Heterogeneity of liver-kidney microsomal autoantibodies in chronic hepatitis C and D virus infection

Durazzo, Marilena; Philipp, Thomas; Pelt, Frank N.A.M. van; Lüttig, B.; Borghesio, E.; Michel, Gerd; Schmidt, Eleonore; Loges, Stephanie; Rizzetto, M.; Manns, Michael P.

doi:10.1016/0016-5085(95)90074-8

Cited by 84 publications

(44 citation statements)

References 26 publications

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“…LKM1 are among the autoantibodies found in sera from HCV-infected patients [5,10] and are directed against a variety of microsomal proteins of rat and human liver [10][11][12][13][14]. The most constant microsomal antigens were the cytochrome P450s from the 2D subfamily [10,12,13]. This study found that about 30% of LKM1 /HCV sera contained anti-P450IID6 antibodies of IgG type by an immunoblot technique.…”

Section: Discussionmentioning

confidence: 70%

“…Different types of organ-and non-organ-specific autoantibodies have been detected in sera from patients with chronic hepatitis C infection, without any clear relationship with the level of disease activity [14,25,26]. LKM1 are among the autoantibodies found in sera from HCV-infected patients [5,10] and are directed against a variety of microsomal proteins of rat and human liver [10][11][12][13][14]. The most constant microsomal antigens were the cytochrome P450s from the 2D subfamily [10,12,13].…”

Section: Discussionmentioning

confidence: 99%

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Study of the B cell response to cytochrome P450IID6 in sera from chronic hepatitis C patients

Parez

Herzog

Jacqz-Aigrain

et al. 1996

Clinical and Experimental Immunology

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SUMMARYSome patients with chronic hepatitis C develop liver/kidney microsome type 1 antibodies. Some of these autoantibodies are directed against the cytochrome P450IID6. The aim of this study was to characterize the immunogenic sites on the P450IID6 molecule recognized by autoantibodies from individuals infected with the hepatitis C virus. Serum from 24 patients with markers of hepatitis C infection and liver/kidney microsome type 1 antibodies were tested by immunoblotting with human liver microsomal proteins. Eight of them with anti-P450IID6 antibodies were tested with synthetic peptides representing P450IID6 putative immunogenic sites and for their capacity to inhibit in vitro P450IID6 enzymatic activity. Anti-P450IID6 antibodies in the sera of chronic hepatitis C patients were of IgG subclass 1 and in one patient also of IgM type. These sera recognized different P450IID6 peptide sequences consisting of amino acids (aa) 200-214 and aa 271-339. The synthetic peptide between aa 321 and 339 appears to represent the main antigenic site. Five out of eight anti-P450IID6 positive sera were also able to inhibit P450IID6 enzymatic activity in vitro at a dilution of 1 : 100. The anti-P450IID6 autoimmune response in chronic hepatitis C patients is polyclonal, probably inducible, and maintained by the liberation of P450IID6 by hepatocyte lysis. The characterization of the P450IID6 immunogenic site recognized by patients with hepatitis C infection may enable a specific test to be designed to identify those patients with autoimmune hepatitis type 2.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Study of the B cell response to cytochrome P450IID6 in sera from chronic hepatitis C patients

Parez

Herzog

Jacqz-Aigrain

et al. 1996

Clinical and Experimental Immunology

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“…These sera also gave two bands, 67-kDa and 92-kDa proteins. Durazzo et al 20) found a 70-kDa protein recognized by LKM-1 serum other than the antigen, CYP2D6. Our 67-kDa protein may be the same protein.…”

Section: Discussionmentioning

confidence: 99%

A New Epitope of CYP2D6 Recognized by Liver Kidney Microsomal Autoantibody from Japanese Patients with Autoimmune Hepatitis

Imaoka

Obata

Hiroi

et al. 2005

Biological & Pharmaceutical Bulletin

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Autoantibodies to liver-kidney microsomes (LKM) were first characterized by immunofluorescence microscopy using rat liver and kidney sections.1) These autoantibodies have been classified into three groups (anti-LKM-1, 2, and 3) according to differences in immnofluorescent staining patterns.1-3) Anti-LKM-1 is found in a subgroup of patients with autoimmune hepatitis (AIH) II and the presence of LKM-1 antibodies is one of the most important criteria for the diagnosis of AIH-II. But anti-LKM-1 is not completely specific to AIH-II. LKM-1 antibody is also produced in the course of chronic hepatitis (CH) C and is detected in about 2-10% of CHC patients. 4,5) In the case of AIH-II, there is no evidence of HCV infection. The pathological profile of AIH-II is quite different from that of CHC. Patients with AIH-II are young and responsive to immunosuppressive drugs. In contrast, patients with CHC tend to be older and have different pathological conditions. Manns et al. 6) suggested that molecular mimicry between the LKM-1 antigen and CHC viral antigen causes LKM-1 antibody to be produced in CHC patients and the presence of LKM-1 antibody does not affect the clinical and biochemical profiles of CHC. In Japan, patients with AIH-II are very rare while there are many patients with CHC, implying that LKM-1-positive patients with CHC outnumber those with AIH-II. 7) Therefore, it is very important to detect AIH-II specifically.The major autoantigen for LKM-1 has been identified as CYP2D6 which is an isoform of cytochrome P450s and has an important role in the metabolism of many drugs in the liver. 8,9) The mechanism of production of LKM-1 antibodies remains unclear but ethnic differences among patients with AIH-II may provide a clue.10) CYP2D6 reveals extensive genetic polymorphism and catalytic activity toward a range of drugs. About 10% of Caucasians have a complete deletion of the CYP2D6 gene but less than 1% of Japanese have such a mutation. 11,12) In Japan, patients with AIH-II are very rare. 7)There may be a relationship between genetic polymorphisms in CYP2D6 and AIH-II in Japanese. 10) LKM-1 antibody recognition sites has been identified in the internal amino acid sequence in CYP2D6. The sequence 257-269 of CYP2D6 was found to be the core of an immunodominant epitope recognized by most anti-LKM-1. 6,9) The antibody also recognizes the amino acid sequences 196-218 and 321-351. 9,13) The antibody from CHC also recognizes some of these sequences.In this study, we systemically investigated epitopes of CYP2D6 recognized specifically by LKM-1 antibody but not CHC antibody to develop a method of distinguishing LKM-1 antibody from CHC antibody. A full-length CYP2D6 was expressed in Escherichia coli and purified. CYP2D6 was digested by several proteases. The resulting peptides were separated by HPLC and each peptide fragment was reacted with LKM-1 and CHC antibodies. The sequence of each peptide was determined and a specific epitope for LKM-1 antibody was identified. MATERIALS AND METHODSPatient Sera Sera were collected from p...

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“…Its potential role in immuno-C, only about 30% of the sera reveal a band of 50 kd in Western blots. 70,75,124,125 Additional bands were detected at pathogenesis of hepatitis C might deserve further evaluation.…”

Section: Virus Associated Autoimmunitymentioning

confidence: 94%

“…75,126 Western blot nega-observed 11 of 81 patients with chronic hepatitis D autoantibodies, which were directed against hepatic microsomes, and tive sera were identified to be anti-P450 2D6 positive by a specific LKM-1 enzyme-linked immunosorbant assay or by the proximal renal tubules. 74 The reaction was stronger when human and primate tissues were used and progressively dean in vitro transcription/translation assay using 35 S-labeled P450 2D6.…”

Section: Virus Associated Autoimmunitymentioning

confidence: 99%

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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Heterogeneity of liver-kidney microsomal autoantibodies in chronic hepatitis C and D virus infection

Cited by 84 publications

References 26 publications

Study of the B cell response to cytochrome P450IID6 in sera from chronic hepatitis C patients

Study of the B cell response to cytochrome P450IID6 in sera from chronic hepatitis C patients

A New Epitope of CYP2D6 Recognized by Liver Kidney Microsomal Autoantibody from Japanese Patients with Autoimmune Hepatitis

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

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