Tytgat Institute for Liver and Intestinal Research

Amsterdam-Zuidoost, Netherlands

Tytgat Institute for Liver and Intestinal Research

Amsterdam-Zuidoost, Netherlands
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Beuers U.,Tytgat Institute for Liver and Intestinal Research | Gershwin M.E.,University of California at Davis
Clinical Reviews in Allergy and Immunology | Year: 2015

It is ironic that the liver, which serves a critical function in immune tolerance, itself becomes the victim of an autoimmune attack. Indeed, liver autoimmunity and the autoimmune diseases associated with both innate and adaptive responses to hepatocytes and/or cholangiocytes are models of human autoimmunity. For example, in primary biliary cirrhosis, there exists a well-defined and characteristic autoantibody and considerable homogeneity between patients. In autoimmune hepatitis, there are clinical characteristics that allow a rigorous subset definition and well-defined inflammatory infiltrates. In both cases, there are defects in a variety of immune pathways and including regulatory cells. In primary sclerosing cholangitis, with its characteristic overlap with inflammatory bowel disease, there are unique defects in innate immunity and particular important contribution of lymphoid homing to disease pathogenesis. In these diseases, as with other human autoimmune processes, there is the critical understanding that pathogenesis requires a genetic background, but is determined by environmental features, and indeed the concordance of these diseases in identical twins highlights the stochastic nature of immunopathology. Unfortunately, despite major advances in basic immunology and in immunopathology in these diseases, there remains a major void in therapy. The newer biologics that are so widely used in rheumatology, neurology, and gastroenterology have not yet seen success in autoimmune liver disease. Future efforts will depend on more rigorous molecular biology and systems analysis in order for successful application to be made to patients. © 2015, Springer Science+Business Media New York.


Seppen J.,Tytgat Institute for Liver and Intestinal Research
Toxicology and Applied Pharmacology | Year: 2012

Soy beans contain genistein, a natural compound that has estrogenic effects because it binds the estrogen receptor with relatively high affinity. Genistein is therefore the most important environmental estrogen in the human diet.Detoxification of genistein is mediated through conjugation by UDP-glucuronyltransferase 1 and 2 (UGT1 and UGT2) isoenzymes.Gunn rats have a genetic deficiency in UGT1 activity, UGT2 activities are not affected. Because our Gunn rats stopped breeding after the animal chow was changed to a type with much higher soy content, we examined the mechanism behind this soy diet induced infertility. Gunn and control rats were fed diets with and without genistein. In these rats, plasma levels of genistein and metabolites, fertility and reproductive parameters were determined. Enzyme assays showed reduced genistein UGT activity in Gunn rats, as compared to wild type rats. Female Gunn rats were completely infertile on a genistein diet, wild type rats were fertile. Genistein diet caused a persistent estrus, lowered serum progesterone and inhibited development of corpora lutea in Gunn rats.Concentrations of total genistein in Gunn and control rat plasma were identical and within the range observed in humans after soy consumption. However, Gunn rat plasma contained 25% unconjugated genistein, compared to 3.6% in control rats. This study shows that, under conditions of reduced glucuronidation, dietary genistein exhibits a strongly increased estrogenic effect. Because polymorphisms that reduce UGT1 expression are prevalent in the human population, these results suggest a cautionary attitude towards the consumption of large amounts of soy or soy supplements. © 2012 Elsevier Inc.


Hubers L.M.,Tytgat Institute for Liver and Intestinal Research
Current Opinion in Gastroenterology | Year: 2017

PURPOSE OF REVIEW: IgG4-related disease (IgG4-RD) is an immune-mediated disease of unknown cause. It predominantly affects the biliary tract [IgG4-associated cholangitis (IAC)] and pancreas [autoimmune pancreatitis (AIP)] of mostly elderly men. Accurate diagnostic tests are lacking. Patients benefit from predniso(lo)ne treatment. However, disease relapse is often seen. This review will address pathophysiological aspects and advances in diagnostic and therapeutic strategies. RECENT FINDINGS: The role of IgG1 and IgG4 in the pathophysiology of IgG4-RD was studied in mice which showed more intense organ damage of pancreas and salivary glands when IgG1 rather than IgG4 of patients with IgG4-RD was injected. Coadministration of IgG1+IgG4 led to dampening of IgG1-mediated injury supporting the view that IgG4 exerts immune-dampening effects. IgG4+ B-cell receptor clones identified by next-generation sequencing and the IgG4/IgG RNA ratio in human blood assessed by quantitative PCR were able to accurately distinguish IAC/AIP from primary sclerosing cholangitis or pancreatobiliary malignancies. Long-term treatment with low-dose prednisolone was safe and reduced the number of flare-ups in patients with AIP. SUMMARY: Early diagnosis by a novel accurate and easy-to-use qPCR test may prevent life-threatening complications, unnecessary interventions and fatal course because of misdiagnosis. Prednisolone treatment remains the standard of care in patients with IgG4-RD. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Beuers U.,Tytgat Institute for Liver and Intestinal Research | Trauner M.,Medical University of Vienna | Jansen P.,Tytgat Institute for Liver and Intestinal Research | Poupon R.,French Institute of Health and Medical Research
Journal of Hepatology | Year: 2015

Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases. © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Bernink J.,Tytgat Institute for Liver and Intestinal Research | Mjosberg J.,Karolinska University Hospital | Spits H.,Tytgat Institute for Liver and Intestinal Research
Immunological Reviews | Year: 2013

Innate lymphoid cells (ILCs) constitute a family of effectors in innate immunity and regulators of tissue remodeling that have a cytokine and transcription factor expression pattern that parallels that of the T-helper (Th) cell family. Here, we discuss how ILCs can be categorized and summarize the current knowledge of Th1- and Th2-like ILCs with regard to the molecular mechanisms of development, effector functions, and their interplay with other cell types. © 2013 John Wiley & Sons A/S.


Beuers U.,Tytgat Institute for Liver and Intestinal Research | Kremer A.E.,Tytgat Institute for Liver and Intestinal Research | Kremer A.E.,Friedrich - Alexander - University, Erlangen - Nuremberg | Bolier R.,Tytgat Institute for Liver and Intestinal Research | Elferink R.P.J.O.,Tytgat Institute for Liver and Intestinal Research
Hepatology | Year: 2014

Pruritus is a common symptom in patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, or hereditary pediatric cholestatic disorders and may accompany, although less frequently, many other liver diseases. Recent findings indicate that lysophosphatidic acid (LPA), a potent neuronal activator, and autotaxin (ATX; ectonucleotide pyrophosphatase/phosphodiesterase 2), the enzyme which forms LPA, may form a key element of the long-sought pruritogenic signaling cascade in cholestatic patients suffering from itch. Serum ATX, but no other pruritogen candidate studied so far, correlates with pruritus intensity and responds to therapeutic interventions. In this comprehensive review, we provide a short update on actual insights in signal transmission related to pruritus and discuss pruritogen candidates in cholestasis. We also summarize evidence-based and guideline-approved as well as experimental therapeutic approaches for patients suffering from pruritus in cholestasis. (Hepatology 2014;60:399-407) © 2014 by the American Association for the Study of Liver Diseases.


Spits H.,Tytgat Institute for Liver and Intestinal Research | Cupedo T.,Erasmus Medical Center
Annual Review of Immunology | Year: 2012

Innate lymphoid cells (ILCs) are immune cells that lack a specific antigen receptor yet can produce an array of effector cytokines that in variety match that of T helper cell subsets. ILCs function in lymphoid organogenesis, tissue remodeling, antimicrobial immunity, and inflammation, particularly at barrier surfaces. Their ability to promptly respond to insults inflicted by stress-causing microbes strongly suggests that ILCs are critical in first-line immunological defenses. Here, we review current data on developmental requirements, lineage relationships, and effector functions of two families of ILCs: (a) Rorγt-expressing cells involved in lymphoid tissue formation, mucosal immunity, and inflammation and (b) type 2 ILCs that are important for helminth immunity. We also discuss the potential roles of ILCs in the pathology of immune-mediated inflammatory and infectious diseases including allergy. © 2012 by Annual Reviews. All rights reserved.


Beuers U.,Tytgat Institute for Liver and Intestinal Research
Hepatology (Baltimore, Md.) | Year: 2010

This review focuses on the hypothesis that biliary HCO(3)(-) secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of this biliary HCO(3)(-) umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl(-)/ HCO(3)(-) exchange and HCO(3)(-) secretion, and alkaline phosphatase-mediated ATP breakdown may guarantee a stable biliary HCO(3)(-) umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO(3)(-) umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis.


Paulusma C.C.,Tytgat Institute for Liver and Intestinal Research | Oude Elferink R.P.J.,Tytgat Institute for Liver and Intestinal Research
FEBS Letters | Year: 2010

P4 ATPases are integral transmembrane proteins implicated in phospholipid translocation from the exoplasmic to the cytosolic leaflet of biological membranes. Our present knowledge on the cellular physiology of P4 ATPases is mostly derived from studies in the yeast Saccharomyces cerevisiae, where P4 ATPases play a pivotal role in the biogenesis of intracellular transport vesicles, polarized protein transport and protein maturation. In contrast, the physiological and cellular functions of mammalian P4 ATPases are largely unexplored. P4 ATPases act in concert with members of the CDC50 protein family, which are putative β-subunits for P4 ATPases. This review highlights the current status of a slowly emerging research field and emphasizes the contribution of P4 ATPases to the vesicle-generating machinery. © 2010 Federation of European Biochemical Societies.


Schaap F.G.,Tytgat Institute for Liver and Intestinal Research
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2012

Purpose of review: Fibroblast growth factor 19 (FGF19) is a postprandial hormone released from the small intestine. FGF19 improves glucose tolerance when overexpressed in mice with impaired glucose tolerance or diabetes. This review summarizes the recent advances in our understanding of the biology of FGF19 and its role in glucose homeostasis, with emphasis on publications from 2010 to 2012. Recent findings: Protein engineering was used to generate FGF19 protein variants that allowed the separation of its mitogenic and metabolic functions. Its cognate receptor in the liver (FGFR4) mediated the effects of FGF19 on proliferation and bile salt synthesis, while this receptor was dispensable for its effects on glucose homeostasis. New metabolic activities of FGF19 were uncovered. FGF19 signaling was shown to stimulate glycogen and protein synthesis, and inhibit gluconeogenesis. FGF19 employed signaling routes distinct from those used by insulin to regulate these pathways. Mice with genetic disruption of Fgf15 (the mouse FGF19 ortholog) were glucose intolerant but had normal insulin levels and normal insulin sensitivity. Reduced hepatic glycogen stores and elevated hepatic gluconeogenesis were observed in the knock-out mice under the conditions in which insulin signaling was active. Summary: FGF19 signaling regulates glucose homeostasis in mice. The (patho)physiological role of FGF19 in glucose homeostasis in humans remains to be determined. Its novel insulin-mimetic actions, combined with the elimination of its mitogenic activity by protein engineering, make FGF19 an attractive candidate for the treatment of type 2 diabetes. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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