Identification of new autoantigens by protein array indicates a role for IL4 neutralization in autoimmune hepatitis

Chiara Zingaretti, Milena Arigò, Angela Cardaci, Monica Moro, Mariacristina Crosti, Antonella Sinisi, Elisa Sugliano, Cristina Cheroni, Francesco Marabita, Renzo Nogarotto, Raoul Jean Pierre Bonnal, Paolo Marcatili, Maurizio Marconi, Annalinda Zignego, Paolo Muratori, Pietro Invernizzi, Piero Colombatto, Maurizia Brunetto, Ferruccio Bonino, Raffaele De FrancescoJens Geginat, Massimiliano Pagani, Luigi Muratori, Sergio Abrignani, Mauro Bombaci

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1885-1897
Number of pages13
JournalMolecular and Cellular Proteomics
Volume11
Issue number12
DOIs
StatePublished - Dec 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry

Cite this

Zingaretti, C., Arigò, M., Cardaci, A., Moro, M., Crosti, M., Sinisi, A., Sugliano, E., Cheroni, C., Marabita, F., Nogarotto, R., Bonnal, R. J. P., Marcatili, P., Marconi, M., Zignego, A., Muratori, P., Invernizzi, P., Colombatto, P., Brunetto, M., Bonino, F., ... Bombaci, M. (2012). Identification of new autoantigens by protein array indicates a role for IL4 neutralization in autoimmune hepatitis. Molecular and Cellular Proteomics, 11(12), 1885-1897. https://doi.org/10.1074/mcp.M112.018713