Papers by Detlef Schuppan
International Journal of Molecular Sciences
Wheat is an important staple crop since its proteins contribute to human and animal nutrition and... more Wheat is an important staple crop since its proteins contribute to human and animal nutrition and are important for its end-use quality. However, wheat proteins can also cause adverse human reactions for a large number of people. We performed a genome wide association study (GWAS) on 114 proteins quantified by LC-MS-based proteomics and expressed in an environmentally stable manner in 148 wheat cultivars with a heritability > 0.6. For 54 proteins, we detected quantitative trait loci (QTL) that exceeded the Bonferroni-corrected significance threshold and explained 17.3–84.5% of the genotypic variance. Proteins in the same family often clustered at a very close chromosomal position or the potential homeolog. Major QTLs were found for four well-known glutenin and gliadin subunits, and the QTL segregation pattern in the protein encoding the high molecular weight glutenin subunit Dx5 could be confirmed by SDS gel-electrophoresis. For nine potential allergenic proteins, large QTLs coul...
Hepatology, 2022
BACKGROUND & AIMS Growing evidence suggests an important role of B cells in the development o... more BACKGROUND & AIMS Growing evidence suggests an important role of B cells in the development of non-alcoholic fatty liver disease (NAFLD). However, a detailed functional analysis of B cell subsets in NAFLD pathogenesis is lacking. APPROACH & RESULTS In wildtype mice, 21 weeks of high fat diet (HFD) feeding resulted in NAFLD with massive macrovesicular steatosis, modest hepatic and adipose tissue inflammation, insulin resistance and incipient fibrosis. Remarkably, Bnull (JHT) mice were partially protected whereas B cell harboring but antibody-deficient IgMi mice were completely protected from the development of hepatic steatosis, inflammation and fibrosis. The common feature of JHT and IgMi mice is that they do not secrete antibodies, while HFD feeding in wildtype mice led to increased levels of serum IgG2c. Whereas JHT mice have no B cells at all, regulatory B cells were found in the liver of both wildtype and IgMi mice. HFD reduced the number of regulatory B cells and interleukin 10 production in the liver of wildtype mice, while these increased in IgMi mice. Livers of patients with advanced liver fibrosis showed abundant deposition of IgG, stromal B cells and low numbers of interleukin 10 expressing cells, compatible with our experimental data. CONCLUSIONS B lymphocytes have both detrimental and protective effects in HFD-induced NAFLD. The lack of secreted pathogenic antibodies protects partially from NAFLD, whereas the presence of certain B cell subsets provides additional protection. Interleukin 10-producing regulatory B cells may represent such a protective B cell subset.
World Journal of Gastroenterology, 2009
AIM: To study the role of advanced glycation end products (AGE) and their specific receptor (RAGE... more AIM: To study the role of advanced glycation end products (AGE) and their specific receptor (RAGE) in the pathogenesis of liver fibrogenesis. METHODS: In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells (HSC) were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin (AGE-BSA) and N ε-(carboxymethyl) lysine (CML)-BSA, or with tumor necrosis factor-α (TNF-α). In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS: In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α. RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis-or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1(Ⅰ) mRNA by AGE-BSA. CONCLUSION: Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.
Journal of Hepatology, 2016
Non-alcoholic fatty liver disease (NAFLD) is considered the most prevalent liver disease worldwid... more Non-alcoholic fatty liver disease (NAFLD) is considered the most prevalent liver disease worldwide. Patients can develop end-stage liver disease resulting in liver cirrhosis or hepatocellular carcinoma, but also develop complications unrelated to liver disease, e.g. cardiovascular disease. Still there is no full understanding of the mechanisms that cause NAFLD. In this study, genetically engineered mice were employed to examine the role of a specific protein in the liver that is involved in inflammation and the metabolism, namely Bcl-3. By this approach, a better understanding of the mechanisms contributing to disease progression was established. This can help to develop novel therapeutic and diagnostic options for patients with NAFLD.
Journal of Biological Chemistry, 2010
European Journal of Clinical Investigation, 1992
Type IV collagen is a major component of the glomerular and tubular basement membrane. We used a ... more Type IV collagen is a major component of the glomerular and tubular basement membrane. We used a specific radioimmunoassay to determine (mean k SD) the concentration of carboxy terminal non-collagenous fragment (NC 1) of type IV procollagen in the serum (normal 6.0_+ I .2 ng ml-I) and urine (normal 1.5 f 2.0 ng ml-') of 142 patients with various kidney diseases. The 15 patients with active glomerulonephritis displayed (ANOVA, Scheffk test) significantly elevated NCI values in their serum (14f8.2 ng m1-I) as compared with the 32 patients with chronic interstitial nephritis (7.8k3.0 ng ml-I), the 17 patients with various other chronic kidney diseases (8.1 k2.4 ng ml-I) and the 23 ambulatory kidney transplant patients (9.1 f 1.7 ng ml-I). The highest serum NCI concentrations were found in nine patients with membranoproliferative glomerulonephritis (1 6 9.4 ng ml-I). Sequential serum NCI concentrations in the one patient with active Goodpasture's syndrome were marginally elevated (< I 1 ng ml-I). Serum NCI did not increase with acute interstitial rejection episodes in six kidney transplant patients. The highest urinary NCI concentrations were found in seven patients with minimal change glomerulonephritis (7.5 k 3.2 ng ml-I). No correlation was found between serum NCl and serum creatinine, NC 1 and creatinine clearance, or renal NCI clearance and creatinine clearance. There was a significant correlation between serum NCI and proteinuria. Serum and urinary NCI concentrations were elevated independently from renal function, thus indicating intrinsic renal disease. We conclude that serum and urinary NCl may be useful parameters for distinguishing active damage to the glomerular and tubular basement membrane from other kidney diseases.
Scientific Reports, 2019
We previously demonstrated that a common dietary protein component, wheat amylase trypsin inhibit... more We previously demonstrated that a common dietary protein component, wheat amylase trypsin inhibitors (ATI), stimulate intestinal macrophages and dendritic cells via toll like receptor 4. Activation of these intestinal myeloid cells elicits an inflammatory signal that is propagated to mesenteric lymph nodes, and that can facilitate extraintestinal inflammation. Mice were fed a well-defined high fat diet, with (HFD/ATI) or without (HFD) nutritionally irrelevant amounts of ATI. Mice on HFD/ATI developed only mild signs of intestinal inflammation and myeloid cell activation but displayed significantly higher serum triglycerides and transaminases compared to mice on HFD alone. Moreover, they showed increased visceral and liver fat, and a higher insulin resistance. ATI feeding promoted liver and adipose tissue inflammation, with M1-type macrophage polarization and infiltration, and enhanced liver fibrogenesis. Gluten, the major protein component of wheat, did not induce these pathologies....
Nutrients, 2018
Celiac disease is a small intestinal inflammatory disease with autoimmune features that is trigge... more Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye. Prevalence of celiac disease is increased in patients with mono-and/or polyglandular autoimmunity and their relatives. We have reviewed the current and pertinent literature that addresses the close association between celiac disease and endocrine autoimmunity. The close relationship between celiac disease and glandular autoimmunity can be largely explained by sharing of a common genetic background. Further, between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5-7% of patients with autoimmune thyroid disease, type 1 diabetes, and/or polyglandular autoimmunity are IgA anti-tissue transglutaminase antibody positive. While a gluten free diet does not reverse glandular autoimmunity, its early institution may delay or even prevent its first manifestation. In conclusion, this brief review highlighting the close association between celiac disease and both monoglandular and polyglandular autoimmunity, aims to underline the need for prospective studies to establish whether an early diagnosis of celiac disease and a prompt gluten-free diet may positively impact the evolution and manifestation of glandular autoimmunity.
Virchows Archiv A Pathological Anatomy and Histopathology, 1987
Twelve oral AIDS-associated Kaposi sarcomas (KS) were studied for the distribution of extracellul... more Twelve oral AIDS-associated Kaposi sarcomas (KS) were studied for the distribution of extracellular matrix components using indirect immunofluorescence. Staining for basement membrane (BM) components revealed two distinct patterns of distribution: a delicate and partly fragmented lining of BMs around sinusoid-like vascular spaces or an occasional diffuse interstitial fluorescence in the tumour stroma; or an irregular broad rim of fluorescence in walls of larger blood vessels. These findings support a vascular cell origin of the endothelial- and spindle cell component in KS. The tumour stroma was almost completely negative for collagen type V and undulin, whereas an intensive fluorescence was noted for procollagens type I, III and collagen type VI. In areas adjacent to KS a loss of procollagens type I and III, collagens type V, VI and undulin was noted. An intimal sheath of collagen type V was usually absent from blood vessels of the tumour or the peritumourous connective tissue. Immunohistochemical findings indicate that the preexisting interstitial connective tissue matrix is destroyed during tumour invasion and that subsequently procollagens type I, III and collagen type VI are synthesized de novo by cells of the tumour stroma.
Journal of Clinical Gastroenterology, 2012
Hepatology, 1999
Hepatic stellate cells are the major cellular sources of extracellular matrix in chronic liver di... more Hepatic stellate cells are the major cellular sources of extracellular matrix in chronic liver diseases leading to fibrosis. We explored the antifibrogenic effect of two histone deacetylase inhibitors, sodium butyrate and trichostatin A (TSA), on this cell type in vitro. Primary hepatic stellate cells as well as culture activated cells were exposed to butyrate (0.01-1 mmol/L) or TSA (1-100 nmol/L); their effect on collagen types I and III and smooth muscle alpha-actin was examined by quantitative immunoprecipitation and by Northern analysis. Their antiproliferative effect was examined by 3H-thymidine incorporation and cell counting. Hyperacetylation of histones was demonstrated by acid urea/Triton-X-100 (AUT) polyacrylamide gel electrophoresis. Possible cytotoxic effects were judged on stellate cells by evaluating de novo total protein synthesis, and on hepatocytes by measuring lactate dehydrogenase (LDH) leakage, albumin secretion, and epoxide hydrolase and ethoxycoumarin O-deethylase activity. TSA at 100 nmol/L and butyrate at 1 mmol/L retarded the morphological changes characteristic for activation of primary stellate cells. TSA at 100 nmol/L inhibited synthesis of collagen types I and III and smooth muscle alpha-actin by 62%, 70%, and 88%. Butyrate at 1 mmol/L showed a modest inhibitory effect on collagen type III and smooth muscle alpha-actin, but had no effect on collagen type I. Northern analysis suggested that these inhibitory effects on collagen type III and smooth muscle alpha-actin were transcriptional, while the effect on collagen type I was largely posttranscriptional. At 100 nmol/L, TSA strongly suppressed proliferation of primary hepatic stellate cells. Inhibition of activation of stellate cells was preceded by hyperacetylation of histone H4. When tested on cells at day 14 in culture, butyrate had no inhibitory effects on the synthesis of collagens or smooth muscle alpha-actin. One hundred or 10 nmol/L TSA modestly inhibited the synthesis of collagens type I (-24%,-22%) and III (-34%,-22%), and smooth muscle alpha-actin (-27%,-12%). We conclude that TSA inhibits transdifferentiation of stellate cells into myofibroblasts by interfering with the level of acetylation of histone H4.
The American Journal of Pathology, 2002
International Journal of Molecular Sciences, 2021
New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and test... more New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC50 values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 ...
Journal of gastroenterology and hepatology, Jan 9, 2018
Nonalcoholic steatohepatitis (NASH) is strongly associated with overnutrition, insulin resistance... more Nonalcoholic steatohepatitis (NASH) is strongly associated with overnutrition, insulin resistance, and predisposition to type 2 diabetes. To critically analyze the translational significance of currently-used animal models of NASH, we reviewed articles published during the last three years that studied NASH pathogenesis using mouse models. Among 146 articles, 34 (23%) used models in which overnutrition was reported, and 36 (25%) demonstrated insulin resistance, with or without glucose intolerance. Half the articles contained no information on whether mice exhibited overnutrition or insulin resistance. While 75 papers (52%) reported >2-fold increase of serum/plasma alanine aminotransferase (ALT) compared to controls, ALT levels were near normal or not reported in 48%. Liver pathology was assessed by a pathologist with an interest in liver pathology in 53% of articles published in gastroenterology/hepatology journals, versus 43-44% in other journals. While there appears to be a tre...
Nutrients, Jan 21, 2017
Gluten-related disorders have recently been reclassified with an emerging scientific literature s... more Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.
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Papers by Detlef Schuppan