Anti-liver kidney microsome antibody recognizes a cytochrome P450 from the IID subfamily.

Guéguen, M.; Meunier–Rotival, Michèle; Bernard, Olivier; Álvarez, Fernando

doi:10.1084/jem.168.2.801

Cited by 125 publications

(56 citation statements)

References 14 publications

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“…In most patients with AIH-2 and LKM1 antibodies, the antibodies recognize cytochrome P450s from the 2D subfamily [6][7][8][9]. In HCV-infected patients with LKM1 antibodies, only 25-34% of them recognize CYP2D6 by immunoblot [10][11][12], but 85% recognize P450IID6 by competitive ELISA [12].…”

Section: Introductionmentioning

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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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: Introductionmentioning

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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“…P450s were identified as specific targets for autoantibodies in idiopathic autoimmune diseases (for a review, see Lecoeur et al, 1996) or in hepatitis induced by such drugs as tienilic acid (Beaune et al, 1987), dihydralazine (Bourdi et al, 1990), anticonvulsivant (Leeder et al, 1992) and halothane (Eliasson and Kenna, 1996). CYP2D6 is the target of anti-LKM1 autoantibodies (anti-CYP2D6) developed in the type 2 autoimmune hepatitis (Gueguen et al, 1988;Zanger et al, 1988;Kiffel et al, 1989;Manns et al, 1989) and in C viral hepatitis (Parez et al, 1996). Different P450 forms were recognized on the outside face of unpermeabilized hepatocytes by these autoantibodies (Loeper et al, 1990(Loeper et al, , 1993.…”

mentioning

confidence: 99%

Yeast Expressed Cytochrome P450 2D6 (CYP2D6) Exposed on the External Face of Plasma Membrane Is Functionally Competent

et al. 1998

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CYP2D6, a xenobiotic metabolizing cytochrome P450 (P450), was found to be present in significant amount on the outer face of cell plasma membrane in addition to the regular microsomal location. Present work demonstrates that this external P450 is catalytically competent and that activity is supported by NADPH-P450 reductase present on the inner face of plasma membrane. Purified plasma membranes from yeast expressing CYP2D6 sustained NADPH-and cumene hydroperoxide-dependent dextromethorphan demethylation and NADPH-cytochrome c activity confirming previous observations in human hepatocytes. CYP2D6 found on the outside of plasma membrane (by differential immuno-inhibition and acidic shift assays on transformed spheroplasts) was catalytically competent at the cell surface for NADPH-supported activities. Anti-yeast P450-reductase antibodies inhibited neither CYP2D6 nor P450-reductase activities upon incubation with intact spheroplasts. In contrast, both activities were inhibited on isolated plasma membrane fragments. This highly suggested a cytosolic-orientation of the plasma membrane P450-reductase. This finding was confirmed by immunostaining in confocal microscopy. Finally, gene deletion of P450-reductase caused a complete loss of plasma membrane NADPH-supported CYP2D6 activity, which suggests that the reductase participates to some degree in the transmembrane electron transfer chain. This work illustrates that the outside-exposed plasma membrane CYP2D6 is active and may play an important metabolic role.

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“…AIH type 2, was proposed by Homberg et al [26] . Three groups independently identified cytochrome P450 IID6 (CYP2D6) as the molecular target of anti-LKM1 antibodies [27][28][29] ; the group of Alvarez [27] was the first to publish its data in the form of a full-length paper.…”

Section: Liver Kidney Microsomal Antibody (Anti-lkm)mentioning

confidence: 99%

“…While the target antigens of ANA and SMA certainly need better molecular definition, that of anti-LKM1 in AIH-2 has been clearly identified as the microsomal enzyme cytochrome P450IID6 (CYP2D6) [5,[26][27][28] . Its identification has enabled the establishment of assays based on the use of recombinant antigens which have proven useful in solving diagnostic uncertainties between AMA and anti-LKM1 [1,60,76] .…”

Section: Lkm1 Antigenmentioning

confidence: 99%

Autoimmune liver serology: Current diagnostic and clinical challenges

Bogdanos¹,

Invernizzi²,

Mackay³

et al. 2008

WJG

193

170

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Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases (AiLD), namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis variants in adults and children. AIH-1 is specified by anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). AIH-2 is specified by antibody to liver kidney microsomal antigen type-1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1). SMA, ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation. PBC is specified by antimitochondrial antibodies (AMA) reacting with enzymes of the 2-oxo-acid dehydrogenase complexes (chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly reacting with nuclear pore gp210 and nuclear body sp100. Sclerosing cholangitis presents as at least two variants, first the classical primary sclerosing cholangitis (PSC) mostly affecting adult men wherein the only (and nonspecific) reactivity is an atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA), also termed perinuclear anti-neutrophil nuclear antibodies (p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis (ASC) with serological features resembling those of type 1 AIH. Liver diagnostic serology is a fast-expanding area of investigation as new purified and recombinant autoantigens, and automated technologies such as ELISAs and bead assays, become available to complement (or even compete with) traditional immunofluorescence procedures. We survey for the first time global trends in quality assurance impacting as it does on (1) manufacturers/purveyors of kits and reagents, (2) diagnostic service laboratories that fulfill clinicians' requirements, and (3) the end-user, the physician providing patient care, who must properly interpret test results in the overall clinical context.

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Anti-liver kidney microsome antibody recognizes a cytochrome P450 from the IID subfamily.

Cited by 125 publications

References 14 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

Yeast Expressed Cytochrome P450 2D6 (CYP2D6) Exposed on the External Face of Plasma Membrane Is Functionally Competent

Autoimmune liver serology: Current diagnostic and clinical challenges

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