De Novo Bile Salt Transporter Antibodies as a Possible Cause of Recurrent Graft Failure After Liver Transplantation: a Novel Mechanism of Cholestasis

被引:84
作者
Keitel, Verena [1 ]
Burdelski, Martin [3 ]
Vojnisek, Zsuzsanna [4 ]
Schmitt, Lutz [2 ]
Haeussinger, Dieter [1 ]
Kubitz, Ralf [1 ]
机构
[1] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infectiol, D-40225 Dusseldorf, Germany
[2] Univ Dusseldorf, Inst Biochem, D-40225 Dusseldorf, Germany
[3] Univ Hosp Schleswig Holstein, Dept Pediat, Kiel, Germany
[4] Semmelweis Univ, Dept Pediat 1, H-1085 Budapest, Hungary
关键词
EXPORT PUMP; INTRAHEPATIC CHOLESTASIS; AUTOIMMUNE HEPATITIS; MUTATIONS; EXPRESSION; AUTOANTIBODIES; IMMUNOGLOBULIN; PROTEINS; RECEPTOR; BSEP;
D O I
10.1002/hep.23083
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 posttra-nsplant 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. (HEPATOLOGY 2009;50:510-517.)
引用
收藏
页码:510 / 517
页数:8
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