Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during α-interferon treatment

Dalekos, Georgios N.; Wedemeyer, Heiner; Obermayer-Straub, Petra; Kayser, Anne; Barut, Ayse; Frank, Helga; Manns, Michael P.

doi:10.1016/s0168-8278(99)80092-0

Cited by 95 publications

(76 citation statements)

References 36 publications

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“…To date, linear epitope mapping of CYP2D6 has been partially performed with either a limited number of synthetic CYP2D6 peptides or by the use of constructs prokaryotically expressed. Although Yamamoto et al (16) identified four linear epitopes, CYP2D6 254 -271 , CYP2D6 321-351 , CYP2D6 [373][374][375][376][377][378][379][380][381][382][383][384][385][386][387][388][389] , and CYP2D6 410 -429 recognized by LKM1 in AIH, Dalekos et al (20) showed that in HCV infection, anti-CYP2D6-positive sera recognize two truncated CYP2D6 proteins (aa 250 -494 and 321-494) expressed in Escherichia coli.…”

Section: Iver Kidney Microsomal Ab Type 1 (Lkm1)mentioning

confidence: 99%

Key Residues of a Major Cytochrome P4502D6 Epitope Are Located on the Surface of the Molecule

Ma¹,

Thomas²,

Okamoto³

et al. 2002

The Journal of Immunology

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Eukaryotically expressed CYP2D6 is the universal target of liver kidney microsomal Ab type 1 (LKM1) in both type 2 autoimmune hepatitis (AIH) and chronic hepatitis C virus (HCV) infection. In contrast, reactivity to prokaryotically expressed CYP2D6 protein and synthetic peptides is significantly lower in HCV infection than in AIH. The aim of the present study was to characterize LKM1 reactivity against a panel of eukaryotically expressed CYP2D6 constructs in the two conditions. LKM1-positive sera obtained from 16 patients with AIH and 16 with HCV infection were used as probes to perform a complete epitope mapping of CYP2D6. Reactivity to the full-length protein and 16 constructs thereof was determined by radioligand assay. We found that antigenicity is confined to the portion of the molecule C-terminal of aa 193, no reactivity being detectable against the aa sequence 1–193. Reactivity increases stepwise toward the C-terminal in both AIH and HCV, but the frequency of reactivity in the two conditions differs significantly between aa 267–337. To further characterize this region, we introduced a five and a three amino acid swap mutation selected from the homologous regions of CYP2C9 and HCV. This maneuver resulted in a substantial loss of LKM1 binding in both conditions, suggesting that this region contains a major epitope. Molecular modeling revealed that CYP2D6316–327 is exposed on the surface of the protein, and may represent a key target for the autoantibody. These findings provide an initial characterization of the antigenic constitution of the target of LKM1 in AIH and HCV infection.

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Section: Iver Kidney Microsomal Ab Type 1 (Lkm1)mentioning

confidence: 99%

Key Residues of a Major Cytochrome P4502D6 Epitope Are Located on the Surface of the Molecule

Ma¹,

Thomas²,

Okamoto³

et al. 2002

The Journal of Immunology

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“…Autoimmune liver diseases can remain silent for variable period of time before developing symptoms [7,8,12,19,26] . Of relevance, viral infections, xenobiotics, drugs and microbes can operate as triggers for the development of liver autoimmunity in genetically predisposed individuals [7][8][9]11,12,14,19,25,27,28] . In all but two patients with chronic HBV and HCV infections described in our study PBC was diagnosed during the follow-up period for viral hepatitis.…”

Section: Discussionmentioning

confidence: 99%

Primary biliary cirrhosis in HBV and HCV patients: Clinical characteristics and outcome

Rigopoulou

Zachou²,

Gatselis³

et al. 2013

WJH

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AIM:To present the characteristics, management and outcome of patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infections concurrent with primary biliary cirrhosis (PBC). METHODS:Since January 2001 to September 2009, we retrospectively evaluated the medical records of all HBV (n = 1493) and HCV patients (n = 526) who are followed in our center for the presence of concurrent PBC. Seventeen patients identified with concurrent viral hepatitis and PBC (8 HCV and PBC; follow-up: 61 ± 37 mo and 9 HBV and PBC; follow-up: 57 ± 38 mo). PBC diagnosis was established if the patients met at least two of the following criteria: positivity for antimitochondrial antibody, elevated cholestatic enzymes and histological lesions of PBC. RESULTS:HCV or HBV diagnosis preceded that of PBC in most patients by many years. PBC diagnosis was based on the presence of antimitochondrial antibody and elevated cholestatic enzymes in all 17 patients, while one third (5/17; 29.4%) experienced severe pruritus many years before diagnosis. Patients with PBC and HBV were significantly younger at diagnosis of PBC compared to patients with PBC and HCV (56.1 ± 11.2 vs 68.5 ± 10.3, respectively, P < 0.05). At initial clinical and histological assessment the majority of patients were cirrhotics (10/17; 58.8%) with the group of PBC and HCV carrying the highest frequency (87.5% vs 33.3% in PBC and HBV; P < 0.05). The patients with HBV and concomitant PBC seem to have better outcome compared to those with HCV and PBC since none of the 6 non-cirrhotics with HBV and PBC developed cirrhosis during follow-up.CONCLUSION: PBC diagnosis in HBV or HCV patients is very difficult and usually delayed. Therefore, in any case, cholestasis should alert physicians to further search for PBC.

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“…We noticed that reactivity to p3 CYP2D6 peptide, which had homology with CYP2A6 [8][9][10][11][12][13][14][15][16][17] and CYP2A7 [8][9][10][11][12][13][14][15][16][17] , correlated with biochemical markers of disease activity, suggesting that p3-specific CD8 T cells may be involved in liver damage. It is also of interest that both CYP2A6 [8][9][10][11][12][13][14][15][16][17] and CYP2A7 [8][9][10][11][12][13][14][15][16][17] have been reported to be cross-reactively recognized with HCV 178-187 by CD8 T cells in chronic hepatitis C virus, 2 whereas we have shown that anti-CYP2A6 antibody may be present in HCV patients. 3 Of note, p3-specific CD8 T cells were not as effective at the cytotoxicity level, 1 and this suggests a dichotomy between CD8 T-cell functions, which is a phenomenon reported in chronic HCV.…”

Section: Autoimmune Hepatitis: Of Host and Pathogenmentioning

confidence: 99%

“…Such patients need to be treated with caution for the underlying diseases as the presence of AIH appears to predispose to severe adverse reactions during antiviral treatment with interferon-alpha. 14,15 The magnitude of aminotransferase activity can be such that suspension of treatment is required. Conversely, immunosuppressive treatment may lead to the exacerbation of the underlying viral disease.…”

Section: Autoimmune Hepatitis: Of Host and Pathogenmentioning

confidence: 99%

Autoimmune hepatitis: Of host and pathogen

Rigopoulou

Dalekos

2008

Hepatology

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Epitope mapping of cytochrome P4502D6 autoantigen in patients with chronic hepatitis C during α-interferon treatment

Cited by 95 publications

References 36 publications

Key Residues of a Major Cytochrome P4502D6 Epitope Are Located on the Surface of the Molecule

Key Residues of a Major Cytochrome P4502D6 Epitope Are Located on the Surface of the Molecule

Primary biliary cirrhosis in HBV and HCV patients: Clinical characteristics and outcome

Autoimmune hepatitis: Of host and pathogen

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