Recognition of uridine diphosphate glucuronosyl transferases by LKM-3 antibodies in chronic hepatitis D

Philipp, Thomas; Durazzo, Marilena; Trautwein, Christian; Alex, B.; Manns, MP; Straub, Petra; Lamb, John G.; Tukey, Robert H.; Ef, Johnson

doi:10.1016/s0140-6736(94)91966-6

Cited by 132 publications

(66 citation statements)

References 28 publications

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“…90 The situation in patients with autoimmune and viral hepatitis. 70,76 Western blots with recombinant cytochromes P450s revealed that cyis different in Japan, where AIH-1 is rare. In Japanese patients, no association with HLA-DR3 is reported; however, tochrome P450 1A2 was the target of this autoantigen.…”

Section: Aid Hepa 0047mentioning

confidence: 99%

“…Manns et al tested a total of 26 LKM hepatitis D, 74,75 and LKM-3 antibodies were shown to react with UDP-glucuronosyltransferases. 76 Because of the low prevpositive sera using Western blotting of partial sequences of recombinant cytochrome P450 2D6. 70 Of these sera, 11 rec-alence of this autoantibody, we were only able to test 5 autoimmune hepatitis sera with LKM-3 autoantibodies.…”

Section: Aid Hepa 0047mentioning

confidence: 99%

“…83 have shown that peripheral blood cells of patients with LKM-1 -positive chronic hepatitis C recognize peptides rep-the target antigen, which is about 55 kd. 76 The molecular target of the LKM-3 autoantibody was identified by screening resenting previously described B-cell epitopes. 83 One of the best indicators of a causal role of HCV in the induction of of a cDNA library.…”

Section: Virus Associated Autoimmunitymentioning

confidence: 99%

“…Sequence analysis revealed UDP glucuronosyltransferase 1.6 (UGT 1.6). 76 Therefore, Western blotting anti-LKM-1 responses comes from a case report, in which LKM-1 autoantibodies developed after liver transplantation with recombinant rabbit UGT 1.6 was used to characterize the clinical significance of LKM-3 autoantibodies. LKM-3 auwith a donor liver carrying HCV virus to an HCV-negative recipient.…”

Section: Virus Associated Autoimmunitymentioning

confidence: 99%

“…130 immune diseases, such as systemic lupus erythematosus. 76,136 UGTs are encoded by a large gene cluster. At least nine Because some sequence homology between HCV and P450 2D6 exists in the core, the envelope, and the NS5 regions of different exons 1 are connected to the constant exons 2 through 5 by differential splicing.…”

Section: Virus Associated Autoimmunitymentioning

confidence: 99%

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Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: Model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease

Manns¹

1997

Hepatology

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Enzymes of phase I (cytochromes P450) and phase II (UDP Interestingly, APS-1 patients may produce various anti-cyto-[uridine diphosphate]-glucuronosyltransferases) of drug me-chrome P450 antibodies. In addition to the hepatic anti-cytotabolism are targets of autoimmunity in the following chronic chrome P450, 1A2 autoantibodies are directed against steliver diseases of different etiology: 1)autoimmune hepatitis roidogenic cytochromes P450, namely P450 c21, P450 scc, (AIH); 2) hepatitis associated with the autoimmune polyendo-and P450 c17. These autoantibodies correlate with adrenal crine syndrome type 1 (APS-1); 3) virus-induced autoimmu-and ovarian failure and often these steroidal cell autoantibodnity; and 4) drug-induced hepatitis. AIH is diagnosed by the ies precede the manifestation of adrenal or ovarian dysfuncfollowing: the absence of infection with hepatitis viruses; the tion. Whether anti-P450 1A2 autoantibodies have a similar presence of a threshold of relevant factors, including circulat-predictive value is not yet known. LKM autoantibodies are ing autoantibodies, hypergammaglobulinemia, female sex (fe-further found in association with chronic hepatitis C and D. male/male ratio 4:1), human leukocyte antigen (HLA) B8, In chronic hepatitis C, the major target of LKM autoantibodies DR3, or DR4; and benefit from immunosuppression. Patients is cytochrome P450 2D6. Predominantly, conformational epiwith autoimmune hepatitis type 2 (AIH-2) are characterized topes are recognized by LKM-1 sera of patients with chronic by antibodies directed against liver and kidney microsomes, hepatitis C. In 13% of patients with chronic hepatitis D, LKMby an early onset of autoimmune hepatitis, which is a more 3 autoantibody is detectable. The target proteins are UGTs aggressive course of the disease, and by a higher prevalence of family 1 and in a minority of sera UGTs of family 2. The of autoimmunity directed against other organs. The major epitopes are conformational. All hepatic diseases discussed target of autoimmunity in patients with AIH-2 is cytochrome earlier have in common that autoimmunity, which is directed P450 2D6. Epitope mapping experiments revealed four short against enzymes of drug metabolizing multigene families. linear epitopes on cytochrome P450 2D6, recognized by liver/ Each disease is characterized by a specific pattern of autoantikidney microsomal autoantibodies type 1 (LKM-1) in patients bodies, with apparently little overlap. For example, LKM-1 with AIH-2. In addition, about 10% of the patient sera contain autoantibodies, which are directed against P450 2D6, seem autoantibodies that detect a conformational epitope on UDP-to overlap between AIH and chronic hepatitis C. However, a glucuronosyltransferases (UGTs) of family 1. Presently, LKM-close examination of these autoantibodies shows differences 1 autoantibodies are used as diagnostic markers for AIH-2. It between LKM-1 autoantibodies from patients with chronic is unclear whether these autoantibodies have a pathogenetic hepatitis C and with AIH. In AI...

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Section: Aid Hepa 0047mentioning

confidence: 99%

Section: Aid Hepa 0047mentioning

confidence: 99%

Section: Virus Associated Autoimmunitymentioning

confidence: 99%

Section: Virus Associated Autoimmunitymentioning

confidence: 99%