Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The normal liver contains a large number of lymphocytes, which include not only specialized natural killer (NK) and NKT cells but also CD4 and CD8 T cells. Whereas some of these cells are terminally differentiated effector cells that are destined to die by apoptosis, many of them are not and include immunocompetent cells that traffic through the liver to provide continuing immune surveillance as well as epithelial-associated effector T cells. In alcoholic liver disease the number of lymphocytes in the liver increases and the type and distribution of these infiltrating cells will determine the nature of the inflammation. For instance, a predominance of parenchymal inflammation is a feature of alcoholic hepatitis, whereas a predominantly portal infiltrate is a feature of cirrhosis. In this article we discuss the molecular mechanisms that regulate the entry of lymphocytes to the inflamed liver in alcoholic hepatitis. Lymphocytes play a critical role in regulating the immune/inflammatory response to alcohol, and understanding how these cells are recruited to the liver has important implications for understanding the pathogenesis of alcoholic liver disease in which parenchymal infiltration is a critical determinant of disease progression. Aberrant recruitment and retention of lymphocytes in the liver may explain why some patients with alcoholic liver disease show progressive inflammatory damage whereas in others the disease takes a more indolent course. Similarly, leukocyte recruitment may present new therapeutic targets in which lymphocyte recruitment to the specific liver compartments can be inhibited, thereby minimizing tissue damage whilst leaving generalized lymphocyte recirculation intact. Potentially the most exciting potential is to modulate the nature of the lymphocyte subsets recruited to the liver, so that harmful cells are excluded and beneficial subsets are preferentially recruited.
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PMID:Lymphocyte recruitment to the liver in alcoholic liver disease. 1206 34

Most cases of infections described after steroid treatment for severe acute alcoholic hepatitis are of bacterial origin. However, the rate of bacterial infections in these patients is not higher than in those who are not treated by steroids. The opportunistic infections are even more rare. We report two cases of patients with cirrhosis and human immunodeficiency virus, treated for alcoholic hepatitis with steroids and who subsequently developed severe pneumopathy due to Pneumocystis carinii. One patient had a concommitant cytomegalovirus infection and both of them died. Pneumocystis carinii infections usually occur in patients a decreased immune cellular response. Steroid treatments and also alcohol may be responsible for these opportunistic infections. Alcohol may have an immunosuppressive effect by decreasing recruitment of CD4 and CD8 lymphocytes to the lungs. In conclusion, Pneumocystis carinii pneumonia is a potential complication of steroid treatments for acute alcoholic hepatitis and should be suspected in case of unexplained pulmonary infection.
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PMID:[Pneumocystis carinii and cytomegalovirus pneumonia after corticosteroid therapy in acute severe alcoholic hepatitis: 2 case reports]. 1212 70

The HBx-derived, HLA-A2.1 restricted peptides, XEP-3, XEP-4, and XEP-6, induced activation of specific CTLs from patients with HBV in vitro. XEP-6 peptide induced the strongest response among the three peptides in CTLs from the blood samples of patients that were HBsAg positive. It was not clear whether the stage of disease (chronic infection, cirrhosis or hepatoma) was related to the responsiveness of the CTLs to each peptide. We vaccinated HLA-A2/K(b) transgenic mice with these peptides encapsulated in pH-sensitive liposomes at various concentrations and tested their ability to protect against challenge with rVV-HBx. Mice immunized with encapsulated peptides were protected against viral challenge whereas those immunized with empty liposomes were not. In general, 5 micro g of each peptide per head inoculation was sufficient to give protection after 2 weeks. After 3 weeks, this protective effect was increased. This effect of time was more important on the level of protection than the initial dose of the peptide. To explain the protective effect, IFN-gamma secreting CD8(+) cells isolated from mice 3 weeks after immunization were analyzed ex vivo. There was little dose dependency of peptide on IFN-gamma secretion except for XEP-3. The variations in the results may reflect the chemical properties of the peptides, such as solubility and binding affinity. In conclusion, epitope peptides derived from HBx can induce specific CTL activation and lead to cellular immunity in vitro and in vivo by inducing the peptide-specific CD8(+) CTLs. Thus, pH-sensitive liposomes increase the immune response following immunization with a peptide vaccine. This could be used for the treatment of HBV-related disease.
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PMID:HLA-A2 1 restricted peptides from the HBx antigen induce specific CTL responses in vitro and in vivo. 1239 8

Chronic hepatitis C virus (HCV) infection develops in 85% of exposed individuals and 20% develop cirrhosis. However, the pathogenesis of this process is not well-understood. The objective of this study was to determine whether HCV-reactive T cells play a role in the process of development of cirrhosis during chronic HCV infection. We analyzed 21 human leukocyte antigen (HLA)-A2 patients with chronic HCV infection (9 with histology of inflammation and 12 with histology of fibrosis/cirrhosis). The frequency of CD8(+) T cells reactive to 12 HCV-derived epitopes was determined by an interferon-gamma enzyme-linked immunospot (ELISPOT) assay. The frequency of CD4(+) Th1 and Th2 cells reactive to the HCV core antigen was determined by interferon-gamma and interleukin-5 ELISPOT assays, respectively. Patients with histology of inflammation showed a significantly higher CD8(+) T-cell response to five HCV-derived epitopes (YLLPRRGPRL [core], CINGVCWTV [NS3], LLCPAGHAV [NS3], ILAGYGAGV [NS4B], and GLQDCTMLV [NS5B]) as compared with patients with histology of fibrosis/cirrhosis. Also, patients with histology of inflammation showed a significantly higher CD4(+) Th1 response to the HCV core antigen as compared to patients with histology of fibrosis/cirrhosis. These results indicate that a lack of an optimal T-cell response to HCV is associated with the development of cirrhosis during chronic HCV infection.
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PMID:Lack of optimal T-cell reactivity against the hepatitis C virus is associated with the development of fibrosis/cirrhosis during chronic hepatitis. 1255 24

Immunological factors are important in the pathogenesis of a wide spectrum of hepatobiliary diseases. Using flow cytometry, we determined the changes in lymphocyte subsets and natural killer cells in 123 individuals (81 patients with liver disease and 42 healthy volunteers). The liver diseases included periportal fibrosis (PPF, 10 patients), liver cirrhosis (LC, 31 patients), and hepatocellular carcinoma (HCC, 40 patients). Schistosomiasis and viral hepatitis B and C were the putative etiological agents of liver diseases. Immunophenotyping by indirect immunofluorescence was conducted using monoclonal antibodies to CD3 (T-lymphocytes), CD4 (helper/inducer T-cells), CD8 (suppressor/cytotoxic T-cells), and CD57 (natural killer cells) cell surface markers. Immunophenotyping of PPF patients showed no significant changes in all markers compared with the healthy controls. However, there was a significant decrease ( P<0.01) in CD3 and CD4 T-cells, and a highly significant increase ( P<0.001) in CD57 T-cells in patients with LC or HCC. In addition, LC and HCC patients showed no significant change in CD8 T-cells compared with controls. In conclusion, the progression of liver diseases is associated with a dysregulation of cellular immune responses. T-lymphocytes and natural killer cells may play a role in the immunopathogenesis of liver cirrhosis and HCC.
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PMID:Dysregulation of blood lymphocyte subsets and natural killer cells in schistosomal liver cirrhosis and hepatocellular carcinoma. 1464 34

The role of CD8(+) T lymphocytes in chronic hepatitis C virus (HCV) infection and in liver injury with subsequent development of fibrosis and cirrhosis is poorly understood. To address this question, we performed a follow-up study including 27 chronically HCV-infected individuals. We determined clonality and phenotypes of circulating CD8(+) T cells employing TCRBV spectratyping. Antigen specificity was tested by rMHC-peptide tetramer staining and stimulation with recombinant HCV antigens. In addition, T-cell clonality and phenotypes were followed during the variable clinical response of interferon- (IFN) alpha treatment. We could demonstrate that CD8(+) T-cell expansions were significantly associated with liver fibrosis and cirrhosis. Likewise, increased oligoclonality of circulating CD8(+) T cells in chronic HCV infection was identified as an indicator for poor clinical response to IFN-alpha therapy. Moreover, we also found that IFN-alpha therapy enhanced the differentiation of CD8(+) T cells towards a late differentiation phenotype (CD28(-) CD57(+)). In cases of virus elimination the disappearance of expanded terminally differentiated CD8(+) cells was observed. Thus, this study identifies an association of clonal expansions of circulating CD8(+) T cells with liver pathology and provides a possible explanation for the fact that response to IFN-alpha therapy diminishes with the duration of infection.
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PMID:Oligoclonal CD8+ T-cell expansion in patients with chronic hepatitis C is associated with liver pathology and poor response to interferon-alpha therapy. 1511 56

The role of lymphocytes in host defence in neoplastic disorders is known. Accumulation of lymphocytes in pleural cavity frequently occurs in different diseases. The aim of the study was to evaluate: 1) the frequency of lymphocyte predominance in different malignant and non-malignant pleural effusions; 2) lymphocyte phenotype and the ratio between helper (CD4+) and cytotoxic/suppressor (CD8+) lymphocytes in malignant and non-malignant effusions. Patients with mesothelioma, lung cancer, lymphoma and metastatic neoplasms were analysed. Analysis was performed on fluids with or without malignant cells. Non-malignant fluids were obtained from patients with: congestive heart failure, liver cirrhosis, pneumonia and tuberculosis. Lymphocytes were the predominant cell type in neoplastic effusions. For further analysis effusions with more than 10% of lymphocytes were included: 12 malignant and 9 non-malignant. For lymphocyte subpopulations analysis, the monoclonal antibodies anti-CD4 and anti-CD8 and APAAP method was used. We observed lower percentage of CD4+ lymphocytes (47%) and higher percentage of CD8+ (39%) lymphocytes in malignant when compared to non-malignant fluids (58% vs 31% respectively). The CD4+/CD8+ ratio was significantly lower in pleural fluid in cases with neoplastic disease when compared to benign cause of pleural involvement (1.03 vs 1.85). Our observations suggest the potential role of lymphocytes, especially CD8+ cells in local response in malignancy in pleural disease.
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PMID:[Lymphocyte and lymphocyte subsets in pleural fluid--comparison of malignant and non-malignant disorders]. 1523 Feb 9

Lymphocyte recruitment to the liver is critical for viral clearance in acute hepatitis and in the pathogenesis of chronic inflammatory liver disease when persistent chronic inflammation leads to fibrosis and cirrhosis. Chemokines regulate leukocyte recruitment and positioning in tissues and are thus critical regulators of chronic inflammation. The chemokine CXCL16, which is found in liver tissue, exists in a transmembrane as well as soluble form, providing a potential mechanism for localization to particular structures. We studied the role of CXCL16 and its receptor CXCR6 in lymphocyte recruitment and retention in the liver. A higher proportion of CXCR6(+) T cells was detected in blood of hepatitis C virus patients compared with healthy subjects, and in chronic inflammatory liver disease >60% of intrahepatic T cells expressed CXCR6, including CD4, CD8, and CD56(+) T cells compared with <30% in matched blood samples. CXCR6(+) lymphocytes were found in association with CXCL16(+) bile ducts in portal tracts and with hepatocytes at sites of interface hepatitis. Analysis of CXCL16 expression and subcellular distribution in cultured human cholangiocytes, sinusoidal endothelial cells, and hepatocytes revealed that all three cell types expressed CXCL16, with the strongest staining seen on cholangiocytes. CXCL16 on the cholangiocyte membrane was able to support lymphocyte adhesion by triggering conformational activation of beta(1) integrins and binding to VCAM-1. Thus, CXCL16 can promote lymphocyte adhesion to epithelial cells and may function to attract and retain effector cells that promote biliary and hepatocyte destruction in inflammatory liver disease.
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PMID:CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. 1563 30

Liver cirrhosis and hepatocellular carcinoma secondary to chronic hepatitis C virus (HCV) infection requiring transplantation represents a significant public health problem. The most remarkable feature of hepatitis C virus is the ability to establish chronic infection in the vast majority of cases. Efforts to define clinical correlates of HCV persistence have focused primarily on CD4 and CD8 T cell responses. Until recently, the role of innate immunity in determining the outcome of HCV infection had received relatively little attention. Natural killer (NK) cells are an important antiviral effector population eliminating virus through direct killing and cytokine production. Recent studies highlighting the cross-talk between NK cells, dendritic cells (DCs) and T cells have prompted reevaluation of the important role NK cells play in regulating and maintaining specific immune responses. Like many other viruses, HCV has evolved strategies to evade detection and elimination by NK cells. T cell defects observed in HCV infection may be a consequence of inhibition of NK:DC interactions. We propose a theoretical model for HCV persistence that places the NK cell at the center of HCV immune evasion strategies. While this model is only theoretical, it provides a plausible interpretation of many published observations and a useful working model to test the role of NK cells in HCV persistence. In conclusion, the role of innate immune cells and their regulation of antigen-specific responses by the initial innate response to the virus, in particular NK cells, may prove to be an informative and clinically relevant avenue of investigation.
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PMID:Natural killer cells: primary target for hepatitis C virus immune evasion strategies? 1649 47

A novel histologic phenotype of chronic esophagitis, ie, lymphocytic esophagitis, is reported in 20 patients. Lymphocytic esophagitis is characterized by high numbers of intraepithelial lymphocytes (IELs) gathered mainly around peripapillary fields and by none (n = 12) to occasional (n = 8) CD15+ intraepithelial granulocytes. IELs expressed CD3, CD4 (42%), CD8 (36%), and granzyme B (0.2%), whereas T-cell intracytoplasmic antigen (TIA) 1 was not expressed. Of the 20 patients, 11 (55%) were 17 years or younger. Of 20 patients, 5 had no symptoms in the upper gastrointestinal tract. Only 4 (20%) of 20 patients had symptoms of gastroesophageal reflux disease and 6 (30%) of gastroduodenitis; 2 (10%) had celiac disease; 4 (20%) had carcinoma of the esophagus (1) or elsewhere (3); 1 (5%) each had hiatus hernia, gastric ulcer/asthma/blood hypertension, Hashimoto thyroiditis, and cirrhosis/diabetes; and 8 (40%) had Crohn disease. Hence, a novel histologic phenotype of chronic esophagitis called lymphocytic esophagitis is reported. Because phenotype is defined as the visible features resulting from the interaction between the genetic makeup and the environment, it is suggested that those factors might have a decisive role in the development of lymphocytic esophagitis.
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PMID:Lymphocytic esophagitis: a histologic subset of chronic esophagitis. 1661 48


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