Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Stindt, J; Kluge, S; Dröge, C; Keitel, V; Stross, C; Baumann, U; Brinkert, F; Dhawan, A; Engelmann, G; Ganschow, R; Gerner, P; Grabhorn, E; Knisely, AS; Noli, KA; Pukite, I; Shepherd, RW; Ueno, T; Schmitt, L; Wiek, C; Hanenberg, H; Häussinger, D; Kubitz, R.
Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency.
Hepatology. 2016; 63(2):524-537
Doi: 10.1002/hep.28311
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Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Knisely Alexander
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- Abstract:
- Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody-induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC-2 patients who suffered from phenotypic disease recurrence post-OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G-class BSEP-reactive antibodies in these patients. In all cases, the N-terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C-terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle-based functional assay, transport inhibition by anti-BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG. PFIC-2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post-OLT. The antibody response is polyclonal, targeting both extra- and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis. © 2015 by the American Association for the Study of Liver Diseases.
- Find related publications in this database (using NLM MeSH Indexing)
- ATP Binding Cassette Subfamily B Member 11 -
- ATP-Binding Cassette Transporters - deficiency
- ATP-Binding Cassette Transporters - immunology
- Adolescent -
- Antibodies - blood
- Child -
- Cholestasis, Intrahepatic - blood
- Cholestasis, Intrahepatic - genetics
- Cholestasis, Intrahepatic - immunology
- Female -
- Humans -
- Liver Transplantation -
- Male -
- Mutation -
- Postoperative Complications - blood
- Postoperative Complications - genetics
- Postoperative Complications - immunology
- Young Adult -