title: Identification of new autoantigens by protein array indicates a role for IL4 neutralization in autoimmune hepatitis.
abstract: Autoimmune hepatitis (AIH) is an unresolving inflammation of the liver of unknown cause. Diagnosis requires the exclusion of other conditions and the presence of characteristic features such as specific autoantibodies. Presently, these autoantibodies have relatively low sensitivity and specificity and are identified via immunostaining of cells or tissues; therefore, there is a diagnostic need for better and easy-to-assess markers. To identify new AIH-specific autoantigens, we developed a protein microarray comprising 1626 human recombinant proteins, selected in silico for being secreted or membrane associated. We screened sera from AIH patients on this microarray and compared the reactivity with that of sera from healthy donors and patients with chronic viral hepatitis C. We identified six human proteins that are specifically recognized by AIH sera. Serum reactivity to a combination of four of these autoantigens allows identification of AIH patients with high sensitivity (82%) and specificity (92%). Of the six autoantigens, the interleukin-4 (IL4) receptor fibronectin type III domain of the IL4 receptor (CD124), which is expressed on the surface of both lymphocytes and hepatocytes, showed the highest individual sensitivity and specificity for AIH. Remarkably, patients' sera inhibited STAT6 phosphorylation induced by IL4 binding to CD124, demonstrating that these autoantibodies are functional and suggesting that IL4 neutralization has a pathogenetic role in AIH.
authors.affiliation: Istituto Nazionale Genetica Molecolare (INGM), 20122 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zingaretti
authors.forename: Milena
authors.initials: M
authors.lastname: Arigò
authors.forename: Angela
authors.initials: A
authors.lastname: Cardaci
authors.forename: Monica
authors.initials: M
authors.lastname: Moro
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Crosti
authors.forename: Antonella
authors.initials: A
authors.lastname: Sinisi
authors.forename: Elisa
authors.initials: E
authors.lastname: Sugliano
authors.forename: Cristina
authors.initials: C
authors.lastname: Cheroni
authors.forename: Francesco
authors.initials: F
authors.lastname: Marabita
authors.forename: Renzo
authors.initials: R
authors.lastname: Nogarotto
authors.forename: Raoul Jean Pierre
authors.initials: RJ
authors.lastname: Bonnal
authors.forename: Paolo
authors.initials: P
authors.lastname: Marcatili
authors.forename: Maurizio
authors.initials: M
authors.lastname: Marconi
authors.forename: Annalinda
authors.initials: A
authors.lastname: Zignego
authors.forename: Paolo
authors.initials: P
authors.lastname: Muratori
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Piero
authors.initials: P
authors.lastname: Colombatto
authors.forename: Maurizia
authors.initials: M
authors.lastname: Brunetto
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Bonino
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Jens
authors.initials: J
authors.lastname: Geginat
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Pagani
authors.forename: Luigi
authors.initials: L
authors.lastname: Muratori
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
authors.forename: Mauro
authors.initials: M
authors.lastname: Bombaci
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000032:analysis / Q000097:blood* / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D019693:Hepatitis, Autoimmune / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation; D040081:Protein Array Analysis; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D053662:Interleukin-4 Receptor alpha Subunit; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4