Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis

Abstract

Organic and inorganic anions participate in the generation Chloride-bicarbonate anion exchanger 2 (AE2) is exof the osmotic force responsible for the bile acid-independent pressed in a variety of tissues, including the liver and flow. 4,5 Secretion of bicarbonate to the bile appears to occur salivary glands, where it may participate in the generathrough Na / -independent chloride-bicarbonate anion extion of hydroionic fluxes into secretions. We have prechangers (AE), and AE proteins are thought to play an imviously reported decreased hepatic levels of AE2 mesportant role in the formation of canalicular and ductular senger RNA in patients with primary biliary cirrhosis bile. 6-9 (PBC), a cholestatic condition frequently associated AE proteins are encoded by a family of genes, three of with pluriglandular exocrine failure. Here we investiwhich (AE1, AE2, and AE3 genes) are now well charactergated the expression of AE2 protein in the liver of PBC ized. 10,11 AE1 (also referred to as band-3 protein) is expressed patients. Using a monoclonal antibody against an AE2 in erythroid cell membranes and in the kidney. AE3 messenpeptide, immunohistochemistry was performed on liver ger RNA (mRNA) has been described in excitable tissues such biopsy specimens from subjects with normal liver (n Å as nervous system and cardiac muscle. AE2 protein (or corre-7), patients with PBC (n Å 13), and patients with cirrhosponding transcript) has been encountered in a variety of sis or cholestasis other than PBC (n Å 17 and 11, respectissues, including the liver and secretory epithelia, where it tively). Immunostaining was graded from 0 to 7, is thought to participate in the generation of hydroionic according to its intensity and distribution. AE2 immunofluxes into secretions. Using a monoclonal antibody against reactivity was observed in normal livers, as previously AE2 developed in our laboratory, we have found that AE2 reported, and in many pathological liver biopsy speciimmunoreactivity localizes to both canaliculi and the luminal mens, being mainly restricted to canaliculi and the lumiside of bile duct epithelial cells. 12 This apical location of AE2 nal membrane of terminal and interlobular bile ducts.is consistent with its participation in bile formation and with Canalicular and ductular scores were significantly recurrent models of biliary bicarbonate secretion and secretinduced in the PBC group compared with each control stimulated ductular choleresis. 13,14 group (normal liver and cirrhosis or cholestasis other PBC is frequently associated with pluriglandular exocrine than PBC), whereas no differences in immunoreactivity failure. 15,16 We hypothesized that abnormalities in bicarbonscores were observed among control groups. When four ate transport mechanisms could underlie both the cholestasis patients with primary sclerosing cholangitis (PSC) were and the exocrine failure that characterize this disease. We analyzed, they also differed from those with PBC. These have already reported a reduction in the levels of AE2 mRNA results su...

Role of the Anion Exchanger 2 in the Pathogenesis and Treatment of Primary Biliary Cirrhosis

“…Interestingly, in the few patients with PBC undergoing treatment with UDCA, the levels of AE2 mRNA in the liver were intermediate, lying between those observed in untreated PBC and controls. Parallel findings were obtained when we analyzed the expression of the AE2 gene at the protein level by using immunohistochemistry in formalin-fixed liver specimens [11]. Thus, immunoreactivity scoring of the different liver structures, i.e.…”

“…Ae2 a,b -deficient mouse cholangiocytes can maintain their resting pH i via supplementary NBC-mediated HCO 3 – secreting activity, which is completely absent in human cholangiocytes [71,83]. But PBC cholangiocytes may in turn maintain resting pH i because they generally display residual AE2 activity [71], due to diminished (rather than absent) AE2 expression in most PBC cases [11]. Such a similar outcome might contribute to the fact that biliary epithelial cells in Ae2 a,b –/– mice become susceptible to an autoimmune attack, as postulated for the human cholangiocytes in PBC [65,84].…”

“…Thus, the essential function of anion carriers in the generation of hydroionic fluxes into secretions (e.g. bile and saliva), together with the observed therapeutic effect of UDCA, led us to postulate that abnormalities in bicarbonate transport mechanisms might play a role in the pathogenesis of PBC [11,12]. Hypothetically, alterations in bicarbonate transport – regardless of whether they are primary or secondary – could lead to disruption of the intracellular homeostasis in effector cells (lymphocytes) and/or targeted cells (bile duct epithelial cells and ductular cells of the salivary and lacrimal glands), and favor autoimmunity.…”

Role of Nuclear Receptors in the Biliary Epithelium

“…The involvement of AE2 in ductular secretion is illustrated by a diminished expression in the liver of patients with primary biliary cirrhosis, a prototypical cholestatic disease [41]. Interestingly, UDCA restores AE2 expression in biliary epithelial cells [41]. The efficacy of UDCA may be improved by corticosteroids [42], suggesting that GR activation may regulate ductal choleresis through transcriptional control.…”

“…The secretion of chloride through the cystic fibrosis transmembrane conductance regulator is then activated by cAMP [38] and results in a procholeretic osmotic gradient that follows the activation of the Cl – /HCO 3 – anion exchanger AE2 [39,40], a protein expressed all along the human biliary tree [25]. The involvement of AE2 in ductular secretion is illustrated by a diminished expression in the liver of patients with primary biliary cirrhosis, a prototypical cholestatic disease [41]. Interestingly, UDCA restores AE2 expression in biliary epithelial cells [41].…”