The High Affinity IgE Receptor FcεRI Is Expressed by Human Intestinal Epithelial Cells

IgE antibodies play a paramount role in the pathogenesis of various intestinal disorders. To gain insights in IgE-mediated pathophysiology of the gut, we investigated the expression of the high affinity IgE receptor Fc epsilonRI in human intestinal epithelium.Fc epsilonRI alpha-chain, as detected by immunohistochemistry, was positive in epithelial cells for eight of eleven (8/11) specimens from colon cancer patients and 5/11 patients with inflammation of the enteric mucosa. The Fc epsilonRIalpha positive epithelial cells co-expressed Fc epsilonRIgamma, whereas with one exception, none of the samples was positive for the beta-chain in the epithelial layer. The functionality of Fc epsilonRI was confirmed in situ by human IgE binding. In experiments with human intestinal tumor cell lines, subconfluent Caco-2/TC7 and HCT-8 cells were found to express the alpha- and gamma-chains of Fc epsilonRI and to bind IgE, whereas confluent cells were negative for gamma-chains.Our data provide the first evidence that the components of a functional Fc epsilonRI are in vitro expressed by the human intestinal epithelial cells depending on differentiation and, more importantly, in situ in epithelia of patients with colon cancer or gastrointestinal inflammations. Thus, a contribution of Fc epsilonRI either to immunosurveillance or pathophysiology of the intestinal epithelium is suggested

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFN?-driven immunopathology

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cyto-kines IFN? and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. © Gawish et al

Nitration of the Egg-Allergen Ovalbumin Enhances Protein Allergenicity but Reduces the Risk for Oral Sensitization in a Murine Model of Food Allergy

Nitration of proteins on tyrosine residues, which can occur due to polluted air under "summer smog" conditions, has been shown to increase the allergic potential of allergens. Since nitration of tyrosine residues is also observed during inflammatory responses, this modification could directly influence protein immunogenicity and might therefore contribute to food allergy induction. In the current study we have analyzed the impact of protein nitration on sensitization via the oral route.BALB/c mice were immunized intragastrically by feeding untreated ovalbumin (OVA), sham-nitrated ovalbumin (snOVA) or nitrated ovalbumin (nOVA) with or without concomitant acid-suppression. To analyze the impact of the sensitization route, the allergens were also injected intraperitoneally. Animals being fed OVA or snOVA under acid-suppressive medication developed significantly elevated levels of IgE, and increased titers of specific IgG1 and IgG2a antibodies. Interestingly, oral immunizations of nOVA under anti-acid treatment did not result in IgG and IgE formation. In contrast, intraperitoneal immunization induced high levels of OVA specific IgE, which were significantly increased in the group that received nOVA by injection. Furthermore, nOVA triggered significantly enhanced mediator release from RBL cells passively sensitized with sera from allergic mice. Gastric digestion experiments demonstrated protein nitration to interfere with protein stability as nOVA was easily degraded, whereas OVA and snOVA remained stable up to 120 min. Additionally, HPLC-chip-MS/MS analysis showed that one tyrosine residue (Y(107)) being very efficiently nitrated is part of an ovalbumin epitope recognized exclusively after oral sensitization.These data indicated that despite the enhanced triggering capacity in existing allergy, nitration of OVA may be associated with a reduced de novo sensitizing capability via the oral route due to enhanced protein digestibility and/or changes in antibody epitopes

Molecular allergology : studies on allergen-enterocyte interaction, sensitization and effector mechanisms

Die Zahl an Allergikern wird weltweit stetig größer und auch allergische Reaktionen gegen Nahrungsmittel werden vor allem in Industrieländern immer häufiger. Trotz intensiver Forschung sind viele grundlegende Mechanismen der Sensibilisierung gegen Nahrungsmittelproteine weitgehend unklar. Im ersten Kapitel dieser Doktorarbeit untersuchten wir mögliche Faktoren, die zur allergischen Sensibilisierung gegen Nahrungsmittelproteine beitragen könnten. Im Zuge dieser Studien konnten wir zeigen, dass Erhitzen des Erdnussallergens Ara h 2 dessen Bindung an humane Intestinalzellen signifikant erhöht. Die anschließenden Analysen zeigten, dass die Hitzebehandlung die räumliche Struktur des Proteins anhaltend verändert, vermehrte Protein-Aggregierung verursacht und in einem Mausmodell für Nahrungsmittelallergie zu einer stärkeren Immunantwort führt. Weiters entdeckten wir, dass humane intestinale Epithelzellen auf Inkubation mit dem Erdnussallergen mit veränderter Genexpression reagieren können. Die Wahrscheinlichkeit einer allergischen Erkrankung nach der Pupertät ist für Frauen größer als für Männer. Im zweiten Dissertationskapitel untersuchten wir daher den Einfluss des weiblichen Geschlechtshormons Östrogen auf die Aktivierung von Mastzellen. Unsere Experimente zeigten dass Östrogen keinen Einfluss auf die Degranulierung von Mastzellen hat, dafür aber anscheinend auf die Synthese und Ausschüttung von Zytokinen. Für das dritte Dissertationskapitel wollten wir ursprünglich die Anwesenheit von Zellen mit dem hoch-affinen IgE Rezeptor, Fc[epsilon]RI, in verschiedenen Erkrankungen des Gastrointestinaltraktes untersuchen. Dabei bemerkten wir, dass dieser Rezeptor auch im intestinalen Epithelium exprimiert ist. Im Rahmen der Studie konnten wir mittels immunohistologischer Analysen erstmals die Expression von Fc[epsilon]RI in Enterozyten in verschiedenen Krankheitsbildern nachweisen.The numbers of allergic patients are worldwide on the rise. Also food related hypersensitivity reactions are spreading in industrialized countries. Despite intensive research efforts, mechanisms which could support sensitization against food still remain unclear. In chapter 1 of this PhD thesis, we concentrated on factors which may contribute to specific sensitization against food proteins in the gastrointestinal tract. These studies showed that heat processing of the peanut allergen Ara h 2 significantly increases the binding of the allergen to intestinal epithelial cells. Structural investigations revealed that heating induces permanent changes in the tertiary structure of Ara h 2, increased oligomer formation and enhanced immunogenic potential in vivo in a oral food allergy mouse model. We furthermore discovered that enterocytes may respond to allergen incubation with altered expression of genes involved in different immune response associated signalling pathways. Epidemiological studies revealed a gender bias of allergic patients towards females after puberty. In thesis chapter 2, we investigated the impact of the female sex hormone estrogen on mast cell activation. Our experiments showed that estrogen does not influence mast cell degranulation but seems to increase cytokine production. Originally intending to investigate the presence of immune cells expressing the high affinity IgE receptor, Fc[epsilon]RI, in different gastrointestinal diseases, we report in thesis chapter 3 the presence of the receptor in the human intestinal epithelium. We performed immunohistologic analyses and observed the expression of Fc[epsilon]RI in enterocytes associated with gastrointestinal diseases.submitted by Philipp StarklAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheAuch erschienen in: PLoS One. 2010 Feb 2;5(2):e9023. / URL: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009023Wien, Med. Univ., Diss., 2010OeBB(VLID)171622

Neutrophils are not required for resolution of acute gouty arthritis in mice

International audienceComment on Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Schauer C, Janko C, Munoz LE, Zhao Y, Kienhöfer D, Frey B, Lell M, Manger B, Rech J, Naschberger E, Holmdahl R, Krenn V, Harrer T, Jeremic I, Bilyy R, Schett G, Hoffmann M, Herrmann M. Nat Med. 2014 May;20(5):511-7. doi: 10.1038/nm.3547. Epub 2014 Apr 28. PMID: 2478423

Mast Cells and IgE can Enhance Survival During Innate and Acquired Host Responses to Venoms.

Mast cells and immunoglobulin E (IgE) antibodies are thought to promote health by contributing to host responses to certain parasites, but other beneficial functions have remained obscure. Venoms provoke innate inflammatory responses and pathology reflecting the activities of the contained toxins. Venoms also can induce allergic sensitization and development of venom-specific IgE antibodies, which can predispose some subjects to exhibit anaphylaxis upon subsequent exposure to the relevant venom. We found that innate functions of mast cells, including degradation of venom toxins by mast cell-derived proteases, enhanced survival in mice injected with venoms from the honeybee, two species of scorpion, three species of poisonous snakes, or the Gila monster. We also found that mice injected with sub-lethal amounts of honeybee or Russell's viper venom exhibited enhanced survival after subsequent challenge with potentially lethal amounts of that venom, and that IgE antibodies, FcepsilonRI, and probably mast cells contributed to such acquired resistance