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)

To study the role of antigen-specific T lymphocytes in the pathogenesis of autoimmune hepatitis, messenger RNA of T-cell receptors (TCR) was analyzed in liver biopsy specimens from four patients with autoimmune hepatitis. Using the TCR beta-chain variable region family specific oligonucleotides, a remarkable bias for the usage of beta-chain variable region 3 was detected in all four patients. Therefore, nucleotide and amino acid sequences of the complementarity-determining region 3 rearranged to the beta-chain variable region 3, which is a putative contact site for peptide fragments from antigens bound in the groove of the human leukocyte antigen molecule, was further analyzed in randomly selected 10 clones from each patient. An Asp-Arg-Pro motif in the complementarity-determining region 3 was identified in three of four patients with human leukocyte antigen DR4, and this motif was always rearranged to the beta-chain junctional region 1.2. From these results, beta-chain variable region 3+, Asp-Arg-Pro+, beta-chain junctional region 1.2+ T-cell clones may be among the responsible lymphocytes involved in the liver damage in autoimmune hepatitis, especially in patients with human leukocyte antigen DR4. Thus, an analysis of the complementarity-determining region 3 may give us an important clue to clarify characteristics of target antigens included in autoimmune hepatitis.
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PMID:Limited usage of T-cell receptor beta chains and sequences of the complementarity determining region 3 of lymphocytes infiltrating in the liver of autoimmune hepatitis. 760 6

Nitric oxide is now established as a biological mediator of clinical relevance. The present study investigated the production of nitric oxide by lympho-mononuclear leukocytes from alcoholic patients with either hepatitis or cirrhosis. The study included 42 patients, 12 without any liver disease and 30 alcoholic patients, 13 of whom had histologically confirmed cirrhosis and 17 alcoholic hepatitis. Cells were obtained from peripheral blood by density gradient and incubated in sterile conditions in RPMI 1640 for 6 h at 37 degrees C. Culture supernatants were assayed for nitrite concentration using the Griess reaction. Cells from cirrhotic but not from hepatopathic patients showed significantly higher nitrite production than controls (cirrhotic, 0.36 +/- 0.07; hepatopathic, 0.13 +/- 0.02; control: 0.25 +/- 0.05 nmol/10(6) cells/6 h). In cirrhotic patients L-Nitro-arginine methylester inhibited nitrite production (0.18 +/- 0.05). These data suggest that alcoholic cirrhotic but nonhepatopathic patients show an increased nitric oxide production by blood lymphomononuclear cells. This production could be involved in the systemic vasodilation in cirrhotic patients.
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PMID:Nitric oxide production by mononuclear leukocytes in alcoholic cirrhosis. 763 39

Targeted RNA recombination was used to construct mouse hepatitis virus (MHV) mutants containing chimeric nucleocapsid (N) protein genes in which segments of the bovine coronavirus N gene were substituted in place of their corresponding MHV sequences. This defined portions of the two N proteins that, despite evolutionary divergence, have remained functionally equivalent. These regions included most of the centrally located RNA-binding domain and two putative spacers that link the three domains of the N protein. By contrast, the amino terminus of N, the acidic carboxy-terminal domain, and a serine- and arginine-rich segment of the central domain could not be transferred from bovine coronavirus to MHV, presumably because these parts of the molecule participate in protein-protein interactions that are specific for each virus (or, possibly, each host). Our results demonstrate that targeted recombination can be used to make extensive substitutions in the coronavirus genome and can generate recombinants that could not otherwise be made between two viruses separated by a species barrier. The implications of these findings for N protein structure and function as well as for coronavirus RNA recombination are discussed.
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PMID:Construction of murine coronavirus mutants containing interspecies chimeric nucleocapsid proteins. 763 93

Mouse hepatitis virus strain A59 encodes a papain-like cysteine proteinase (PLP-1) that, during translation of ORF1a, cleaves p28 from the amino terminus of the growing polypeptide chain. In order to determine the amino acid sequences surrounding the p28 cleavage site, the first 4.6 kb of murine hepatitis virus strain A59 ORF1a was expressed in a cell-free transcription-translation system. Amino-terminal radiosequencing of the resulting downstream cleavage product demonstrated that cleavage occurs between Gly-247 and Val-248. Site-directed mutagenesis of amino acids surrounding the p28 cleavage site revealed that substitutions of Arg-246 (P2) and Gly-247 (P1) nearly eliminated cleavage of p28. Single-amino-acid substitutions of other residues between P7 and P2' were generally permissive for cleavage, although a few changes did greatly reduce proteolysis. The relationship between the p28 cleavage site and other viral and cellular papain proteinase cleavage sites is discussed.
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PMID:Identification of the murine coronavirus p28 cleavage site. 781 47

Woodchuck hepatitis virus surface antigen (WHsAg) stimulated hepatocytes in culture to produce nitric oxide (NO.), as evidenced by the accumulation of nitrite in the medium. NO. synthesis by hepatocytes was positively correlated with WHsAg concentration. WHsAg-induced NO. synthesis was inhibited by NG-monomethyl-L-arginine and anti-WHsAg antibody. To our knowledge, this is the first demonstration of an increase in NO. formation by a viral antigen. These data, when considered in the light of the known genotoxicity of NO., raise the possibility that viral hepatitis increases the risk of liver cancer by increasing the production of NO.. Long-term elevated production of NO. free radicals due to stimulation by WHsAg in chronic hepatitis may directly cause reactions with cellular DNA leading to mutagenesis, as well as the formation of hepatocarcinogenic N-nitroso compounds. This provides a new mechanism by which hepatitis B virus infection might hypothetically increase the risk of liver cancer.
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PMID:Woodchuck hepatitis virus surface antigen induces nitric oxide synthesis in hepatocytes: possible role in hepatocarcinogenesis. 800 Dec 49

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

The frequencies of HLA B54, DR4, DR53 and DQ4 were significantly higher in patients with autoimmune hepatitis than in healthy controls. HLA-DR4 was most frequently associated with autoimmune hepatitis. To define the HLA class II gene which has the susceptibility or resistance to autoimmune hepatitis, we performed HLA class II genotyping using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method. The frequency of DRB1*0405 was significantly higher in autoimmune hepatitis than in controls. However, there was no significant difference in the frequency of the DR4 associated Dw-allele between the patients and the controls who were DR4-positive. Six DR4-negative patients had DR2, but there was no significant difference in the frequency of the DR2-associated Dw-alleles compared with the DR2-positive controls. Comparison of the amino acid residues of DRB1 chain suggested that the basic amino acid at position 13, which is present only on the DR2 and DR4 B1 molecules (Arg on DR2 and His on DR4), contributes to the susceptibility to autoimmune hepatitis among Japanese.
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PMID:[Molecular biological analysis of HLA class II gene in autoimmune hepatitis among Japanese]. 809 52

The biosynthesis of the secretory core gene product of the woodchuck hepatitis virus (WHV) was studied in human cells. We have shown that the WHV e antigen was a N-glycosylated (most likely a diglycosylated) protein, with an apparent M(r) of 24K. To demonstrate that the WHV precore protein was correctly processed in human cells, we engineered chimeric proteins in which signal peptides or arginine-rich domains of WHV and hepatitis B virus (HBV) precore proteins were exchanged. Our results showed that both the signal peptide and the arginine-rich region of WHV precore protein were cleaved off during the secretion pathway, as previously reported for precore protein of human HBV and duck HBV. These observations demonstrate that the maturation process of the e antigen is conserved in hepadnaviruses. In addition, on the basis of inhibition experiments, we suggest that the cleavage of the carboxy terminus of the WHV precore protein occurred in a post-endoplasmic reticulum compartment, most likely beyond the medial Golgi, and that this cleavage was catalysed by an aspartyl protease.
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PMID:Characterization and biosynthesis of the woodchuck hepatitis virus e antigen. 811 24

Hepatitis delta virus (HDV) encodes two proteins, the small hepatitis delta antigen (SHDAg) and large hepatitis delta antigen (LHDAg). Both proteins are identical except for the presence of additional 19 amino acids at the C terminus of LHDAg. While SHDAg is required for HDV RNA replication, LHDAg inhibits replication and is required together with hepatitis B surface antigen for the assembly of HDV. The C-terminal last 4 amino acids of LHDAg (Cys-Arg-Pro-Gln) is an isoprenylation motif. It has previously been shown that the mutation of the Cys inhibited the assembly of HDV. In order to discern whether this effect is due to change of amino acid residue or abolition of isoprenylation, we constructed several LHDAg mutants of the terminal three amino acid residues and tested their abilities to be packaged with HBsAg by cotransfection experiments. We also made GST-fusion proteins of these mutants and tested their abilities to be isoprenylated in rabbit reticulocyte lysate system. We found that some, but not all, of the substitutions of the amino acid residues other than the Cys also inhibited isoprenylation and that the status of isoprenylation of these mutant proteins correlated well with their abilities to be packaged with HBsAg into virions. This result indicates that isoprenylation, rather than the primary amino acid sequence, is required for LHDAg packaging. Furthermore, we found that the attachment of an isoprenylation motif to SHDAg did not enable it to be packaged with HBsAg and that the deletions of any 5 amino acids in the last 15 amino acids (amino acids 196 to 210) unique to the LHDAg abolished the packaging ability. In contrast, the deletion of 33 amino acids (amino acids 163 to 195) upstream of the last C-terminal 19 amino acids of LHDAg did not interfere with its packaging ability. Therefore, we conclude that the 15 amino acids upstream of the isoprenylation site of LHDAg are also essential for HDV assembly, and a large portion of the alleged C-terminal Pro/Gly-rich region (amino acids 146 to 195) is not required for the assembly process.
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PMID:Isoprenylation of large hepatitis delta antigen is necessary but not sufficient for hepatitis delta virus assembly. 811 40

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


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