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 language | English (US) |
|---|---|
| Pages (from-to) | 1885-1897 |
| Number of pages | 13 |
| Journal | Molecular and Cellular Proteomics |
| Volume | 11 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2012 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Analytical Chemistry
Cite this
Identification of new autoantigens by protein array indicates a role for IL4 neutralization in autoimmune hepatitis. / Zingaretti, Chiara; Arigò, Milena; Cardaci, Angela; Moro, Monica; Crosti, Mariacristina; Sinisi, Antonella; Sugliano, Elisa; Cheroni, Cristina; Marabita, Francesco; Nogarotto, Renzo; Bonnal, Raoul Jean Pierre; Marcatili, Paolo; Marconi, Maurizio; Zignego, Annalinda; Muratori, Paolo; Invernizzi, Pietro; Colombatto, Piero; Brunetto, Maurizia; Bonino, Ferruccio; De Francesco, Raffaele; Geginat, Jens; Pagani, Massimiliano; Muratori, Luigi; Abrignani, Sergio; Bombaci, Mauro.
In: Molecular and Cellular Proteomics, Vol. 11, No. 12, 12.2012, p. 1885-1897.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of new autoantigens by protein array indicates a role for IL4 neutralization in autoimmune hepatitis
AU - Zingaretti, Chiara
AU - Arigò, Milena
AU - Cardaci, Angela
AU - Moro, Monica
AU - Crosti, Mariacristina
AU - Sinisi, Antonella
AU - Sugliano, Elisa
AU - Cheroni, Cristina
AU - Marabita, Francesco
AU - Nogarotto, Renzo
AU - Bonnal, Raoul Jean Pierre
AU - Marcatili, Paolo
AU - Marconi, Maurizio
AU - Zignego, Annalinda
AU - Muratori, Paolo
AU - Invernizzi, Pietro
AU - Colombatto, Piero
AU - Brunetto, Maurizia
AU - Bonino, Ferruccio
AU - De Francesco, Raffaele
AU - Geginat, Jens
AU - Pagani, Massimiliano
AU - Muratori, Luigi
AU - Abrignani, Sergio
AU - Bombaci, Mauro
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84870713369&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84870713369&partnerID=8YFLogxK
U2 - 10.1074/mcp.M112.018713
DO - 10.1074/mcp.M112.018713
M3 - Article
C2 - 22997428
AN - SCOPUS:84870713369
VL - 11
SP - 1885
EP - 1897
JO - Molecular and Cellular Proteomics
JF - Molecular and Cellular Proteomics
SN - 1535-9476
IS - 12
ER -