjunction with Tukey's post hoc test to analyze flow cytometric data. RESULTS: PDL cells phagocytosed foreign particles under both inflammatory and non-inflammatory conditions. Furthermore, IL-17A significantly downregulated RANKL expression while significantly upregulating OPG expression in PDL cells. These immunomodulatory cytokines were also demonstrable in both inflammatorily altered periodontal tissues and root resorption lacunae, while the incidence of IL-7A was strikingly variable in resorption areas. CONCLUSION: PDL cells were demonstrated to effect phagocytosis and to express immunomodulatory molecules, which proves their capability of participating in periodontal osteoimmunological processes. The development of root resorption and periodontitis appears to be governed by similar pathophysiological mechanisms.
