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Identification 1F9 Antigen on Hepatocyte Canalicular Membrane and Observation Its Pathophysiological Value in PBC

Author: WangXueChang
Tutor: HanYing；ShiYongQuan
School: Fourth Military Medical University
Course: Internal Medicine
Keywords: Primary biliary cirrhosis Polar molecules 1F9 Endosomes
CLC: R575.2
Type: Master's thesis
Year: 2011
Downloads: 11
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Abstract


Background Primary Biliary Cirrhosis (Primary biliary cirrhosis, PBC) is a disease of the intrahepatic cholestasis, the main pathological features of the portal area and inflammatory cell infiltration, destruction of intrahepatic bile duct, leading to liver fiber , cirrhosis of the liver. In recent years, with the increasing knowledge of the PBC and the launching of serum autoantibodies, PBC detection rate increased year by year, up to 940/100, 000 population. As an important non-viral liver disease, PBC serious harm to people's health. PBC pathogenesis is not yet fully elucidated, is generally believed that the disease is in the interaction of genetic and environmental factors, via immune-mediated. The PBC clinical manifestations and pathological changes are not specific to, the majority of patients are diagnosed in the late stage of the session. Study the hepatocyte bile excretion related molecules will help to reveal the mechanisms of the pathogenesis of PBC PBC is a cholestatic disease, and help develop PBC diagnostic reagents. Liver cells is a polar epithelial cell, the cell membrane can be divided into sinusoids side membrane and the duct side membrane. The hepatocyte bile duct side of the cell membrane surface there is the distribution of a variety of specific expression of transporter and regulatory proteins to participate in the physiological function of the liver cells biliary excretion. Previous studies have shown that abnormal expression of these molecules or dysfunction is closely related to the pathogenesis of PBC. In patients with PBC, bile acid excretion of protein (BSEP) and bilirubin export pump (MRP2) significantly lowered the level of expression in the liver cells, this down by the transcription factor HNF1α and of RXRα / RARα expression in MSC-mediated's. The researchers also found in the patients with PBC the hepatocyte bile duct side of the membrane transporter molecules expression changes in the distribution, this change may be related to the abnormal distribution of Ezrin was certified. Pauli-Magnus et al found that the the BSEP gene of two missense mutations G620D and the A1228V with PBC pathogenesis, suggesting that changes in the the hepatocyte bile duct side the membrane polar molecule gene SNP sites may also be involved in the pathogenesis of PBC. Cholestasis is the main characteristics of the PBC, Ursodeoxycholic acid (UDCA) is the only effective drug for the treatment of PBC, after formal treatment, some patients can achieve normal expectations. Concerned the UDCA to promote bile excretion mechanism, researchers have found in animal experiments, it can to promote the expression of BSEP and MRP2 transcriptional or post-transcriptional level thus contributing to the efflux of bile. However, the known side of the bile duct membrane polar molecules can not fully explain the the PBC the biliary excretion barriers molecular mechanisms, found a new hepatocyte bile duct side membrane molecules will help elucidate the pathogenesis of cholestasis and PBC. [Objective] was prepared and screened for the polarity distribution of a monoclonal antibody in the the hepatocyte bile duct side membrane was to explore its pathophysiological significance in the PBC and its antigen identified. [Methods] 1 by density gradient centrifugation of the PBC liver cells in the bile duct side film bodies, polarity staining of liver cell membrane was prepared according to standard hybridoma screening monoclonal antibodies. Immune electron microscopy and laser scanning confocal microscope to observe the subcellular localization of 1F9. 3, the liver tissue samples collected the PBC at different stages and other liver diseases, using immunohistochemical methods observed and 1F9 expression changes, and to evaluate the pathophysiological significance in the PBC. 4, using immunoprecipitation plus MS analysis and cDNA library screening methods separation 1F9 antigen recognized. [Results] 1, a total of four in the hepatocyte bile duct polarity side of the membrane was stained with a monoclonal antibody, named 1F2, 1F3, 1F5, 1F9. 2, laser scanning confocal microscopy and immuno-electron microscopy found 1F9 antigen mainly located of hepatocyte bile duct side membrane endosomes wall. By immunohistochemical staining of tissue specimens of different liver diseases and the statistical analysis found that, 1F9 no obvious correlation with other liver diseases, only related with PBC, manifested in two aspects: First, the organization's change of position, PBC liver, 1F9 not only in the top of the liver cell endosomes, and distribution in the lysosomes; expression intensity changes in the liver of patients with PBC, 1F9 expression intensity gradually increased, with the staging of the disease progress in Ⅲ and Ⅳ in some cases, 1F9 expression distribution of disorders and loss of polarity. 4, immunoprecipitation and western blot showed that 1F9 identify the target antigen of molecular weight of 120kDa. 5, LC-MS/MS mass spectrometry 41 proteins. 7 gene fragment 1F9 cDNA expression library screening. Bioinformatic analysis of these genes and proteins found Calsyntenin target antigen 1F9 recognition. [Conclusion] using hybridoma technology, four monoclonal antibody distribution in the the hepatocyte bile duct side of the membrane was polarity. 2,1 F9 expression increased in the PBC liver, and gradually increased with PBC installments increased; 1F9 expression and distribution of disorder in the PBC liver, suggesting that the 1F9 with PBC is closely correlated. 3, Calsyntenin 1F9 antigen.

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CLC: > Medicine, health > Internal Medicine > Digestive and abdominal diseases > Liver and gall bladder disease > Cirrhosis
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