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)

Antibodies to asialoglycoprotein receptor have diagnostic specificity for autoimmune hepatitis, but it is uncertain if they are complementary or redundant markers of the disease. Our aims were to assess their frequency and significance in type 1 autoimmune hepatitis and determine their contribution to the evaluation of these patients. Sera from 54 well-characterized patients were evaluated for antibodies to asialoglycoprotein receptor by a radioimmunofiltration assay based on rabbit-derived protein. Forty-four patients (82%) were seropositive. Seropositive patients were distinguished from seronegative counterparts by having higher serum gamma globulin (3.7 +/- 0.2 g/dl vs 2.3 +/- 0.3 g/dl, P = 0.0007) and immunoglobulin G levels (3707 +/- 179 mg/dl vs 2203 +/- 263 mg/dl, P = 0.0005) at presentation and a greater frequency of relapse after drug withdrawal (88% vs 33%, P = 0.01). Seropositivity for smooth muscle and/or antinuclear antibodies did not define treatment outcomes and antinuclear antibodies occurred less frequently than the other markers. Concurrent testing for antibodies to asialoglycoprotein receptor and smooth muscle identified all patients. We conclude that antibodies to asialoglycoprotein receptor are common in type 1 autoimmune hepatitis and they identify patients with a high frequency of relapse after corticosteroid withdrawal. Concurrent testing for these antibodies and smooth muscle antibodies has the same diagnostic sensitivity as testing for antinuclear and smooth muscle antibodies but a greater prognostic implication.
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PMID:Frequency and significance of antibodies to asialoglycoprotein receptor in type 1 autoimmune hepatitis. 879 87

Since the first tests for antibodies to components of the hepatitis C virus became widely available there has been considerable interest in evidence linking HCV infection with autoimmune liver diseases and other autoimmune conditions. With respect to autoimmune hepatitis, it is now clear that the early tests were quite non-specific and that it was the abnormalities in serum globulins in autoimmune hepatitis which led to such high positivity rates in this disease. Careful surveys across Europe have now made it clear that there are true associations between HCV infection and autoimmune liver diseases, but that their frequency is much higher in the south than the north. This is particularly striking for that variety of autoimmune hepatitis positive for antibodies to the liver/kidney microsomal antigen (cytochrome P450 2D6). Here there are distinct subgroups; one a "true" autoimmune group of younger females with more active disease, and a second, containing older patients with a more even sex distribution, where the virus seems to be driving an autoimmune reaction. The mechanisms underlying these associations are not yet clear, although analysis of the amino-acid sequences of selected virus and host proteins has shown some significant homology. Interestingly, and surprisingly, the overall incidence of periportal hepatitis is lower in HCV infection than in acute or chronic HBV infection, or acute HAV hepatitis. There is a parallel distribution in the frequency and titre of antibodies to the asialoglycoprotein receptor, one of the important targets for autoimmune reactions on the liver cell membrane. There are many reports of associations between HCV infection and other immune-mediated conditions, and although the strength of such associations is always difficult to judge, HCV infection in some conditions, such as cryglobulinaemia, is clearly an important driving force. Here, treatment of the HCV infection with interferon may led to striking remission in associated vascular lesions. Clinically, it can be very difficult to distinguish between liver disease due to HCV infection and autoimmune hepatitis co-existing with HCV infection, but because the treatment for these two conditions is quite different, the distinction is important. Alpha-interferon, the current treatment of choice for HCV infection, often induces a relapse in autoimmune hepatitis, while steroids, the treatment of choice for autoimmune hepatitis, may be permissive for HCV replication, and thus, at least in theory, may militate against the success of a subsequent course of alpha-interferon. A pragmatic approach to the choice of a first therapeutic agent is recommended based on the relative local prevalence of the two conditions, the use of readily available clinical tests, and the results of appropriate specialised assays in the most difficult cases.
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PMID:Hepatitis C infection and autoimmunity. 883 90

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.
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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.
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PMID:Virus-induced anti-asialoglycoprotein receptor autoimmunity in experimental hepadnaviral hepatitis. 904 20

Circulating anti asialoglycoprotein receptor antibodies (anti-ASCPR) and soluble interleukin-2 receptor levels (sIL-2R) were blindly determined in sera of 23 patients with autoimmune hepatitis and compared to 18 healthy individuals. All patients underwent liver biopsy which was blindly staged and graded. 14 of 23 (61%) patients but none of normal controls showed anti-ASCPR positivity. Eleven of twelve (92%) patients with biopsy-proven grade 3 hepatitis were high-titered anti-ASCPR positive compared to three of eleven patients with grade I hepatitis. Mean levels of sIL-2R +/- standard deviation were 1.175 +/- 663 units/ml in the total number of patients with auto-immune hepatitis comparing to 372 +/- 69 units/ml in healthy controls (p < 0.001). Eleven of twelve patients with grade 3 hepatitis had significant higher sIL-2R levels (1,669 +/- 559) than patients with mild disease (635 +/- 113). Chi-square analysis demonstrated a significant correlation between positive anti-ASCPR titer and elevated sIL-2R values. A follow-up analysis of six patients showed a significant decrease of both anti-ASCPR titer and sIL-2R levels after three to nine months of immunosuppressive therapy. These findings suggest that elevated sIL-2R levels and anti-ASCPR titer are associated in patients with autoimmune hepatitis and- as a function of either T or B cell activation, respectively- could serve as reliable humoral marker for disease-specific activity.
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PMID:Anti asialoglycoprotein receptor antibodies and soluble interleukin-2 receptor levels as marker for inflammation in autoimmune hepatitis. 912 53

To investigate the possible involvement of autoimmune mechanisms in the development of hepatosplenic schistosomiasis (HSS), 234 patients with chronic Schistosoma mansoni infections were screened for a wide range of non-organ-specific autoantibodies as well as for antibodies reacting with the GOR peptide and with a liver-specific autoantigen, the hepatic asialoglycoprotein receptor (ASGP-R). Thirty-five (15.0%) were seropositive for antinuclear, smooth muscle or gastric parietal cell antibodies at low titres (< or = 1:80), and 15/176 (8.5%) had anti-GOR, all of whom had concomitant hepatitis C viral (HCV) infections. Anti-ASGP-R was found in 64 (27.4%) of the 234 patients at titres similar to those found in 18 untreated auto-immune hepatitis patients studied concurrently. Anti-ASGP-R seropositivity occurred significantly (P < 0.005) more frequently in patients with HSS (62/190, 32.6%) than in those with hepatointestinal schistosomiasis (2/44, 4.5%), but did not correlate with severity of liver disease or with the presence of the non-organ-specific autoantibodies. Anti-ASGP-R was found significantly (P < < 0.0005) less frequently in HSS patients who had had a splenectomy for portal hypertension (5/86, 5.8%) than in those who had not had a splenectomy (57/104, 54.8%). The findings suggest that liver-specific autoreactivity may play a role in the development of HSS.
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PMID:Specific liver autoreactivity in schistosomiasis mansoni. 923 Dec 5

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.
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PMID:Complement-mediated cytotoxicity and inhibition of ligand binding to hepatocytes by woodchuck hepatitis virus-induced autoantibodies to asialoglycoprotein receptor. 962 Mar 36

The aim of this study was to identify the epitopes recognized by antibodies to the asialoglycoprotein receptor, a specific hepatocyte protein, from sera of patients with autoimmune hepatitis. An ELISA test was used to detect anti-asialoglycoprotein receptor antibodies in the sera of patients with autoimmune hepatitis. Positive sera were tested against the same antigen by slot blot, by Western blot and by immunoprecipitation of the untreated protein and following treatment with beta-mercaptoethanol (beta-ME) and endoglycosidase F. The mature, unglycosylated and partially glycosylated forms of the asialoglycoprotein receptor synthesized by HepG2 cells were tested against positive patients' sera, as well as the in vitro translated unglycosylated form of the H1 subunit of the receptor. Sera from patients with autoimmune hepatitis recognized equally the native form, as well as the beta-ME-modified form, but less well the deglycosylated form of the human mature receptor. No reactivity was found when these sera were tested against the denatured human protein. In addition, neither the unglycosylated H1 subunit nor any of the HepG2-synthesized asialoglycoprotein receptor forms bound to the antibodies. Altogether, these results show that anti-asialoglycoprotein receptor antibodies in the sera of patients with autoimmune hepatitis are directed against conformational structures of the mature hetero-oligomeric form of the human liver protein and that at least some epitopes were located on the extracellular domain of the antigen.
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PMID:Study of antigenic sites on the asialoglycoprotein receptor recognized by autoantibodies. 973 60

A 6 year-old boy with autoimmune hepatitis accompanied with cirrhosis was reported. He was admitted to our hospital because of abdominal distention, high fever, and diarrhea. Laboratory examination revealed abnormalities in hepatic function, cholestasis, anemia, thrombocytopenia, hypoalbuminemia, hypocomplementemia, and low concentration of coagulation factors. Abdominal MRI, and asialoglycoprotein receptor-mediated liver scintigraphy strongly indicated liver cirrhosis. Viral hepatitis, Wilson's disease, and antitrypsin deficiency were excluded serologically. Instead, hypergammaglobulinemia, and positive antinuclear antibody suggested autoimmune hepatitis, and the survey of anti-mitochondrial antibody, anti-smooth muscle antibody, and anti-LKM-1 antibody was negative, indicating type I autoimmune hepatitis. Finally, the histology of liver biopsy specimen indicating the destruction of hepatic lobular architecture, dense mononuclear cell infiltrates, and severe fibrosis confirmed the diagnosis. He was treated firstly with methylprednisolone pulses, and then prednisolone p.o. + azathioprine p.o. All of the abnormal laboratory parameters improved to normal levels, indicating that the immunosuppressive therapy will be effective for the severe AIH with cirrhosis.
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PMID:[An infant of autoimmune hepatitis (type I) with cirrhosis]. 1053 82

An arabinogalactan conjugate containing a 9 kDa fragment of arabinogalactan and adenine-9-beta-D-arabinofuranoside 5'-monophosphate (araAMP), denoted AG(9 kDa)-araAMP, has been synthesized and characterized. In 2.2.15 (human hepatoblastoma) cells, the attachment of araAMP to AG(9 kDa), a ligand of the asialoglycoprotein receptor, decreased the effective concentration for inhibiting extracellular hepatitis B virus (HBV) production by 90% (EC90) from 17 to 0.9 microM adenine arabinoside (araA) equivalents, and increased the cytotoxic concentration (CC50) from 188 to > 17 300 microM araA equivalents. Hence, the selectivity index (CC50/EC90) of araA was improved from 11 (188/17) to > 19200 (17 300/0.9) by conjugation with the 9 kDa fragment of arabinogalactan. AG(9 kDa)-araAMP did not affect the production of viral RNA or viral proteins. In the woodchuck hepatitis model, AG(9 kDa)-araAMP inhibited woodchuck hepatitis virus (WHV) DNA replication at a dose of 0.3 mg of araA equivalents per kg; in this case, AG(9 kDa)-araAMP was 20-30 times more potent than was unconjugated araA. AG(9 kDa)-araAMP was effective by intramuscular or subcutaneous administration. The reduction in HBV DNA levels obtained in 2.2.15 cells and of WHV DNA levels in woodchucks was sustained after treatment with AG(9 kDa)-araAMP ceased. In both cases, viral DNA gradually returned to pre-treatment levels.
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PMID:Antiviral activity of a conjugate of adenine-9-beta-D-arabinofuranoside 5'-monophosphate and a 9 kDa fragment of arabinogalactan. 1132 48


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