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)

The sequence 'GOR47-1' is a consistent part of human DNA; the expressed polypeptide of it 'GOR' is accepted to be an autoantigen, and the anti-GOR an autoantibody. However, GOR47-1 was originally isolated through a cDNA clone from blood of a chimpanzee. This animal belonged to a series of chimpanzees, in which human plasma of a patient with non-A, non-B hepatitis had been passaged. To date, nothing is known how it is that this 'sequence GOR47-1' without recognizable self-replicating properties and allocated to the human genome could be isolated from a chimpanzee plasma. The aim of this study was to detect by polymerase chain reaction GOR47-1 sequences in healthy, anti-HCV-negative humans, HCV-positive patients, chimpanzee, snake, and in maize and tobacco plants. The GOR47-1 sequence is present not only in human DNA but also with a high degree of homology in chimpanzee DNA. Essential parts of this sequence are also present in DNA of a snake and the two plants listed above. Our findings reveal that the GOR47-1 sequence isolated from a chimpanzee was probably of the chimpanzee origin. This fact has not yet been considered up until now, when discussing the role of GOR/anti-GOR in humans particularly suffering from chronic hepatitis C.
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PMID:The GOR47-1 sequence in human DNA encoding for a potential autoantigen in connection with hepatitis C--a sequence not only reserved for humans. 984 65

Type 1 autoimmune hepatitis (AIH-1) is an organ-specific autoimmune liver disease for which no tissue-specific autoantigen has yet been identified. We examined the reactivity by sensitive immunoblotting with enhanced chemiluminescence (IB-ECL) of 43 sera from patients with AIH-1 and 182 sera from patients with other diseases on hepatocyte plasma membrane derived from rat or human liver (RHPM, HHPM) and separated by aqueous two-phase partition. The sera studied were from patients with AIH-1, primary biliary cirrhosis, chronic viral hepatitis, and systemic lupus erythematosus (SLE); and from normal subjects. Specificity of reactivity by IB-ECL was sought: (i) by testing sera on human or rat liver membrane; (ii) by testing sera on liver or kidney membrane; (iii) by serial titration of reactive sera; and (iv) by testing reactive sera from AIH-1 before and after successful treatment with prednisolone. The results were that in AIH-1 there were multiple reactive components which were not species-specific, since they were detected with both RHPM and HHPM, but were mostly tissue-specific for liver. There was no significant correlation between antinuclear antibodies (ANA) titer and the frequencies of sera reactivities against RHPM. Most of these reactive components were demonstrable at a lesser frequency in other liver diseases and in SLE. There was a striking decrease in reactivity by IB-ECL of AIH-1 sera with liver membrane after clinical remission, further suggesting that differences between AIH-1 and other inflammatory liver diseases and SLE are predominantly quantitative rather than qualitative. However, our study did point to candidate liver membrane antigens with molecular sizes of 136, 116, 81, and 49 kDa, additional to components previously described by others. The molecular identification of these prominent reactants with AIH-1 sera could prove informative for ascertaining pathogenesis.
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PMID:Autoimmune reactivity of sera to hepatocyte plasma membrane in type 1 autoimmune hepatitis. 1075 98

Genetic susceptibility to type 1 autoimmune hepatitis in white northern Europeans is related to female sex, HLA alleles encoding the six amino acid sequence LLEQKR at positions 67-72 of the DRB1 polypeptide, and CTLA-4 gene polymorphism. The principal HLA alleles associated with type 1 autoimmune hepatitis in Britain and North America are DRB1*0301 and DRB1*0401. In this model of susceptibility, lysine at position 71 of the expressed DR molecule is the critical amino acid. In Japan, Argentina and Mexico, susceptibility is linked to DRB1*0405 and DRB1*0404. These two alleles encode arginine at position 71 rather than lysine, but they share the motif LLEQ-R with DRB1*0401 and DRB1*0301. Thus, K or R at position 71 in the context of LLEQ-R may be critical for susceptibility. This "shared motif" or "epitope" may optimize T-cell recognition of autoantigen, and other alleles that encode lysine at DRbeta71 may also affect susceptibility and outcome, possibly by increasing the density of lysine or arginine 71 molecules on the surface of antigen-presenting cells. Since the DRB1*0301 allele is part of the extended ancestral 8.1 haplotype, it carries with it additional risk factors for autoimmunity, including TNFA*2 and C4A*Q0. Type 1 autoimmune hepatitis is a polygenic disorder and other yet undefined polymorphic genes may be non-specific immunoregulators. These additional MHC encoded genes and other non-MHC encoded genes may be important determinants of disease susceptibility and severity in type 1 autoimmune hepatitis.
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PMID:Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. 1080 21

Cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) are targets of autoantibodies in several hepatic and extrahepatic autoimmune diseases. Autoantibodies directed against hepatic CYPs and UGTs were first detected by indirect immunofluorescence as antiliver and/or kidney microsomal antibodies. In autoimmune hepatitis (AIH) type 2, liver and/or kidney microsomal (LKM) type 1 autoantibodies are detected and are directed against CYP2D6. About 10% of AIH-2 sera further contain LKM-3 autoantibodies directed against family 1 UGTs. Chronic infections by hepatitis C virus and hepatitis delta virus may induce several autoimmune phenomena, and multiple autoantibodies are detected. Anti-CYP2D6 autoantibodies are detected in up to 4% of patients with chronic hepatitis C, and anti-CYP2A6 autoantibodies are detected in about 2% of these patients. In contrast, 14% of patients with chronic hepatitis delta virus infections generate anti-UGT autoantibodies. In a small minority of patients, certain drugs are known to induce immune-mediated, idiosyncratic drug reactions, also known as 'druginduced hepatitis'. Drug-induced hepatitis is often associated with autoantibodies directed against hepatic CYPs or other hepatic proteins. Typical examples are tienilic acid-induced hepatitis with anti-CYP2C9, dihydralazine hepatitis with anti-CYP1A2, halothane hepatitis with anti-CYP2E1 and anticonvulsant hepatitis with anti-CYP3A. Recent data suggest that alcoholic liver disease may be induced by mechanisms similar to those that are active in drug-induced hepatitis. Autoantibodies directed against several CYPs are further detected in sera from patients with the autoimmune polyglandular syndrome type 1. Patients with autoimmune polyglandular syndrome type 1 with hepatitis often develop anti-CYP1A2; patients with adrenal failure develop anti-CYP21, anti- CYP11A1 or CYP17; and patients with gonadal failure develop anti-CYP11A1 or CYP17. In idiopathic Addison disease, CYP21 is the major autoantigen.
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PMID:Target proteins in human autoimmunity: cytochromes P450 and UDP- glucuronosyltransferases. 1085 Dec 84

Autoantibodies, markers of autoimmune diseases, can also be detected in chronic allograft rejection. However, the appearance of these autoantibodies in acute rejection after orthotopic liver transplantation has not yet been reported. Liver-kidney-microsome type-1 (LKM-1) antibodies directed against the autoantigen cytochrome CYP2D6 define a group of patients with autoimmune hepatitis type-2 (AIH-2), distinct from autoimmune hepatitis type-1 (AIH-1) in which anti-nuclear antibodies and anti-smooth muscle antibodies (SMA) with actin specificity are present in patient sera. Autoantibodies were studied by the quantitative CYP2D6 radioligand assay (RLA) that uses a radiolabeled CYP2D6 as antigen, immunoblotting using recombinant CYP2D6 protein and human liver microsomal and cytosolic fractions, and indirect immunofluorescence (IIF) using rat kidney-stomach-liver cryostat sections. In addition, the specificity of anti-SMA was detected by IIF on HEp2 cell line harvested with colchicin. This report describes the time course of CYP2D6 antibodies and the appearance of anti-SMA (without anti-actin, cytokeratin and vimentin reactivity) associated with acute rejection during a 2-year follow-up, in a patient who underwent transplantation at end-stage type 2 autoimmune hepatitis. In addition, we report a new reactivity against an unknown 40-kDa protein using a rat cytosolic fraction. The detection of autoantibodies in sequential samples may be important to better predict rejection or relapse, and to establish adequate therapy.
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PMID:Autoantibodies associated with acute rejection after liver transplantation for type-2 autoimmune hepatitis. 1090 2

Germander, a plant used in folk medicine, caused an epidemic of cytolytic hepatitis in France. In about half of these patients, a rechallenge caused early recurrence, suggesting an immunoallergic type of hepatitis. Teucrin A (TA) was found responsible for the hepatotoxicity via metabolic activation by CYP3A. In this study, we describe the presence of anti-microsomal epoxide hydrolase (EH) autoantibodies in the sera of patients who drank germander teas for a long period of time. By Western blotting and immunocytochemistry, human microsomal EH was shown to be present in purified plasma membranes of both human hepatocytes and transformed spheroplasts and to be exposed on the cell surface where affinity-purified germander autoantibodies recognized it as their autoantigen. Immunoprecipitation of EH activity by germander-induced autoantibodies confirmed this finding. These autoantibodies were not immunoinhibitory. The plasma membrane-located EH was catalytically competent and may act as target for reactive metabolites from TA. To test this hypothesis CYP3A4 and EH were expressed with human cytochrome P450 reductase and cytochrome b(5) in a "humanized" yeast strain. In the absence of EH only one metabolite was formed. In the presence of EH, two additional metabolites were formed, and a time-dependent inactivation of EH was detected, suggesting that a reactive oxide derived from TA could alkylate the enzyme and trigger an immune response. Antibodies were found to recognize TA-alkylated EH. Recognition of EH present at the surface of human hepatocytes could suggest an (auto)antibody participation in an immune cell destruction.
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PMID:Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes. 1095 47

Primary biliary cirrhosis (PBC) is characterized by an immune mediated, irreversible destruction of the small intrahepatic bile ducts leading to progressive liver cirrhosis and frequently to liver failure. The course of the disease is variable and an early diagnosis is desirable to identify individuals with rapidly progressing disease, to initiate adequate therapeutic measures and to evaluate the necessity of liver transplantation. Serological tests represent the single most important diagnostic feature of PBC because liver histology, biochemistry, or clinical syndrome alone are not reliable in this respect. The molecular definition of the autoantigen targets of antimitochondrial antibodies (AMA) has resulted in the development of reproducible and effective serological testing strategies. AMA directed against the ketoacid dehydrogenase complex are highly disease-specific but not directed against liver-specific target structures. Despite a high disease specificity, their usefulness for predicting the course of disease, the timing of liver transplantation, or disease recurrence after transplantation is limited. The realization that about 5% of patients with PBC do not display AMA has led to the identification of PBC-specific antinuclear autoantibodies directed against the nuclear pore complex and other targets. The overlap of PBC with autoimmune hepatitis and primary sclerosing cholangitis represents a diagnostic challenge in which autoantibody determinations play a central role and contribute to the administration of suitable treatment options.
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PMID:Autoimmune tests in primary biliary cirrhosis. 1097 16

Numerous human Cytochrome P450 enzymes (CYPs) associated with 'phase I' drug metabolism have been identified. Among them, CYP2D6 is thought to be the major target autoantigen to anti-liver kidney microsome (LKM)-1 autoantibody, a characteristic feature of autoimmune hepatitis (AIH) type II. In this study, we were able to clone CYP2D6 cDNA from a human liver cDNA library and express the CYP2D6 recombinant protein, and also to prepare four other representative human CYP proteins (CYP1A2, 2C9, 2E1, and 3A4). These preparations were used to assay the immunoreactivity of patients with AIH type I (n=35) and type II (n=9). As comparison groups, sera from patients with chronic hepatitis B (n=15), chronic hepatitis C (n=55; 24 anti-LKM-1-positive, 31 anti-LKM-1-negative), and from normal controls (n=30) were included. The five CYP proteins did not react with sera from normal controls nor from patients with chronic hepatitis B. CYP2D6 reacted with sera from 100% (9/9) of AIH type II patients, 79% (19/24) of patients with anti-LKM-1-positive chronic hepatitis C, and 6.5% (2/31) of patients with anti-LKM-1-negative chronic hepatitis C. In contrast, CYP1A2 reacted with serum from one patient with AIH type I, CYP2E1 reacted with sera from two patients with AIH type I, one patient with anti-LKM-1-positive chronic hepatitis C, and two patients with anti-LKM-1-negative chronic hepatitis C, and CYP3A4 reacted with sera from one patient with AIH type II and one patient with anti-LKM-1-positive chronic hepatitis C. CYP2C9 did not react with any of the sera included in this study. From these results, it is suggested that CYPs other than CYP2D6 can function as immunotargets in certain disease conditions.
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PMID:Immunoreactivity to various human cytochrome P450 proteins of sera from patients with autoimmune hepatitis, chronic hepatitis B, and chronic hepatitis C. 1120 50

Autoimmune hepatitis is a chronic liver disease characterized by immune-mediated, progressive hepatocellular damage, although the target autoantigen remains speculative. Intrahepatic biliary lesions are not a feature of this disease. We describe herein a female patient, 57 years, with autoimmune hepatitis who developed hepatic regenerative mass after acute exacerbation of hepatitis. This hepatic regenerative mass was clinically diagnosed as hepatocellular carcinoma and was surgically resected after transcatheter arterial embolization therapy. Widespread nonsuppurative destructive granulomatous cholangitis as well as necrotizing, granulomatous arteritis of the intrahepatic small arteries were found in the surgically resected hepatic regenerative mass. The bile duct lesions were histologically and immunohistochemically very similar to the granulomatous cholangitis of primary biliary cirrhosis. We would like to propose that these unusual lesions in the intrahepatic bile ducts and intrahepatic arteries represent a reaction of this patient to an anti-cancer drug included in chemoembolization. No such cases have been reported so far.
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PMID:Intrahepatic cholangitis and arteritis after transcatheter arterial embolization in a patient with tumor-like lesion-associated autoimmune hepatitis. 1120 18

Immunologic injury in the liver involves immigrant T and B lymphocytes and a resident lymphoid population that comprises distinct lymphocytic cells and accessory cells. The forerunner to autoimmunity is breaching of natural self-tolerance and hence the disruption of a fundamental property of the immune system. Such breaching occurs by processes that include inflammatory activation of immunocytes and macrophages, spillage of intracellular constituents, and epitope mimicry by constituents of microorganisms, with these acting on a genetically conditional phenotype; compounding factors include aberrations of apoptosis, whether insufficient or excess. The downstream end requires specifically directed inflammatory leukocyte traffic as an essential component of autoimmune expressions in the liver. The culmination is an orchestrated attack on hepatocytes or biliary epithelial cells by multiple effector pathways. Progress in type 1 autoimmune hepatitis still requires knowledge of a disease-specific autoantigen(s) involved in T-cell reactivity, although such knowledge in type 2 autoimmune hepatitis, in which the known autoantigen is cytochrome P4502D6, has not yet been integrated into a clearly defined scheme of pathogenesis. For PBC there has been a very promising amalgamation of molecular knowledge of the mitochondrial autoantigens. Future insights require deeper analysis of molecular, genetic, macroenvironmental, and microenvironmental elements in predisposition.
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PMID:The lymphoid liver: considerations on pathways to autoimmune injury. 1131 20


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