De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis.
出处：Hepatology 2009 Aug 50(2) :510-7
作者：Keitel V;Burdelski M;Vojnisek Z;Schmitt L;Haussinger D;Kubitz R
PMID：19642168
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.
专家评价：
Johannes R Hov and
Tom Hemming Karlsen
Rikshospitalet-Radium hospitalet Medical Center, University of Oslo, Norway
Gastroenterology & Hepatology
This article reports a novel mechanism for cholestatic liver failure after liver transplantation for progressive familial intrahepatic cholestasis type 2 (PFIC-2) by functional antibodies against the bile acid transporter ‘bile salt export pump’ (BSEP).
PFIC-2 is caused by homozygous deleterious mutations in the BSEP. The patient with PFIC-2 in this paper carried mutations leading to the complete non-expression of BSEP. After liver transplantation, inhibitory autoantibodies against BSEP developed, leading to a PFIC-2-like phenotype. The condition appeared once more after retransplantation. Plasmapheresis and rituximab reduced bile acid levels but not symptoms. The study presents a convincing chain of evidence (with adequate controls) for the pathogenesis of this novel clinical entity: (a) congenital absence of BSEP expression caused by a combination of mutations (a prerequisite for BSEP intolerance); (b) no sign of acute rejection or other causes of graft failure; (c) the presence of immunoglobulin (Ig)G antibodies against BSEP in patient serum and bound to the canalicular membrane in affected livers; (d) the antibody targeted an epitope in the first extracellular loop of BSEP, important for activity; (e) the patient serum was shown to inhibit BSEP activity. Three cases of transplanted PFIC-2 patients described by Jara et al. confirm the presence of this disease entity {1}. Their cases presented with an episodic relapse of pruritus or jaundice after transplantation, and there was no sign of rejection. The cholestatic attacks could be managed by changes in the immunosuppressive regimen. Patient serum was administered to rats, and patient antibodies did target the canalicular membrane and impair bile acid secretion. These case reports give important biological insights into BSEP function and the development of immune (autoimmune) reactions. An entirely novel but presumably rare cause of graft failure is established.
References: {1} Jara et al. N Engl J Med 2009, 361:1359-67 [PMID:19797282].