title: De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis.
abstract: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations of the bile salt export pump (BSEP [ABCB11]), an ATP-binding cassette (ABC)-transporter exclusively expressed at the canalicular membrane of hepatocytes. An absence of BSEP from the canalicular membrane causes cholestasis and leads to liver cirrhosis, which may necessitate liver transplantation in early childhood. We report on the first case of a child with PFIC-2 suffering from repeated posttransplant recurrence of progressive intrahepatic cholestasis due to autoantibodies against BSEP. These antibodies occurred after transplantation and were detected in the patient's serum and at the canalicular membrane of two consecutive liver transplants. The antibodies were reactive toward the first extracellular loop of BSEP, were of high affinity, and inhibited transport activity of BSEP, thus causing severe cholestasis. The patient had three homozygous, missense changes in the BSEP gene. Their combination resulted in the complete absence of BSEP, which explains the lack of tolerance, a prerequisite of autoantibody formation toward BSEP. The findings illustrate a novel disease mechanism due to a new class of functionally relevant autoantibodies resulting in cholestasis and subsequent liver failure.
authors.affiliation: Department of Gastroenterology, Heinrich-Heine-University of Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Keitel
authors.forename: Martin
authors.initials: M
authors.lastname: Burdelski
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Vojnisek
authors.forename: Lutz
authors.initials: L
authors.lastname: Schmitt
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Ralf
authors.initials: R
authors.lastname: Kubitz
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001707:Biopsy, Needle; D002460:Cell Line; D002780:Cholestasis, Intrahepatic / Q000235:genetics / Q000276:immunology* / Q000601:surgery; D000939:Epitopes; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D008099:Liver / Q000473:pathology; D017093:Liver Failure / Q000276:immunology* / Q000473:pathology; D016031:Liver Transplantation; D009154:Mutation; D051381:Rats; D012086:Reoperation
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001323:Autoantibodies; D000939:Epitopes