UMLS:C0019158 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0019158 (hepatitis)
30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic inflammatory liver diseases can be induced by virus infections, toxic-metabolic factors and/or autoimmune mechanisms. This overview deals with the immunopathogenesis of chronic hepatitis B and C and autoimmune hepatitis (AIH). 1. Chronic hepatitis B: The immune response to HBV-antigens is responsible both for viral clearance and disease pathogenesis during HBV-infection. The humoral immune response to HBsAg contributes to the clearance of circulating virus particles, the cell mediated immune response to HBsAg, HBcAg and polymerase antigen eliminates infected cells. The class I- and class II restricted T-cell-responses to HBV is strong, polyclonal and multispecific in acute HB with successful clearance of the virus, but weak or incomplete in chronic HB with viral persistence. In addition to ineffective immune response host and viral factors as well as abnormalities in virus-host interactions may be the main reasons for the maintenance of HBV-carrier status. 2. Chronic hepatitis C develop in more than 60% of infected patients. There is increasing evidence that the immune response to HCV-epitopes plays an important role in the course and the pathogenesis of the disease. It has been shown that CD4+ and CD8+ T-cells recognize viral peptides in the presence of class I and II molecules. The fine specificity and functional significance of liver infiltrating and peripheral blood T-cells demonstrate HCV specific immunodominant epitopes targeted by class Ii restricted CD4+ cells in patients with chronic HCV infection. The T-cell response correlates with disease activity. The cytokine release of T-cells resemble a TH1-like profile. Studies of the humoral immune response to HCV show a correlation between IgM-anti-HCV and disease activity. In vitro and in vivo anti-HCV secretion by PBMC is due to persistent antigenic stimulation of B-cells by ongoing production of viral antigens and reflects HCV replication in PBMC. Of special interest are several immune mediated disease and immune abnormalities in chronic hepatitis C. 3. Autoimmune hepatitis (AIH) is a distinct group of acute and chronic necro-inflammatory disorders of unknown etiology characterized by immunological and autoimmunological features including the presence of autoantibodies but without an antecedent of viral infections. Marker autoantibodies define 3 subtypes: Type I (ANA/SMA), Type II (LKM1-AB), Type II (SLA-AB). AIH is associated with a distinct genetic background (HLA A1, B8, DR3 or DR4). Several studies clearly demonstrate that liver cell damage in AIH is mediated by autoimmune reactions against normal constituents of hepatocytes. Although the precise mechanisms are not yet fully understood, there is now considerable evidence that autoantigens of the hepatocellular membrane in particular the ASGPR are important targets of liver damaging autoreactions in AIH. Cellular and humoral immune reactions against the human ASGPR correlate with disease activity and usually disappear under immunosuppressive therapy.
...
PMID:[Immunopathology of chronic liver diseases]. 860 Jun 84

The number of autoantibodies associated with chronic liver disease continues to burgeon and characterization of these immunoreactivities will undoubtedly enhance understanding of the autoantigens that are targeted by cytodestructive immunocytes. Assays for the majority of these immunoserological species are not generally available and in most instances, assessments are restricted to individual laboratories with vested interests in characterizing a particular species. For clinical diagnosis and management of autoimmune liver disease, assays for ANA, SMA, anti-LKM1 and AMA are essential. This conventional armamentarium, however, must be upgraded on a regular basis to ensure availability and application of the most useful assays. Unfortunately, there are no formal mechanisms for improving the diagnostic resources and standardizing testing strategies. An important first step must be taken by the basic laboratories that advocate individual assay systems. These facilities must share methodologies and exchange serum samples so that the most clinically pertinent and cost-effective immunoserological batteries can be defined and promulgated. Industry can then respond to need and facilitate the commercialization of assays for general use. Currently, the assays that warrant dissemination are those that detect antibodies to the E2 subunits of the pyruvate dehydrogenase complex and antibodies to asialoglycoprotein receptor. Both assays have high diagnostic specificity and each reflects reactivity to an important target autoantigen of probable pathogenic importance. Each autoantibody species can supplant conventional assays such as those for AMA and ANA and they each may impart useful clinical information. In the case of antibodies to the E2 subunits, titres may reflect histological progression of PBC. In the case of anti-ASGPR, disappearance of the autoantibodies in patients with autoimmune hepatitis may secure a confident treatment end-point. Great progress has been made in defining the immunoserological manifestations of chronic liver disease but little has been done to distribute the resources.
...
PMID:Autoantibodies. 890 2

The relationship between hepatitis virus invasion and emergence of liver-specific autoantibodies against asialoglycoprotein receptor (anti-ASGPR) and the occurrence patterns, prognostic value, and specificity of these autoantibodies toward polypeptides of host ASGPR were investigated in experimental viral hepatitis in the woodchuck system. Sequential sera (n = 231) obtained before and after inoculation with woodchuck hepatitis virus (WHV) from animals which resolved acute infection (n = 7) or developed chronic hepatitis (n = 6) were tested for anti-ASGPR using radio and enzyme-immunodetection assays. In addition, the outcome of WHV hepatitis was analyzed in 30 other woodchucks whose preinoculation sera were tested for anti-ASGPR. The receptor subunit specificity of virus-induced anti-ASGPR was determined by Western blotting and compared with that of anti-ASGPR raised in woodchucks challenged with a heterologous (rabbit) receptor. The results revealed that WHV infection triggered anti-ASGPR in all except one of the initially autoantibody nonreactive animals (eight of nine; 89.9%). Once induced, anti-ASGPR were detectable throughout the entire follow-up independent of histological severity of liver damage or the outcome of hepatitis. In healthy WHV-naive woodchucks, anti-ASGPR occurred at low titers in approximately one third of the animals. Importantly, woodchucks reactive for anti-ASGPR before WHV inoculation developed chronic hepatitis with a significantly greater frequency (55.5%) than those autoantibody negative (15.6%; P < .05). In contrast to anti-ASGPR elicited by immunization with a heterologous receptor, which initially recognized only the ASGPR 40-kd polypeptide, anti-ASGPR emerging after virus invasion reacted with both the ASGPR 40- and 47-kd subunits from the moment of their appearance. This study provides the first direct evidence that hepatitis virus in the natural host triggers autoantibodies against a unique hepatocyte antigen and shows that anti-ASGPR autoimmunity existing before virus infection is associated with a high rate of progression to chronic disease in experimental hepadnaviral hepatitis.
...
PMID:Virus-induced anti-asialoglycoprotein receptor autoimmunity in experimental hepadnaviral hepatitis. 904 20

HCV has been implicated in a variety of immune disorders as Sjogren's Syndrome, thyroiditis, glomerulonephritis, panarteritis nodosa and AIH. Soon after its discovery HCV has been causative associated with AIH due to a high incidence of antibodies against the virus tested by first generation assays. However applying more specific systems and by direct demonstration of the HCV RNA we have found only 2% of patients with confirmed AIH to harbour the virus. About 19% of patients with virus Hepatitis C may present with autoantibodies in the serum as RNA, SNA and only 2% have antibodies against LKM Type 1. Liver biopsies from patients with chronic Hepatitis C and autoantibodies display features typical for chronic hepatitis C as described in the literature and not those of the autoimmune type. Furthermore immunohistological findings show a predominance of CD8 lymphocytes and only a weak expression of ASGPR, parameters that are easily found in autoimmune hepatitis. On the basis of serological, histopathological and immunohistological studies it seems very unlikely that HCV can be regarded as a causative agent for the induction of autoimmune Hepatitis.
...
PMID:[Hepatitis C virus and autoimmune hepatitis: coincidence or causal relationship?]. 906 98

Hepadnavirus invasion in woodchucks has been identified as a potent inducer of autoantibodies against asialoglycoprotein receptor (anti-ASGPR), a molecule essentially unique to hepatocytes that mediate clearance of desialylated serum proteins. We evaluated the possible pathogenetic importance of anti-ASGPR triggered by woodchuck hepatitis virus (WHV), using anti-ASGPR-reactive serum immunoglobulins (Igs) from five animals with different stages of WHV hepatitis or self-limited WHV infection and isolated woodchuck hepatocytes or HepG2 cells as targets. The results revealed that WHV-induced anti-ASGPR can specifically inhibit asialoglycoprotein recognition by both homologous and heterologous liver cells, as tested in an asialofetuin (ASFN)-binding radioassay. However, the extent of the interference significantly varied (from 85% inhibition to none) for anti-ASGPR with similar titer from different animals, indicating a high degree of heterogeneity in the ASGPR epitope specificity and in the potential biological effects of these autoantibodies. The WHV-triggered anti-ASGPR also induced complement-mediated hepatocytolysis in a microculture tetrazolium (MTT) assay, which ranged from 8.9% +/- 0.3% to 33.6% +/- 3.6% (mean +/- SD) for different animals and target cell numbers. This cytopathic effect was strictly ASGPR-specific, complement-dependent, and was not related to the anti-ASGPR ability to inhibit ligand-hepatocyte binding. Our findings indicate that among pathways by which anti-ASGPR autoimmunity could cause liver damage, hepadnavirus-induced anti-ASGPR might impair hepatocytes by both disrupting clearance of desialylated proteins and activation of the complement-mediated cytolysis. These cytopathic effects might contribute to the pathogenesis, aggravate severity, and prolong recovery from liver injury in viral hepatitis.
...
PMID:Complement-mediated cytotoxicity and inhibition of ligand binding to hepatocytes by woodchuck hepatitis virus-induced autoantibodies to asialoglycoprotein receptor. 962 Mar 36

Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by hypergammaglobulinaemia, non-organ and liver-related autoantibodies, association with HLA-DR3 or DR4 and a favourable response to immunosuppression. The current classification of AIH and the several autoantibodies/target autoantigens found in this disease are reported. The importance of these markers in the differential diagnosis and the study of pathogenesis of AIH is also given. AIH is subdivided into two major types: AIH type 1 (AIH-1) and AIH type 2 (AIH-2). AIH-1 is characterised by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Antineutrophil cytoplasmic autoantibodies (ANCA), in most cases of perinuclear pattern (p-ANCA), by the indirect immunofluorescence assay, antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of individuals who are seronegative for ANA/SMA. AIH-2 is characterised by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). For these reasons, the distinction between AIH and chronic viral hepatitis is of particular importance. Cytochrome P450 2D6 (CYP2D6) is the major target autoantigen of anti-LKM-1 autoantibodies in both conditions (AIH-2 and HCV infection). Recent data have demonstrated the expression of CYP2D6 on the surface of hepatocytes, suggesting a pathogenetic role of anti-LKM-1 autoantibodies in liver injury. Family 1 of UDP-glycuronosyltransferases has been identified as the target autoantigen of anti-LKM-3. The molecular target of anti-SLA/LP autoantibodies has been identified recently as a 50 kDa protein with unknown structure and function. A liver-specific enzyme, the formiminotransferase cyclodeaminase, was identified as the target autoantigen of anti-LC1 autoantibodies. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate better with the severity of AIH and the response to treatment. The latter may suggest a pathogenic role of these autoantibodies in the hepatocellular damage in AIH. In general, however, autoantibodies should not be used to monitor treatment or to predict AIH activity or outcome. Finally, current knowledge concerning a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyglandular syndrome type-1 (APS-1), is also discussed. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies found in AIH as a disease component of APS-1. However, anti-LM autoantibodies have also been described in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target autoantigen of anti-LM autoantibodies in both disease entities.
...
PMID:Autoantibodies and defined target autoantigens in autoimmune hepatitis: an overview. 1214 8

No longitudinal study has investigated whether autoantibody titres and serum IgG levels correlate with disease activity in autoimmune liver disease. To determine this, we investigated prospectively 19 patients on 254 occasions between 10 months to 5 years from diagnosis. Nine had anti-nuclear and/or anti-smooth muscle antibody (ANA/SMA) positive autoimmune hepatitis (type 1 AIH), 5 liver kidney microsomal type 1 (LKM-1) positive AIH (type 2 AIH) and 5 ANA/SMA positive autoimmune sclerosing cholangitis (ASC). Correlation between IgG levels, titres of ANA, SMA and LKM-1 and levels of the organ specific autoantibodies anti-liver specific protein (anti-LSP), and anti-asialoglycoprotein receptor (anti-ASGPR) with biochemical evidence of disease activity, as measured by serum aspartate amino transferase (AST) levels, was sought during the course of the disease. AST levels correlated with levels of anti-LSP, anti-ASGPR and IgG in type 1 and 2 AIH, but not in ASC. Positive correlation with AST was also observed for LKM-1 titres in type 2 AIH and for SMA titres in type 1 AIH, but not in ASC. In both AIH and ASC, AST levels correlated with the T cell-dependent immune responses anti rubella IgG and anti tetanus toxoid IgG, but not with the T cell-independent IgG2 response to pneumococcal capsular polysaccaride. Our results indicate that measurement of organ and non-organ specific autoantibodies and IgG levels may be used to monitor disease activity in AIH.
...
PMID:Organ and non-organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease. 1276 77

Viral hepatitis is frequently accompanied by humoral autoimmune responses toward both organ-nonspecific and liver-specific antigens, but contribution of these reactivities to liver injury remains unrecognized. Infection with woodchuck hepatitis virus (WHV) has been identified as a potent inducer of autoantibodies against asialoglycoprotein receptor (anti-ASGPR), a molecule essentially unique to hepatocytes that mediates clearance of desialylated serum proteins. In this study, we applied the WHV-woodchuck model of hepatitis B to examine the effect of experimentally elicited anti-ASGPR on the progression and the severity of WHV hepatitis in initially healthy animals immunized with the receptor and then infected with WHV and in woodchucks with ongoing chronic WHV hepatitis. The results implied that the induction of anti-ASGPR prior to WHV infection tends to modulate acute viral hepatitis toward chronic outcome and, in animals with established chronic WHV infection, exacerbates histologic severity of liver lesions. The findings also suggest that the liver compromised by chronic hepadnavirus infection might be prone to anti-ASGPR-directed complement-mediated hepatocellular injury and that this is associated with formation of the ASGPR-anti-ASGPR immune complexes on hepatocyte surface. In conclusion, the host's immune response mounted against a hepatocyte-specific autoantigen may modulate both the outcome and the severity of liver injury in viral hepatitis.
...
PMID:Modulation of the outcome and severity of hepadnaviral hepatitis in woodchucks by antibodies to hepatic asialoglycoprotein receptor. 1293 89

Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver characterized by hypergammaglobulinemia, characteristic autoantibodies, association with HLA DR3 or DR4 and a favorable response to immunosuppressive treatment. The etiology is unknown. The detection of non-organ and liver-related autoantibodies remains the hallmark for the diagnosis of the disease in the absence of viral, metabolic, genetic, and toxic etiology of chronic hepatitis or hepatic injury. The current classification of AIH and the several autoantibodies/target-autoantigens found in this disease are reported. Current aspects on the significance of these markers in the differential diagnosis and the study of pathogenesis of AIH are also stated. AIH is subdivided into two major types; AIH type 1 (AIH-1) and type 2 (AIH-2). AIH-1 is characterized by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Determination of antineutrophil cytoplasmic autoantibodies (ANCA), antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies against to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of patients who are seronegative for ANA/SMA. AIH-2 is characterized by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). Cytochrome P450 2D6 (CYP2D6) has been documented as the major target-autoantigen of anti-LKM-1 autoantibodies in both AIH-2 and HCV infection. Recent convincing data demonstrated the expression of CYP2D6 on the surface of hepatocytes suggesting a pathogenetic role of anti-LKM-1 autoantibodies for the liver damage. Family 1 of UDP-glycuronosyltransferases has been identified as the target-autoantigen of anti-LKM-3. For these reasons the distinction between AIH and chronic viral hepatitis (especially of HCV) is of particular importance. Recently, the molecular target of anti-SLA/LP and anti-LC1 autoantibodies were identified as a 50 kDa UGA-suppressor tRNA-associated protein and a liver specific enzyme, the formiminotransferase cyclodeaminase, respectively. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate closely with disease severity and response to treatment suggesting a pathogenetic role of these autoantibodies for the hepatocellular injury. In general however, autoantibodies should not be used to monitor treatment, predict AIH activity or outcome. Finally, the current aspects on a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) are also given. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies detected in AIH as a disease component of APECED but also in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target-autoantigen of anti-LM autoantibodies in both APECED-related AIH and dihydralazine-induced hepatitis. The latter may indicate that similar autoimmune pathogenetic mechanisms can lead to liver injury in susceptible individuals irrespective of the primary defect. Characterization of the autoantigen-autoantibody repertoire continues to be an attractive and important tool to get access to the correct diagnosis and to gain insight into the as yet unresolved mystery of how hepatic tolerance is given up and AIH ensues.
...
PMID:Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease. 1567 7

Autoimmune hepatitis (AIH) is a disease of unknown etiology, characterized by liver-related autoantibodies. Autoimmune hepatitis is subdivided into two major types: AIH type 1 is characterized by the detection of ANA, SMA, ANCA, anti-ASGP-R, and anti-SLA/LP. Autoimmune hepatitis type 2 is characterized to be mainly related with drug-metabolizing enzymes as autoantigens, such as anti-LKM (liver-kidney microsomal antigen)-1 against CYP2D6, anti-LKM-2 against CYP2C9-tienilic acid, anti-LKM-3 against UGT1A, and anti-LC1 (liver cytosol antigen)-1 and anti-APS (autoimmune polyglandular syndrome type-1) against CYP1A2, CYP2A6, and others. Anti-LKM-1 sera inhibited CYP2D6 activity in vitro but did not inhibit cellular drug metabolism in vivo. CYP2D6 is the major target autoantigen of LKM-1 and expressed on plasma membrane (PM) of hepatocytes, suggesting a pathogenic role for anti-LKM-1 in liver injury as a trigger. Anti-CYP1A2 was observed in dihydralazine-induced hepatitis, and radiolabeled CYP1A2 disappeared from the PM with a half-life of less than 30 min, whereas microsomal CYP1A2 was stably radiolabeled for several hours. Main antigenic epitopes on CYP2D6 are aa 193-212, aa 257-269, and aa 321-351; and D263 is essential. The third epitope is located on the surface of the protein CYP2D6 and displays a hydrophobic patch that is situated between an aromatic residue (W316) and histidine (H326). Some drugs such as anticonvulsants (phenobarbital, phenytoin, and carbamazepine) and halothane are suggested to induce hepatitis with anti-CYP3A and anti-CYP2E1, respectively. Autoantibodies against CYP11A1, CYP17, and/or CYP21 involved in the synthesis of steroid hormones are also detected in patients with adrenal failure, gonadal failure, and/or Addison disease.
...
PMID:Autoantibodies against CYP2D6 and other drug-metabolizing enzymes in autoimmune hepatitis type 2. 1574 2

1 2 Next >>