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Clinical and Vaccine Immunology, February 2006, p. 258-265, Vol. 13, No. 2
1071-412X/06/$08.00+0     doi:10.1128/CVI.13.2.258-265.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of CYP2E1 Immunoglobulin G4 Subclass Antibodies and Complement in Pathogenesis of Idiosyncratic Drug-Induced Hepatitis

Departments of Anesthesiology and Critical Care Medicine,¹ Pathology,² W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205,³ Centro Nacional de Microbiologia, Unidad de Respuesta Immune, Madrid 28220, Spain⁴

Received 1 June 2005/ Returned for modification 11 August 2005/ Accepted 22 November 2005

Idiosyncratic drug-induced hepatitis (IDDIH) is the third most common cause for acute liver failure in the United States. Previous studies have attempted to identify susceptible patients or early stages of disease with various degrees of success. To determine if total serum immunoglobulin subclasses, CYP2E1-specific subclass autoantibodies, complement components, or immune complexes could distinguish persons with IDDIH from others exposed to drugs, we studied persons exposed to halogenated volatile anesthetics, which have been associated with IDDIH and CYP2E1 autoantibodies. We found that patients with anesthetic-induced IDDIH had significantly elevated levels of CYP2E1-specific immunoglobulin G4 (IgG4) autoantibodies, while anesthetic-exposed healthy persons had significantly elevated levels of CYP2E1-specific IgG1 autoantibodies. Anesthetic IDDIH patients had significantly lower levels of C4a, C3a, and C5a compared to anesthetic-exposed healthy persons. C1q- and C3d-containing immune complexes were significantly elevated in anesthetic-exposed persons. In conclusion, our data suggest that anesthetic-exposed persons develop CYP2E1-specific IgG1 autoantibodies which may form detectable circulating immune complexes subsequently cleared by classical pathway activation of the complement system. Persons susceptible to anesthetic-induced IDDIH develop CYP2E1-specific IgG4 autoantibodies which form small, nonprecipitating immune complexes that escape clearance because of their size or by direct inhibition of complement activation.

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