Immune-Mediated Liver Injury

Eksteen, Bertus; Afford, Simon C.; Wigmore, Stephen J.; Holt, Andrew; Adams, David H.

doi:10.1055/s-2007-991512

Cited by 53 publications

(42 citation statements)

References 106 publications

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“…Immune cell and cytokine composition in the periphery determines the progression of autoimmunity (43,44). Our study demonstrates that loss of control over metalloproteinase activity significantly affects multiple cytokines, both systemically and in the liver microenvironment.…”

Section: Discussionmentioning

confidence: 76%

Stromal TIMP3 Regulates Liver Lymphocyte Populations and Provides Protection against Th1 T Cell-Driven Autoimmune Hepatitis

Murthy

Shao

Defamie

et al. 2012

The Journal of Immunology

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Lymphocyte infiltration into epithelial tissues and proinflammatory cytokine release are key steps in autoimmune disease. Although cell-autonomous roles of lymphocytes are well studied in autoimmunity, much less is understood about the stromal factors that dictate immune cell function. Tissue inhibitor of metalloproteinases 3 (TIMP3) controls systemic cytokine bioavailability and signaling by inhibiting the ectodomain shedding of cytokines and their receptors. The role of TIMP3 in cytokine biology is emerging; however, its contribution to cellular immunology remains unknown. In this study, we show that TIMP3 produced by the hepatic stroma regulates the basal lymphocyte populations in the liver and prevents autoimmune hepatitis. TIMP3 deficiency in mice led to spontaneous accumulation and activation of hepatic CD4+, CD8+, and NKT cells. Treatment with Con A in a model of polyclonal T lymphocyte activation resulted in a greatly enhanced Th1 cytokine response and acute liver failure, which mechanistically depended on TNF signaling. Bone marrow chimeras demonstrated that TIMP3 derived from the stromal rather than hematopoietic compartment provided protection against autoimmunity. Finally, we identified hepatocytes as the major source of Timp3 in a resting liver, whereas significant Timp3 gene transcription was induced by hepatic stellate cells in the inflamed liver. These results uncover metalloproteinase inhibitors as critical stromal factors in regulating cellular immunity during autoimmune hepatitis.

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Section: Discussionmentioning

confidence: 76%

Stromal TIMP3 Regulates Liver Lymphocyte Populations and Provides Protection against Th1 T Cell-Driven Autoimmune Hepatitis

Murthy

Shao

Defamie

et al. 2012

The Journal of Immunology

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“…5D). Natural killer and natural killer T cells may also be expected to contribute to liver pathology [30][31][32][33] ; however, depletion of these cells in clodronate-treated mice with the PK136 monoclonal antibody did not prevent liver cell damage (Supporting Fig. 4).…”

Section: Resultsmentioning

confidence: 99%

Tissue Macrophages Suppress Viral Replication and Prevent Severe Immunopathology in an Interferon-I-Dependent Manner in Mice

et al. 2010

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The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology. Conclusion: Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication. (HEPATOLOGY 2010;52:25-32) P ersistent infection with hepatitis B or hepatitis C virus is one of the leading causes of lethal liver disease resulting from the development of liver cirrhosis and/or hepatocellular cancer.1 Because both viruses are poorly cytopathic, most of the ensuing liver destruction results from CD8 þ T cell responses directed against virus-infected hepatocytes. These cells prevent rapid dissemination of the virus and control viral replication by secreting interferon (IFN)-c and perforin. However, in the event of viral persistence, exaggerated and prolonged T cell activation results in severe liver pathology which can eventually be fatal. 2,3Thus CD8 þ T cells play a crucial role in both virus control and immunopathology. [4][5][6][7][8] Macrophages are resident in every organ of the body.9-11 With their potent phagocytic capacity, theyAbbreviations: ALT, alanine aminotransferase; IFN, interferon; IFNAR, IFN-a receptor; LCMV, lymphocytic choriomeningitis virus; LCMV-NP, lymphocytic choriomeningitis virus nucleoprotein.From the

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“…In liver cirrhosis, both antigenspecific and non-specific mechanisms work together to induce an immune-mediated injury. It has been considered that repeated cycles of inflammation and damage sustain a continuing recruitment of effector leucocytes within the liver and amplify effector responses mediated by T cells, macrophages, natural killer or neutrophils [46,47]. Moreover, in recent years much attention has been devoted to the ability of cytokines and regulatory T cells to control the proliferation of memory T cells in the absence of antigen stimulation [48].…”

Section: Cd25mentioning

confidence: 99%

Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis

Márquez¹,

Fernández-Gutiérrez²,

Montesdeoca³

et al. 2009

Clinical and Experimental Immunology

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SummaryThe objectives of this work were the analysis of the functional characteristics of circulating monocytes and T lymphocytes in patients with liver cirrhosis, and evaluation of the relationship with an increased exposure to antigens due to bacterial translocation. Forty patients with liver cirrhosis (20 with compensated cirrhosis and 20 with ascitic decompensation) and 20 healthy control subjects were studied. Bacterial translocation was evaluated by serum levels of lipopolysaccharide binding protein (LBP). Macrophage activation was studied by CD40 antigen expression. T lymphocytes were analysed for activation (CD25 + , CD122 + ), effector function (CD8 + CD45RO + CD57 + ), apoptosis (CD95 + ) and regulatory abilities, either by analysis of the membrane expression of co-stimulatory molecules CD80, CD86 and CD28, or by quantification of regulatory T cells CD4 + CD25 high forkhead box P3 (FoxP3). The percentage of activated monocytes and T lymphocytes in patients was increased significantly. The proportions of effector senescent cells and of those near to apoptosis were also significantly higher. With respect to these proportions, there were no significant differences between patients in function of the presence or absence of decompensation or in function of the increased or normal values of LBP. Conversely, those patients with elevated levels of LBP presented a significantly higher frequency of regulatory T cells than those with normal levels. In conclusion, patients with liver cirrhosis showed an intensive activation state with a higher percentage of cells committed to activation-induced death, even in non-advanced stages. It is possible that bacterial permeability and endotoxaemia contribute to the expansion of those lymphocyte populations implicated in the prevention of a more severe antigen-induced immunopathology.

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Immune-Mediated Liver Injury

Cited by 53 publications

References 106 publications

Stromal TIMP3 Regulates Liver Lymphocyte Populations and Provides Protection against Th1 T Cell-Driven Autoimmune Hepatitis

Stromal TIMP3 Regulates Liver Lymphocyte Populations and Provides Protection against Th1 T Cell-Driven Autoimmune Hepatitis

Tissue Macrophages Suppress Viral Replication and Prevent Severe Immunopathology in an Interferon-I-Dependent Manner in Mice

Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis

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