1. Identification of new autoantigens by protein array indicates a role for IL4 neutralization in autoimmune hepatitis
- Author
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Antonella Sinisi, Mariacristina Crosti, Renzo Nogarotto, Massimiliano Pagani, Paolo Muratori, Anna Linda Zignego, Milena Arigò, Jens Geginat, Elisa Sugliano, Francesco Marabita, Chiara Zingaretti, Luigi Muratori, Maurizio Marconi, Pietro Invernizzi, Cristina Cheroni, Raoul J. P. Bonnal, Paolo Marcatili, Piero Colombatto, Sergio Abrignani, Monica Moro, Raffaele De Francesco, Maurizia Rossana Brunetto, Angela Cardaci, Mauro Bombaci, Ferruccio Bonino, Zingaretti C, Arigo' M, Cardaci A, Moro M, Crosti M, Sinisi A, Sugliano E, Cheroni C, Marabita F, Nogarotto R, Bonnal RJ, Marcatili P, Marconi M, Zignego A, Muratori P, Invernizzi P, Colombatto P, Brunetto M, Bonino F, De Francesco R, Geginat J, Pagani M, Muratori L, Abrignani S, and Bombaci M.
- Subjects
Microarray ,Protein Array Analysis ,Autoimmune hepatitis ,Biology ,Autoantigens ,Biochemistry ,Analytical Chemistry ,law.invention ,immune system diseases ,law ,medicine ,Humans ,Phosphorylation ,Receptor ,Molecular Biology ,Interleukin 4 ,Autoantibodies ,Autoimmune Hepatitis ,Hepatitis B Virus ,Hepatitis C Virus ,Healthy Donor ,Interleukin-4 receptor ,Interleukin-4 receptor Fibronectin Type III domain ,Mean Fluorescence Intensity ,Viral Hepatitis ,Research ,Autoantibody ,Interleukin-4 Receptor alpha Subunit ,medicine.disease ,Antibodies, Neutralizing ,Molecular biology ,Recombinant Proteins ,digestive system diseases ,Protein Structure, Tertiary ,Hepatitis, Autoimmune ,Liver ,AUTOIMMUNE HEPATITIS ,Immunology ,Protein microarray ,Recombinant DNA ,Interleukin-4 ,STAT6 Transcription Factor ,Biomarkers ,Immunostaining ,Signal Transduction - 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.
- Published
- 2012