Ralf Kubitz - Academia.edu (original) (raw)
Papers by Ralf Kubitz
Encyclopedia of Molecular Mechanisms of Disease, 2009
Familial benign chronic pemphigus [1] Definition and Characteristics Hailey-Hailey disease is an ... more Familial benign chronic pemphigus [1] Definition and Characteristics Hailey-Hailey disease is an autosomal dominant skin disorder characterized by erosive plaques. The disease usually starts between the second and fourth decade. The course of the disease is characterized by spontaneous exacerbations and remissions with marked predilection for the intertriginous areas [2]. Hailey-Hailey disease presents with vesicles, papules, crusted erosions, and oozing plaques. Pain and unpleasant smell lead to a social handicap. Lesions can be triggered on almost all body sites by minor trauma, friction, tape stripping, and inflammation caused by UV radiation, allergens, toxic components or infectious agents. Finger nails may show asymptomatic longitudinal white bands. Mucosal involvement is unusual [1].
Encyclopedia of Molecular Mechanisms of Disease, 2009
International Journal of Molecular Sciences, 2020
We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cell... more We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133+BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133+BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133+BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133+BMSC homing to the injured liver with heightened transmigration towards the extra sinuso...
Pediatric Transplantation, 2016
PFIC due to BSEP mutations (PFIC type 2) often necessitates OLT. It has recently been recognized ... more PFIC due to BSEP mutations (PFIC type 2) often necessitates OLT. It has recently been recognized that some PFIC-2 patients develop phenotypic disease recurrence post-OLT due to the appearance of anti-BSEP antibodies. Here, we describe a boy who became cholestatic four yr after OLT during modification of immunosuppression. Canalicular antibody deposits were detected in biopsies of the transplant and antibodies specifically reacting with BSEP were identified at high titers in his serum. These antibodies bound extracellular epitopes of BSEP and inhibited BS transport and were assumed to cause disease recurrence. Consequently, anti-BSEP antibody depletion was pursued by IA and B-cell depletion by anti-CD20 antibodies (rituximab) along with a switch of immunosuppression. This treatment resulted in prolonged relief of symptoms. Depletion of pathogenic anti-BSEP antibodies causing AIBD after OLT in PFIC-2 patients should be considered as a central therapeutic goal.
Data Revues 22107401 Unassign S2210740112001878, Jul 14, 2012
Page 1. AUS DER KLINIK FÜR GASTROENTEROLOGIE, HEPATOLOGIE UND INFEKTIOLOGIE HEINRICH-HEINE-UNIVER... more Page 1. AUS DER KLINIK FÜR GASTROENTEROLOGIE, HEPATOLOGIE UND INFEKTIOLOGIE HEINRICH-HEINE-UNIVERSITÄT DÜSSELDORF PROFESSOR DR. MED. DIETER HÄUSSINGER REGULATION HEPATOBILIÄRER TRANSPORTPROTEINE ...
Seminars in Liver Disease, 2000
On a short term basis, canalicular secretion is under control of the hepatocellular hydration sta... more On a short term basis, canalicular secretion is under control of the hepatocellular hydration state, substrates, cytokines, toxins, and hormones. Regulation occurs at the level of substrate availability, covalent modification of transporters, and their regulated exocytic insertion into or endocytic retrieval from the membrane. A variety of signal transduction pathways involving the activation of mitogen-activated protein kinases, protein kinases A and C, participates in these processes. However, much has still to be learned about the crosstalk of different signaling systems and their molecular targets that determine the outcome for canalicular secretion.
AJP: Gastrointestinal and Liver Physiology, 2010
Bile salts influence signaling and metabolic pathways. In hepatocytes, the sodium taurocholate co... more Bile salts influence signaling and metabolic pathways. In hepatocytes, the sodium taurocholate cotransporting polypeptide (Ntcp) is a major determinant of intracellular bile salt levels. Short-term downregulation of Ntcp is not well characterized to date. FLAG and enhanced green fluorescent protein (EGFP) tags were cloned to the extra- and intracellular termini of Ntcp. Endocytosis of Ntcp in transfected HepG2 cells was visualized by fluorescence of EGFP, and membrane surface expression of Ntcp was quantified by flow cytometry with fluorochrome-labeled FLAG antibodies. Activation of protein kinase C (PKC) by phorbolester or thymeleatoxin an activator of Ca2+-dependent conventional PKCs (cPKCs), induced endocytosis of Ntcp, whereas the Na+-K+-ATPase remained in the plasma membrane. The PKC inhibitor BIM I and the cPKC-selective inhibitor Gö6976 abolished PMA-induced endocytosis. Because of this internalization, cell surface expression of Ntcp was reduced by 36 ± 7%, bile salt uptake ...
Liver International, 2013
The bile salt export pump (BSEP, ABCB11) is essential for bile salt secretion at the canalicular ... more The bile salt export pump (BSEP, ABCB11) is essential for bile salt secretion at the canalicular membrane of liver cells. Clinical phenotypes associated with BSEP mutations are commonly categorized as benign recurrent intrahepatic cholestasis (BRIC-2) or progressive familial intrahepatic cholestasis (PFIC-2). The molecular basis of BSEP-associated liver disease in a sibling pair was characterized by immunostaining, gene sequencing, bile salt analysis and recombinant expression in mammalian cells and yeast for localization and in vitro activity studies respectively. Benign recurrent intrahepatic cholestasis was considered in a brother and sister who both suffered from intermittent cholestasis since childhood. Gene sequencing of ABCB11 identified the novel missense mutation p.G374S, which is localized in the putative sixth transmembrane helix of BSEP. Liver fibrosis was present in the brother at the age of 18 with progression to cirrhosis within 3 years. Immunofluorescence of liver tissue showed clear canalicular BSEP expression; however, biliary concentration of bile salts was drastically reduced. In line with these in vivo findings, HEK293 cells showed regular membrane targeting of human BSEP(G374S), whereas in vitro transport measurements revealed a strongly reduced transport activity. The novel mutation p.G374S impairs transport function without disabling membrane localization of BSEP. While all other known BSEP mutations within transmembrane helices are associated with PFIC-2, the new p.G374S mutation causes a transitional phenotype between BRIC-2 and PFIC-2.
Scientific reports, 2016
The bile salt export pump BSEP mediates bile formation. Over 150 BSEP mutations are associated wi... more The bile salt export pump BSEP mediates bile formation. Over 150 BSEP mutations are associated with progressive familial intrahepatic cholestasis type 2 (PFIC-2), with few characterised specifically. We examined liver tissues from two PFIC-2 patients compound heterozygous for the splice-site mutation c.150 + 3A > C and either c.2783_2787dup5 resulting in a frameshift with a premature termination codon (child 1) or p.R832C (child 2). Splicing was analysed with a minigene system and mRNA sequencing from patients' livers. Protein expression was shown by immunofluorescence. Using the minigene, c.150 + 3A > C causes complete skipping of exon 3. In liver tissue of child 1, c.2783_2787dup5 was found on DNA but not on mRNA level, implying nonsense-mediated mRNA decay (NMD) when c.2783_2787dup5 is present. Still, BSEP protein as well as mRNA with and without exon 3 were detectable and can be assigned to the c.150 + 3A > C allele. Correctly spliced transcripts despite c.150 + 3A ...
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Familial benign chronic pemphigus [1] Definition and Characteristics Hailey-Hailey disease is an ... more Familial benign chronic pemphigus [1] Definition and Characteristics Hailey-Hailey disease is an autosomal dominant skin disorder characterized by erosive plaques. The disease usually starts between the second and fourth decade. The course of the disease is characterized by spontaneous exacerbations and remissions with marked predilection for the intertriginous areas [2]. Hailey-Hailey disease presents with vesicles, papules, crusted erosions, and oozing plaques. Pain and unpleasant smell lead to a social handicap. Lesions can be triggered on almost all body sites by minor trauma, friction, tape stripping, and inflammation caused by UV radiation, allergens, toxic components or infectious agents. Finger nails may show asymptomatic longitudinal white bands. Mucosal involvement is unusual [1].
Encyclopedia of Molecular Mechanisms of Disease, 2009
International Journal of Molecular Sciences, 2020
We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cell... more We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133+BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133+BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133+BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133+BMSC homing to the injured liver with heightened transmigration towards the extra sinuso...
Pediatric Transplantation, 2016
PFIC due to BSEP mutations (PFIC type 2) often necessitates OLT. It has recently been recognized ... more PFIC due to BSEP mutations (PFIC type 2) often necessitates OLT. It has recently been recognized that some PFIC-2 patients develop phenotypic disease recurrence post-OLT due to the appearance of anti-BSEP antibodies. Here, we describe a boy who became cholestatic four yr after OLT during modification of immunosuppression. Canalicular antibody deposits were detected in biopsies of the transplant and antibodies specifically reacting with BSEP were identified at high titers in his serum. These antibodies bound extracellular epitopes of BSEP and inhibited BS transport and were assumed to cause disease recurrence. Consequently, anti-BSEP antibody depletion was pursued by IA and B-cell depletion by anti-CD20 antibodies (rituximab) along with a switch of immunosuppression. This treatment resulted in prolonged relief of symptoms. Depletion of pathogenic anti-BSEP antibodies causing AIBD after OLT in PFIC-2 patients should be considered as a central therapeutic goal.
Data Revues 22107401 Unassign S2210740112001878, Jul 14, 2012
Page 1. AUS DER KLINIK FÜR GASTROENTEROLOGIE, HEPATOLOGIE UND INFEKTIOLOGIE HEINRICH-HEINE-UNIVER... more Page 1. AUS DER KLINIK FÜR GASTROENTEROLOGIE, HEPATOLOGIE UND INFEKTIOLOGIE HEINRICH-HEINE-UNIVERSITÄT DÜSSELDORF PROFESSOR DR. MED. DIETER HÄUSSINGER REGULATION HEPATOBILIÄRER TRANSPORTPROTEINE ...
Seminars in Liver Disease, 2000
On a short term basis, canalicular secretion is under control of the hepatocellular hydration sta... more On a short term basis, canalicular secretion is under control of the hepatocellular hydration state, substrates, cytokines, toxins, and hormones. Regulation occurs at the level of substrate availability, covalent modification of transporters, and their regulated exocytic insertion into or endocytic retrieval from the membrane. A variety of signal transduction pathways involving the activation of mitogen-activated protein kinases, protein kinases A and C, participates in these processes. However, much has still to be learned about the crosstalk of different signaling systems and their molecular targets that determine the outcome for canalicular secretion.
AJP: Gastrointestinal and Liver Physiology, 2010
Bile salts influence signaling and metabolic pathways. In hepatocytes, the sodium taurocholate co... more Bile salts influence signaling and metabolic pathways. In hepatocytes, the sodium taurocholate cotransporting polypeptide (Ntcp) is a major determinant of intracellular bile salt levels. Short-term downregulation of Ntcp is not well characterized to date. FLAG and enhanced green fluorescent protein (EGFP) tags were cloned to the extra- and intracellular termini of Ntcp. Endocytosis of Ntcp in transfected HepG2 cells was visualized by fluorescence of EGFP, and membrane surface expression of Ntcp was quantified by flow cytometry with fluorochrome-labeled FLAG antibodies. Activation of protein kinase C (PKC) by phorbolester or thymeleatoxin an activator of Ca2+-dependent conventional PKCs (cPKCs), induced endocytosis of Ntcp, whereas the Na+-K+-ATPase remained in the plasma membrane. The PKC inhibitor BIM I and the cPKC-selective inhibitor Gö6976 abolished PMA-induced endocytosis. Because of this internalization, cell surface expression of Ntcp was reduced by 36 ± 7%, bile salt uptake ...
Liver International, 2013
The bile salt export pump (BSEP, ABCB11) is essential for bile salt secretion at the canalicular ... more The bile salt export pump (BSEP, ABCB11) is essential for bile salt secretion at the canalicular membrane of liver cells. Clinical phenotypes associated with BSEP mutations are commonly categorized as benign recurrent intrahepatic cholestasis (BRIC-2) or progressive familial intrahepatic cholestasis (PFIC-2). The molecular basis of BSEP-associated liver disease in a sibling pair was characterized by immunostaining, gene sequencing, bile salt analysis and recombinant expression in mammalian cells and yeast for localization and in vitro activity studies respectively. Benign recurrent intrahepatic cholestasis was considered in a brother and sister who both suffered from intermittent cholestasis since childhood. Gene sequencing of ABCB11 identified the novel missense mutation p.G374S, which is localized in the putative sixth transmembrane helix of BSEP. Liver fibrosis was present in the brother at the age of 18 with progression to cirrhosis within 3 years. Immunofluorescence of liver tissue showed clear canalicular BSEP expression; however, biliary concentration of bile salts was drastically reduced. In line with these in vivo findings, HEK293 cells showed regular membrane targeting of human BSEP(G374S), whereas in vitro transport measurements revealed a strongly reduced transport activity. The novel mutation p.G374S impairs transport function without disabling membrane localization of BSEP. While all other known BSEP mutations within transmembrane helices are associated with PFIC-2, the new p.G374S mutation causes a transitional phenotype between BRIC-2 and PFIC-2.
Scientific reports, 2016
The bile salt export pump BSEP mediates bile formation. Over 150 BSEP mutations are associated wi... more The bile salt export pump BSEP mediates bile formation. Over 150 BSEP mutations are associated with progressive familial intrahepatic cholestasis type 2 (PFIC-2), with few characterised specifically. We examined liver tissues from two PFIC-2 patients compound heterozygous for the splice-site mutation c.150 + 3A > C and either c.2783_2787dup5 resulting in a frameshift with a premature termination codon (child 1) or p.R832C (child 2). Splicing was analysed with a minigene system and mRNA sequencing from patients' livers. Protein expression was shown by immunofluorescence. Using the minigene, c.150 + 3A > C causes complete skipping of exon 3. In liver tissue of child 1, c.2783_2787dup5 was found on DNA but not on mRNA level, implying nonsense-mediated mRNA decay (NMD) when c.2783_2787dup5 is present. Still, BSEP protein as well as mRNA with and without exon 3 were detectable and can be assigned to the c.150 + 3A > C allele. Correctly spliced transcripts despite c.150 + 3A ...
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009
Encyclopedia of Molecular Mechanisms of Disease, 2009