Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the liver biopsies of 78 patients with hepatitis virus-related chronic liver diseases (B type; 14 patients, C type; 64 patients) by immunoelectron microscopy with the Leu-7 monoclonal antibody in order to determine the association of NK/K cells in virus-related chronic liver diseases. Most Leu-7 positive cells in the liver had the Pit cell morphology but a few Pit cells were Leu-7 negative. A few Leu-7 positive cells had neither Pit cell nor typical T cell morphology. No ultrastructural difference was observed in Leu-7 positive cells between hepatitis B virus- and hepatitis C virus-related chronic liver diseases. Regardless of virus type and hepatitis activity, the fine morphology of extravascular Leu-7 positive cells differed considerably from intravascular cells. Leu-7 positive cells were regularly seen in the cellular infiltrates but the ratio of Leu-7 positive cells/whole infiltrates was low. There was no correlation between the inflammatory activity of the disease and the level of Leu-7 positive cell infiltration. A virus aetiology (hepatitis-C or hepatitis-B) did not affect Leu-7 positive cell infiltration. We conclude that NK cells play only a small role in the pathogenesis of hepatitis B virus or hepatitis C virus-related hepatocytolysis, during the chronic stage.
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PMID:Immunoelectron microscopic observations on Leu-7 positive cells in virus-related chronic liver diseases. 751 91

The pathogenesis and perpetuation of hepatocellular injury in hepatitis C viral infection remains unclear. It has been proposed that a direct viropathic effect, the host immune response, or both mediate cell damage. To address this issue, the immunophenotype of the inflammatory infiltrate in the liver of 18 patients with abnormal liver function tests and serologically detectable hepatitis C virus antibodies was compared with seven control patients (three cases with hepatitis B virus infection, two with alcoholic hepatitis, and one patient each with primary biliary cirrhosis and autoimmune hepatitis). The immunohistochemical markers included UCHL1, L26, Ham-56, Mac-387, CD68, Leu-M1, and cathepsin B. We found that T cells represent the predominant cell type in both histopathologic patterns of hepatitis C, ie, chronic active hepatitis and chronic persistent hepatitis, but the intensity of the T-cell infiltrate displayed marked differences. B-cell infiltrates were only seen in the germinal centers of lymphoid follicles in portal tracts. Furthermore, significant numbers of CD68-positive macrophages/monocytes were seen in the more aggressive form of hepatitis C viral infection. These data suggest that the T-lymphocyte-mediated host immune response is similar in chronic active and chronic persistent hepatitis patterns of hepatitis C viral infection, but varies in its intensity. In addition, macrophages/monocytes may play a role in hepatocyte and bile duct injury in chronic hepatitis C.
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PMID:Chronic hepatitis C. Analysis of host immune response by immunohistochemistry. 753 56

The carboxyl-terminal Lys-Asp-Glu-Leu (KDEL), or a closely-related sequence, is important for ER localization of both lumenal as well as type II membrane proteins. This sequence functions as a retrieval signal at post-ER compartment(s), but the exact compartment(s) where the retrieval occurs remains unresolved. With an affinity-purified antibody against the carboxyl-terminal sequence of the mammalian KDEL receptor, we have investigated its subcellular localization using immunogold labeling on thawed cryosections of different tissues, such as mouse spermatids and rat pancreas, as well as HeLa, Vero, NRK, and mouse L cells. We show that rab1 is an excellent marker of the intermediate compartment, and we use this marker, as well as budding profiles of the mouse hepatitis virus (MHV) in cells infected with this virus, to identify this compartment. Our results demonstrate that the KDEL receptor is concentrated in the intermediate compartment, as well as in the Golgi stack. Lower but significant labeling was detected in the rough ER. In general, only small amounts of the receptor were detected on the trans side of the Golgi stack, including the trans-Golgi network (TGN) of normal cells and tissues. However, some stress conditions, such as infection with vaccinia virus or vesicular stomatitis virus, as well as 20 degrees C or 43 degrees C treatment, resulted in a significant shift of the distribution towards the trans-TGN side of the Golgi stack. This shift could be quantified in HeLa cells stably expressing a TGN marker. No significant labeling was detected in structures distal to the TGN under all conditions tested. After GTP gamma S treatment of permeabilized cells, the receptor was detected in the beta-COP-containing buds/vesicles that accumulate after this treatment, suggesting that these vesicles may transport the receptor between compartments. We propose that retrieval of KDEL-containing proteins occurs at multiple post-ER compartments up to the TGN along the exocytotic pathway, and that within this pathway, the amounts of the receptor in different compartments varies according to physiological conditions.
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PMID:Localization of the Lys, Asp, Glu, Leu tetrapeptide receptor to the Golgi complex and the intermediate compartment in mammalian cells. 779 12

The functions of delta antigens (HDAgs) in the morphogenesis of hepatitis delta virus (HDV) have been studied previously. The C terminus of large HDAg has been shown to complex with the small surface antigen (HBsAg) of helper hepatitis B virus, whereas the assembly of small HDAg requires interaction with the N terminus of large HDAg (M.-F. Chang, C.-J. Chen, and S. C. Chang, J. Virol. 68:646-653, 1994). To further examine the molecular mechanisms by which HDAgs are involved in the assembly of HDV RNA, we have cotransfected Huh-7 cells with plasmids representing a longer than unit-length HDV and the small HBsAg cDNAs. We found that HDAg mRNA could be generated from an endogenous promoter within the HDV cDNA that was translated into large HDAg. Large HDAg is capable of complexing with monomeric HDV genomic RNA to form ribonucleoprotein particles (RNPs) and is capable of forming enveloped HDV-like particles in the presence of small HBsAg without undergoing HDV replication. In addition, the middle region from amino acid residues 89 to 145 of large HDAg is required for assembly of the RNPs but is dispensable for assembly of the enveloped particles. RNA assembly is also demonstrated with small HDAg when it is cotransfected with a packaging-defective large HDAg mutant and small HBsAg. Leu-115 within the putative helix-loop-helix structure of the small HDAg is important for the replication of HDV but is not essential for RNA assembly, suggesting that conformational requirements of small HDAg for replication and assembly of viral RNA may be different. Further studies indicate that a 312-nucleotide linear HDV RNA from one end of the HDV and structure is sufficient to form RNP complexes competent for assembly of virus-like particles with large HDAg and small HBsAg.
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PMID:Functional domains of delta antigens and viral RNA required for RNA packaging of hepatitis delta virus. 788

The dual observations that human leukocyte antigens have an antigen-binding groove and that the polymorphism we study as human leukocyte antigen types is largely related to amino acid substitutions in and around that groove have provided a new focus for immunogenetic studies. In autoimmune liver disease, recent studies have described specific amino acid substitutions in the antigen-binding groove of human leukocyte antigen DR molecules that may determine both disease susceptibility, through their direct influence on antigen binding, and the severity of the disease. In autoimmune hepatitis, lysine residues at DR beta position 71 in European subjects and arginine or histidine residues at DR beta position 13 in Japanese subjects may be responsible for much human leukocyte antigen-encoded disease susceptibility. Similar claims have been made for leucine residues at DR beta 38 in primary sclerosing cholangitis and for leucine residues at DP beta 35 in Japanese patients with primary biliary cirrhosis. To date, our knowledge of genetic susceptibility to autoimmune liver disease is incomplete. Other genes may contribute to susceptibility to autoimmune liver disease--for example the contribution of TAP genes, upstream promoter sequences and class III genes on chromosome 6 and the T-cell receptor genes and complement genes elsewhere in the human genome is currently unclear. Additional information concerning the immunogenetic contribution to disease severity is needed to complete the picture.
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PMID:The molecular genetics of autoimmune liver disease. 802 Aug 93

Susceptibility to autoimmune hepatitis in white patients is associated with the human leukocyte antigen class II antigens DR3 and DR4. To analyze the molecular basis of these associations, we used oligonucleotide probes to determine the DRB, DQA and DQB hypervariable nucleotide sequences in 119 patients with autoimmune hepatitis and 177 matched controls. DRB3*0101, which encodes DR52a, predisposed patients most strongly to the disease. It was present in 58% of patients and 25% of controls (corrected P < 0.000005), whereas DQA1*0101 and 0102 conferred protection in males only. The DR4 subtype, DRB1*0401, was raised in the DRB3*0101-negative patients; 81% possessed either DRB3*0101 or DRB1*0401, compared with 42% of controls (corrected P < 0.0000001). These alleles encode the amino acid sequence Leu-Leu-Glu-Gln-Lys-Arg at positions 67 to 72 of the DR beta polypeptide, which was present in 94% of patients and 64% of controls (corrected P < 0.000001) and in all patients who tested positive for autoantibodies to the hepatic asialoglycoprotein receptor. The patients with DRB1*0401 had less severe disease, relapsed less frequently and were first seen significantly later in life than those patients with DRB3*0101; and whereas a single copy of DRB1*0401 predisposed to autoimmune hepatitis, DRB3*0101-associated susceptibility had a dose-related effect. These data provide evidence that specific residues in the DR beta polypeptides predispose to autoimmune hepatitis in white patients and genes linked to DRB3*0101 and DRB1*0401 may determine two clinically distinct disease patterns.
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PMID:Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. 811 85

Mouse hepatitis virus strain A59 causes a persistent productive, but nonlytic, infection of cultured glial cells. We have mutants isolated from persistently infected glial cell cultures which have been shown to be fusion-defective due to a histidine to aspartic acid mutation (H716D) near the cleavage site of the peplomer protein, S. Here, we examine the pathogenicity of these mutants and show differences in hepatotropism and virulence compared to wild-type virus (WT). Two mutants chosen for detailed study, B11 and C12, were impaired in their abilities to cause hepatitis and/or replicate in the liver of susceptible mice. Furthermore, B11 and C12 display two separate hepatotropic phenotypes. The ability of B11 to replicate in the liver was dependent on infectious dose and route of inoculation, while C12 consistently displayed decreased hepatotropism regardless of dose and route of inoculation. However, B11 and C12 were shown to replicate in the CNS of infected animals similarly to WT. Like WT, the mutants produced meningoencephalitis during acute infection, with viral antigen exhibiting a similar distribution in the brain, and demyelination during chronic infection. Sequence analysis of wild-type, mutant, and revertant S proteins indicates that (1) a mutation in the N terminal subunit of S (S1), resulting in a glutamine to leucine amino acid substitution (Q159L), may affect hepatotropism and (2) a cleavage site mutation which determines fusogenicity is not responsible for altered hepatotropism. Furthermore, since B11, C12, and a nonattenuated fusion mutant (B12) have identical S protein sequences, there must be additional mutations outside of S which influence both virulence and hepatotropism.
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PMID:MHV-A59 fusion mutants are attenuated and display altered hepatotropism. 812 13

The genetic background of autoimmune diseases becomes more and more evident. Immunogenetics comprises the analysis of genes and their products located at the region 6p21 on the short arm of chromosome 6, which is also known as the major histocompatibility complex (MHC). MHC class I and II genes are highly polymorphic. The complement genes C2, C4A, C4B, and BF, which are also polymorphic, became known as MHC class III genes. In autoimmune hepatitis type 1, there is a dual association for white persons with either HLA-A1-B8-DR3 or HLA-DR4. In patients from Japan, autoimmune hepatitis type 1 is predominantly associated with HLA-DR4. This dual association is confirmed at the DNA level. Whereas only limited data are available for autoimmune hepatitis type 2, the association of primary biliary cirrhosis with HLA-DR8 is based on several studies. Primary sclerosing cholangitis is associated with HLA-B8-DR3 and -DR52a. This association was confirmed at the DNA level because of a significant increase of the DRB3*0101 allele. For DRB3*0101-negative individuals, a second association with DRB5*0101 (= DR2) was described. Further analysis of the hypervariable region of the HLA class II molecule indicates that lysine at position 71 is crucial for autoimmune hepatitis type 1 in white persons, whereas position 13 is important for people from Japan. In contrast, leucine at position 35 is important for patients with primary biliary cirrhosis, whereas leucine at position 38 is an important risk factor for primary sclerosing cholangitis. The MHC class III allele C4A-QO is significantly increased in autoimmune hepatitis type 1 and 2 and in primary biliary cirrhosis. Advances in immunogenetics will certainly increase our knowledge of the etiology and pathogenesis of immune-mediated liver diseases, which hopefully will lead to more specific therapeutic interventions.
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PMID:Immunogenetics of chronic liver diseases. 819 17

The functions of delta antigens (HDAgs) in the replication of hepatitis delta virus (HDV) have been identified previously. The small HDAg acts as a transactivator, whereas the large HDAg has a negative effect on replication. To understand the molecular mechanisms involved in the control of HDV replication, we have established a replication system in Huh-7 cells by cotransfecting a monomeric cDNA genome of HDV and a plasmid encoding the small HDAg. We demonstrate that a leucine repeat in the middle domain of the small HDAg is involved in binding to the HDV genome and transactivation of HDV replication. When the leucine repeat was disrupted by a substitution of valine for leucine at position 115, both RNA-binding and transactivation activity of the small HDAg were abolished. In contrast, the binding and transactivation activities were not affected when Leu-37 and Leu-44 of the small HDAg were replaced by valines. In addition, small and large HDAgs can interact with each other to form protein complexes in vitro. The complex formation that may lead to the trans-dominant negative regulation of large HDAg in HDV replication is mediated by a cryptic signal located between amino acid residues 35 and 65 other than the putative N-terminal leucine zipper motif. Furthermore, an extra 21-amino-acid extension near the N terminus converts the small HDAg into a pseudo-large HDAg with negative regulation activity of HDV replication even though the extreme C-terminal residue is unchanged.
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PMID:Functional motifs of delta antigen essential for RNA binding and replication of hepatitis delta virus. 847 58

The capsid particle of hepadnaviruses is assembled from its dimer precursors. However, the mechanism of the protein-protein interaction is still poorly understood. A small region in the capsid protein of woodchuck hepatitis virus (WHV) contains four hydrophobic residues, including leucine 101, leucine 108, valine 115, and phenylalanine 122, that are conserved and spaced every seventh residue in the primary sequence to form a hydrophobic heptad repeat (hhr). A hydrophobic force often plays an important role in the interaction of proteins. Therefore, to investigate the role of this region in capsid assembly, we individually changed the codons specifying these four hydrophobic amino acids to codons specifying alanine or proline. In addition, we examined the in vivo infectivity of a WHV genome bearing a naturally occurring single amino acid change (histidine 104-->proline) in the hhr region. The phenotype of each altered genome was determined in both eukaryotic and prokaryotic systems by a capsid protein assay and electron microscopic examination. We show that replacement of any one of the four hydrophobic residues with alanine did not prevent capsid assembly. However, assembled capsid particles were not detected if combinations of any two of the four residues were substituted with alanines or if the spacing of these four hydrophobic residues was changed. An individual introduction of a proline (which dramatically changes the secondary structure of proteins) into different positions of this small region also abolished capsid assembly in vitro or viral replication in vivo. These results suggested that the hhr region of the core protein of WHV was critical for capsid assembly.
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PMID:A hydrophobic heptad repeat of the core protein of woodchuck hepatitis virus is required for capsid assembly. 879 54


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