Demographics of anti-asialoglycoprotein receptor autoantibodies in autoimmune hepatitis

Treichel, Ulrich; McFarlane, Barbara M.; Seki, Takeshi; Krawitt, Edward L.; Alessi, Nuntiata; Stickel, Felix; McFarlane, Ian G.; Kiyosawa, Kendo; Furuta, S; Freni, M.; Gerken, Guido; Büschenfelde, Karl‐Hermann Meyer zum

doi:10.1016/0016-5085(94)90129-5

Cited by 83 publications

(29 citation statements)

References 17 publications

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“…5 The above observations support the conclusion that the topological arrangement of subunits in the isolated and the hepatocyte surface woodchuck ASGPR is not entirely compatible and that their antigenic properties also are not identical. 5 Considering ASGPR interspecies homology, this might imply that the use of the isolated whole ASGPR in the currently used immunoassays 27 does not allow for detection of the complete spectrum of anti-ASGPR in patient sera, particularly autoantibodies to the minor receptor subunits. The development of subunit-or epitope-specific assays should provide more detailed insight into the occurrence patterns and the pathogenic relevance of the anti-ASGPR response.…”

Section: Discussionmentioning

confidence: 99%

Complement-mediated cytotoxicity and inhibition of ligand binding to hepatocytes by woodchuck hepatitis virus-induced autoantibodies to asialoglycoprotein receptor

1998

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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 WHVtriggered 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, complementdependent, 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. (HEPA-TOLOGY 1998;27:1623-1631.)

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Section: Discussionmentioning

confidence: 99%

Complement-mediated cytotoxicity and inhibition of ligand binding to hepatocytes by woodchuck hepatitis virus-induced autoantibodies to asialoglycoprotein receptor

1998

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“…Soluble ASGPR was prepared from human liver as described previously. 22 Normal erythrocytes were collected in heparinized tubes from healthy individuals and patients with ALC with blood groups A1, B, and O (after written informed consent) and were immediately stored on ice. Erythrocytes were isolated within 30 minutes after collection.…”

Section: Experimental Methodsmentioning

confidence: 99%

Asialoglycoprotein receptor facilitates hemolysis in patients with alcoholic liver cirrhosis

et al. 2004

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Hemolysis in patients with advanced alcoholic liver disease is a common clinical problem and indicates an unfavorable prognosis. In many cases, the etiology of the hemolysis remains unknown. We observed three patients with alcoholic liver disease, suffering from severe hemolytic anemia, requiring multiple blood transfusions. Steroid therapy was ineffective and two of the patients died. All patients had a soluble variant of the human asialoglycoprotein receptor (s-ASGP-R) in their serum, as well as high titers of autoantibodies against this receptor (anti-ASGP-R). Consecutively, examination of 60 patients with alcoholic liver disease revealed a high incidence for s-ASGP-R (36%) and anti-ASGP-R (27%) in patients with alcoholic liver cirrhosis (ALC) compared to patients with cirrhosis due to viral hepatitis. The potential etiology of hemolysis was studied in vitro on erythrocytes from patients with ALC and from healthy donors. Isolated ASGP-R but not anti-ASGP-R bound to the surface of erythrocytes preferentially of blood group A1 and caused dose-dependent agglutination and hemolysis, while this phenomenon was much lower using erythrocytes of the blood group B and almost absent with blood group O-erythrocytes. Furthermore, agglutination and hemolysis only occurred in erythrocytes from ALC-patients or after the pretreatment of cells with neuraminidase. ASGP-R induced agglutination and hemolysis was blocked by the competitive ASGP-R inhibitor asialofetuin. In conclusion, our results indicate a new, non-immunological mechanism for hemolysis in patients with alcoholic liver disease, mediated through agglutination by a soluble variant of the human asialoglycoprotein receptor and mechanical shear stress.

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“…In earlier times much effort was put into the characterisation of a preparation called liver-specific lipoprotein (LSP) [73] , and assessment of the autoantigenic potential of this claimed liver-specific molecule [74] . Stemming from this was the recognition of the liverspecific membrane antigen, the asialoglycoprotein receptor [75] , but this has not quite fulfilled the earlier hopes [76] . The liver cell membrane has been repeatedly studied, mostly by immunoblotting using AIH sera, for a molecular signal corresponding to a specific autoantigenic moiety, with the consistent finding being that of multiple reactive components of mw ranging from 20 to > 100 kDa [77,78] , but with none of these reaching candidate status as a liver-specific or diseasespecific autoantigen.…”

Section: Lkm-1 Antigenmentioning

confidence: 99%

Historical reflections on autoimmune hepatitis

Mackay

2008

WJG

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Autoimmune hepatitis (AIH), initially known as chronic active or active chronic hepatitis (and by various other names), first came under clinical notice in the late 1940s. However, quite likely, chronic active hepatitis (CAH) had been observed prior to this and was attributed to a persistently destructive virus infection of the liver. An earlier (and controversial) designation in 1956 as lupoid hepatitis was derived from associated L.E. cell test positivity and emphasized accompanying multisystem features and immunological aberrations. Yo u n g w o m e n f e a t u r e d p r o m i n e n t l y i n e a r l y descriptions of CAH. AIH was first applied in 1965 as a descriptive term. Disease-characteristic autoantibodies were defined from the early 1960s, notably antinuclear antibody (ANA), smooth muscle antibody (SMA) and liver-kidney microsomal (LKM) antibody. These are still widely used diagnostically but their relationship to pathogenesis is still not evident. A liver and disease specific autoantigen has long been searched for but unsuccessfully. Prolonged immunosuppressive therapy with prednisolone and azathioprine in the 1960s proved beneficial and remains standard therapy today. AIH like many other autoimmune diseases is associated with particular HLA alleles especially with the "ancestral" B8, DR3 haplotype, and also with DR4. Looking forwards, AIH is one of the several enigmatic autoimmune diseases that, despite being (relatively) organ specific, are marked by autoimmune reactivities with non-organ-specific autoantigens. New paradigms are needed to explain the occurrence, expressions and pathogenesis of such diseases.

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Demographics of anti-asialoglycoprotein receptor autoantibodies in autoimmune hepatitis

Cited by 83 publications

References 17 publications

Complement-mediated cytotoxicity and inhibition of ligand binding to hepatocytes by woodchuck hepatitis virus-induced autoantibodies to asialoglycoprotein receptor

Complement-mediated cytotoxicity and inhibition of ligand binding to hepatocytes by woodchuck hepatitis virus-induced autoantibodies to asialoglycoprotein receptor

Asialoglycoprotein receptor facilitates hemolysis in patients with alcoholic liver cirrhosis

Historical reflections on autoimmune hepatitis

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