603 Correlation between anti-cyp2E1 titre and lymphocyte infiltration in ALD — an autoimmune disease in some patients?

Stewart, Stephen; Jones, David; Vidali, Matteo; Haugk, Beate; Burt, AD; Albano, Emanuele; Day, CP

doi:10.1016/s0168-8278(04)90602-2

Cited by 4 publications

(3 citation statements)

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“…In subsequent studies using a larger cohort of patients we have confirmed that high titers of anti-CYP2E1 auto-antibodies are present in about 40% of the subjects with advanced ALD and 11% of the heavy drinkers with fatty liver only [40] . In the former the presence of anti-CYP2E1 IgG correlates with the extent of lymphocyte infiltration and the number of apoptotic hepatocytes in liver biopsies [41] , suggesting a possible contribution of auto-immune mechanisms in the pathogenesis of alcohol liver injury. The presence of anti-CYP2E1 immunity in ALD is not surprising, as these subjects frequently have signs of auto- and allo-immune reactions that are associated with the stimulation of lobular inflammation [42,43] .…”

Section: Autoimmune Reactions Targeting Cyp2e1mentioning

confidence: 97%

CYP2E1 autoantibodies in liver diseases

Sutti¹,

Rigamonti

Vidali

et al. 2014

Redox Biology

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Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also detectable in about one third of the patients with advanced alcoholic liver disease (ALD) and chronic hepatitis C (CHC). In these latter the presence of anti-CYP2E1 auto-antibodies is an independent predictor of extensive necro-inflammation and fibrosis and worsens the recurrence of hepatitis following liver transplantation, indicating that CYP2E1-directed autoimmunity can contribute to hepatic injury. The molecular characterization of the antigens recognized by anti-CYP2E1 auto-antibodies in ALD and CHC has shown that the targeted conformational epitopes are located in close proximity on the molecular surface. Furthermore, these epitopes can be recognized on CYP2E1 expressed on hepatocyte plasma membranes where they can trigger antibody-mediated cytotoxicity. This does not exclude that T cell-mediated responses against CYP2E1 might also be involved in causing hepatocyte damage. CYP2E1 structural modifications by reactive metabolites and molecular mimicry represent important factors in the breaking of self-tolerance against CYP2E1 in, respectively, ALD and CHC. However, genetic or acquired interferences with the mechanisms controlling the homeostasis of the immune system are also likely to contribute. More studies are needed to better characterize the impact of anti-CYP2E1 autoimmunity in liver diseases particularly in relation to the fact that common metabolic alterations such as obesity and diabetes stimulates hepatic CYP2E1 expression.

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Section: Autoimmune Reactions Targeting Cyp2e1mentioning

confidence: 97%

CYP2E1 autoantibodies in liver diseases

Sutti¹,

Rigamonti

Vidali

et al. 2014

Redox Biology

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“…Antibody-dependent cytotoxicity would also result from the recognition of plasma membrane CYP2E1 by anti-CYP2E1 auto-antibodies. Indeed, preliminary data (Stewart et al 2004a) indicates that high titres of anti-CYP2E1 auto-antibodies correlate with the extension of lymphocyte infiltration and the number of apoptotic hepatocytes.…”

Section: Free Radical Mechanisms In Immune Reactions Associated With mentioning

confidence: 99%

Alcohol, oxidative stress and free radical damage

2006

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The involvement of free radical mechanisms in the pathogenesis of alcoholic liver disease (ALD) is demonstrated by the detection of lipid peroxidation markers in the liver and the serum of patients with alcoholism, as well as by experiments in alcohol-feed rodents that show a relationship between alcohol-induced oxidative stress and the development of liver pathology. Ethanol-induced oxidative stress is the result of the combined impairment of antioxidant defences and the production of reactive oxygen species by the mitochondrial electron transport chain, the alcohol-inducible cytochrome P450 (CYP) 2E1 and activated phagocytes. Furthermore, hydroxyethyl free radicals (HER) are also generated during ethanol metabolism by CYP2E1. The mechanisms by which oxidative stress contributes to alcohol toxicity are still not completely understood. The available evidence indicates that, by favouring mitochondrial permeability transition, oxidative stress promotes hepatocyte necrosis and/or apoptosis and is implicated in the alcohol-induced sensitization of hepatocytes to the pro-apoptotic action of TNF-a. Moreover, oxidative mechanisms can contribute to liver fibrosis, by triggering the release of pro-fibrotic cytokines and collagen gene expression in hepatic stellate cells. Finally, the reactions of HER and lipid peroxidation products with hepatic proteins stimulate both humoral and cellular immune reactions and favour the breaking of self-tolerance during ALD. Thus, immune responses might represent the mechanism by which alcohol-induced oxidative stress contributes to the perpetuation of chronic hepatic inflammation. Together these observations provide a rationale for the possible clinical application of antioxidants in the therapy for ALD.

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“…These observations have been confirmed in humans, showing that high titers of anti-CYP2E1 autoantibodies are present in about 40% of patients with advanced alcoholic liver disease but not in heavy drinkers without liver damage (6). In the former, the presence of anti-CYP2E1 IgG correlated with the extent of lymphocyte infiltration in liver biopsies (7), suggesting a possible contribution of autoimmune mechanisms in the pathogenesis of alcohol liver injury.…”

mentioning

confidence: 91%

Use of Molecular Simulation for Mapping Conformational CYP2E1 Epitopes

Vidali

Hidestrand

Eliasson

et al. 2004

Journal of Biological Chemistry

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The identification of the epitopes recognized by autoantibodies against cytochrome P450s (CYPs) associated with drug-induced hepatotoxicity is difficult because of their conformational nature. In the present investigation, we used a novel approach based on the analysis of the whole molecule antigenic capacity following single amino acid substitutions to identify the conformational epitopes on CYP2E1. A molecular model of CYP2E1 was generated based on the CYP2C5 crystal structure, and potential motifs for amino acid exchanges were selected by computer simulation in the surface of ␣ helices and ␤ sheets. Fourteen modified, apparently correctly folded CYP2E1 variants were produced in Escherichia coli and evaluated in immunoprecipitation experiments using sera with anti-CYP2E1 autoreactivity from 10 patients with halothane hepatitis and 12 patients with alcoholic liver disease. Ala substitution of Glu-248 and Lys-251 as well as of Lys-324, Lys-342, Lys-420, and Phe-421 severely decreased or abolished CYP2E1 recognition by the majority of both the halothane hepatitis and alcoholic liver disease sera, whereas the other substitutions had only minor effects. Based on the structural model, these substitutions identified two distinct epitopes on the CYP2E1 surface corresponding to the G-helix and an area formed by juxtaposition of the J and K؆ helices, respectively. The combined use of molecular modeling and single amino acid mutagenesis is thus a useful approach for the characterization of conformational epitopes recognized by autoantibodies.

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603 Correlation between anti-cyp2E1 titre and lymphocyte infiltration in ALD — an autoimmune disease in some patients?

Cited by 4 publications

References 0 publications

CYP2E1 autoantibodies in liver diseases

CYP2E1 autoantibodies in liver diseases

Alcohol, oxidative stress and free radical damage

Use of Molecular Simulation for Mapping Conformational CYP2E1 Epitopes

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