Dendritic cells in oral tolerance in the gut

Oral tolerance is a process that allows generation of systemic unresponsiveness to food antigens. Hence if the same antigen is introduced systemically even under immunogenic conditions it does not induce immune responsiveness. Dendritic cells (DCs) have been identified as essential players in this process. DCs in the gut are located in a strategic position as they can interact directly with luminal antigens or indirectly after their transcytosis across epithelial cells. DCs can then migrate to associated lymphoid tissues to induce tolerance. Antigen presenting cells in the gut are specialized in function and have divided their labour so that there are cells capable to migrate to the draining mesenteric lymph node for induction of T regulatory cells, while other subsets are resident and are required to enforce tolerance locally in the gut after food antigen exposure. In this review, I shall summarize the characteristics of antigen presenting cells in the gut and their involvement in oral tolerance induction. In addition, I will also emphasize that tolerance to food allergens may be contributed by plasmacytoid DCs in the liver that participate to the elimination or anergy of allergen-specific CD8 T cells. Hence specialized functions are associated to different subsets of antigen presenting cells and different organs

The Gut Immune Barrier and the Blood-Brain Barrier: Are They So Different?

In order to protect itself from a diverse set of environmental pathogens and toxins, the body has developed a number of barrier mechanisms to limit the entry of potential hazards. Here, we compare two such barriers: the gut immune barrier, which is the primary barrier against pathogens and toxins ingested in food, and the blood-brain barrier, which protects the central nervous system from pathogens and toxins in the blood. Although each barrier provides defense in very different environments, there are many similarities in their mechanisms of action. In both cases, there is a physical barrier formed by a cellular layer that tightly regulates the movement of ions, molecules, and cells between two tissue spaces. These barrier cells interact with different cell types, which dynamically regulate their function, and with a different array of immune cells that survey the physical barrier and provide innate and adaptive immunity

Dendritic cells sample HIV-1 through an intestinal epithelial cell monolayer

The intestinal mucosa is a preferential portal of entry for HIV-1 during mother-to-child transmission. Oral infection is also a well documented route for transmission of HIV-1 in neonates. Neonates can acquire the disease by breast-feeding, moreover presence of blood in gastric aspirates of neonates born to HIV-1 infected mothers has also been incriminated as a risk factor in the transmission of HIV-1. Multiple mechanisms for mucosal HIV-1 transmission have been proposed, however the exact role played by dendritic cells in facilitating viral passage across intestinal epithelium have not been fully defined. We had hypothesized that sub-mucosal dendritic cells (DCs) can mediate mucosal transmission of HIV-1 through a process similar to bacterial sampling through gastrointestinal epithelium (Rescigno M., Nat.Immun.2001)

Dendritic cells sample HIV-1 through an intestinal epithelial cell monolayer

The intestinal mucosa is a preferential portal of entry for HIV-1 during mother-to-child transmission. Oral infection is also a well documented route for transmission of HIV-1 in neonates. Neonates can acquire the disease by breast-feeding, moreover presence of blood in gastric aspirates of neonates born to HIV-1 infected mothers has also been incriminated as a risk factor in the transmission of HIV-1. Multiple mechanisms for mucosal HIV-1 transmission have been proposed, however the exact role played by dendritic cells in facilitating viral passage across intestinal epithelium have not been fully defined. We had hypothesized that sub-mucosal dendritic cells (DCs) can mediate mucosal transmission of HIV-1 through a process similar to bacterial sampling through gastrointestinal epithelium (Rescigno M., Nat.Immun.2001)

All’origine di una burocrazia moderna: il personale del Ministero delle Finanze nel Mezzogiorno di primo Ottocento

[Italiano]: Il passaggio dal Decennio francese agli anni della seconda Restaurazione rappresenta un momento qualificante nella storia del Mezzogiorno. Strettamente connessa con il tema dello Stato, colto nei suoi tratti peculiari, la costruzione di una burocrazia moderna viene prendendo forma proprio a partire da quello snodo, contribuendo ad una maggiore articolazione del periodo borbonico. Al centro del volume è la struttura ministeriale delle Finanze, indagata focalizzando l’attenzione sul personale che ne faceva parte. Attraverso un’ampia ed inedita documentazione di archivio, combinata con un’altrettanto consistente documentazione bibliografica, in larga parte coeva, la ricerca incrocia temi diversi: dal piano dell’azione governativa a quello più specifico dell’istituzione, dal piano dell’individuo a quello del territorio. La crescita dell’amministrazione, che l’indagine porta allo scoperto, sembra incidere in più di un senso sul profilo della società meridionale, rinviando ad una dinamica dimensione statale. Sullo sfondo un territorio tutt’altro che inerte: lo Stato si conferma infatti come identificatore e classificatore di luoghi, anche attraverso un processo di definizione di un’identità burocratica, che si costruisce nel rapporto con le dimensioni locali in cui si va ad operare./ [English]: The transition from the French Decade to the years of the Second Restoration represents a qualifying moment in the history of Southern Italy. Closely connected to the topic of the State-Building, studied in its peculiar traits, the construction of a modern bureaucracy begins precisely from that point, contributing to a greater articulation of the Bourbon period. The core of the volume is the structure of the Ministry of Finance, investigated by focusing on its personnel.Through extensive and unpublished records, combined with a consistent bibliography, broadly composed of primary sources, the book crosses different subjects: from governmental action to the institutional one; from the individual prospective to that of the territory. The growth of the administration, which the investigation reveals, seems to influence in many aspects the profile of southern society, suggesting a dynamic dimension of the State. In the background, there was a territory far from being inactive: in fact, the State confirms his role of place identifier and classifier, even through a process of defining a bureaucratic identity in relation to the local dimensions in which it operates

Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement

Cells lining the gastrointestinal tract serve as both a barrier to and a pathway for infectious agent entry. Dendritic cells (DCs) present in the lamina propria under the columnar villus epithelium of the small bowel extend processes across this epithelium and capture bacteria, but previous studies provided limited information on the nature of the stimuli, receptors, and signaling events involved in promoting this phenomenon. Here, we use immunohistochemical as well as dynamic explant and intravital two-photon imaging to investigate this issue. Analysis of CD11c–enhanced green fluorescent protein (EGFP) or major histocompatibility complex CII-EGFP mice revealed that the number of trans-epithelial DC extensions, many with an unusual “balloon” shape, varies along the length of the small bowel. High numbers of such extensions were found in the proximal jejunum, but only a few were present in the terminal ileum. The extensions in the terminal ileum markedly increased upon the introduction of invasive or noninvasive Salmonella organisms, and chimeric mouse studies revealed the key role of MyD88-dependent Toll-like receptor (TLR) signaling by nonhematopoietic (epithelial) elements in the DC extension response. Collectively, these findings support a model in which epithelial cell TLR signaling upon exposure to microbial stimuli induces active DC sampling of the gut lumen at sites distant from organized lymphoid tissues

Contrasting roles of SPARC-related granuloma in bacterial containment and in the induction of anti–Salmonella typhimurium immunity

The role of matricellular proteins in bacterial containment and in the induction of pathogen-specific adaptive immune responses is unknown. We studied the function of the matricellular protein secreted protein, acidic and rich in cysteine (SPARC/osteonectin) in the dissemination of locally injected Salmonella typhimurium and in the subsequent immune response. We show that SPARC was required for the development of organized acute inflammatory reactions with granuloma-like (GL) features and for the control of bacterial spreading to draining lymph nodes (DLNs). However, SPARC-related GL also inhibited dendritic cell (DC) migration to the DLNs and limited the development of adaptive immune response, thus conferring increased susceptibility to the pathogen. In SPARC-deficient mice, both DC migration and antigen-specific responses were restored against bacteria, leading to protective anti–S. typhimurium immunity. This highlights a new function of matricellular proteins in bacterial infection and suggests that initial containment of bacteria can have drawbacks

Biomimetic cellulose-based superabsorbent hydrogels for treating obesity

In the treatment of obesity, nutritional and behavioral modifications are difficult to implement and maintain. Since vegetable consumption is a fundamental part of many dietary interventions and daily nutrient requirements, we developed a novel cellulose-based superabsorbent hydrogel (CB-SAH) platform, inspired by the composition and mechanical properties of raw vegetables, as a mechanobiological therapy. The CB-SAHs properties were studied in a simulated gastrointestinal environment, while their impact on gut tissue was investigated by an ex vivo organ culture (EVOC) model. Functional fibers and raw vegetables were used as reference. CB-SAHs demonstrated orders of magnitude higher elasticity in comparison to the tested functional fibers, however performed similar to the tested raw vegetables. Notably, the biomimetic CB-SAHs with elasticity levels similar to raw vegetables showed benefits in preserving and regulating the gut tissue in the EVOC model. Non-systemic oral mechanotherapeutics based on this technology were advanced through clinical studies, with a first product cleared as an aid for weight management in the US and Europe