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Amsterdam-Zuidoost, Netherlands

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. Source

Hreggvidsdottir H.S.,University of Amsterdam | Hreggvidsdottir H.S.,Tytgat Institute for Liver and Intestinal Research | Noordenbos T.,University of Amsterdam | Baeten D.L.,University of Amsterdam
Molecular Immunology | Year: 2014

Spondyloarthritis is the second most common form of chronic inflammatory arthritis and a unique hallmark of the disease is pathologic new bone formation. Several cytokine pathways have been genetically associated with ankylosing spondylitis (AS), the prototypic subtype of SpA, and additional evidence from human and animal studies support a role of these pathways in the disease. TNF has a key role in SpA as blockade significantly reduces inflammation and destruction, however the treatment does not halt new bone formation. New insights into the TNF pathway were recently obtained from an animal model specifically overexpressing the transmembrane form of TNF. This model leads to axial and peripheral new bone formation which is not seen in soluble TNF overexpression models, indicating different pathogenic roles of soluble and transmembrane TNF in arthritis development. Besides TNF, the IL-23/IL-17 axis is emerging as an important inflammatory pathway in SpA, as a SNP in the IL-23R locus has been associated with developing AS, mice overexpressing IL-23 develop SpA-like features and IL-17 blockade has been shown to be efficacious for AS patients in a phase II trial. In this review, we focus on the cytokine pathways that have recently been genetically associated with SpA, i.e. TNF, IL-1, IL-6 and IL-23/IL-17. We review the current genetic, experimental and human in vivo data available and discuss how these different pathways are involved in the pathophysiology of SpA. Additionally, we discuss how these pathways relate to the pathogenic new bone formation in SpA. © 2013 Elsevier Ltd. Source

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. Source

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. Source

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. Source

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