Induction of gut homing T cells by systemic dendritic cells

An effective vaccine against mucosal pathogens such as the Human Immunodeficiency Virus 1 (HIV-1) must provide immunity at the mucosal level. Understanding the ability of mucosal dendritic cells (DCs) to induce gut homing lymphocytes plays a crucial parameter in the development of vaccines that mount a specific immune response in the intestine. Gut-tropic T cells are characterised by the expression of the integrin heterodimer α4β7 and the chemokine receptors CCR9 and CCR10, with CCR9 being specific for the small intestine. While CCR10 has been suggested to play a role in lymphocyte homing to the large intestine, together with CCR4, it has been implicated in lymphocyte trafficking to the skin. In addition, it is thought that induction of gut homing T cells is associated with the ability of intestinal DCs to metabolise vitamin A to retinoic acid (RA). Mucosal vaccination is known to induce mucosal and systemic immune responses, while systemic vaccination has been thought to only induce systemic immune responses. However, recent publications have shown systemic vaccination to induce mucosal immune responses. This project investigates the ability of different types of human systemic DCs to modulate expression of receptors specific to mucosal and skin homing T cells in the presence of retinoids and vitamin D. Co-culture of DCs with various T cell populations in the presence of RA revealed the ability of systemic DCs to increase α4β7 expression and decrease surface expression of cutaneous lymphocyte-associated antigen (CLA), a marker for skin homing T cells. We also showed that vitamin D plays a role in modulating CCR4 and CCR10 expression. Having investigated the ability of RA to modulate homing receptor expression on T cells, we confirmed the potential of systemic DCs to metabolize retinol and retinal in vitro by molecular means and flow cytometric analysis. Finally, we examined the role of retinoic acid receptors (RARs) in regulating α4β7 and CLA expressing T cells. This is the first study that investigates the potential of different subsets of human systemic DCs to differentially induce and modulate homing properties of T cells in vitro. The findings presented in this thesis could have major implications in the development of systemic vaccines aimed at inducing mucosal immune responses

Porous structures used as flameproof pressure relief elements a novel approach of flameless venting

Here, a novel approach to flameless venting is presented, which offers the possibility of improving the design of flameproof enclosures without reducing any safety aspects. This approach is based on the integration of porous structures – such as traditional sintered metals or sintered metal fibers – into the enclosure walls acting as venting and flame-quenching elements. It is shown that proper use of these structures can enormously decrease the maximum explosion pressure while safely avoiding flame transmissions, even for a large number of consecutive internal explosions. However, the transmission of a gas explosion through porous structures is a transient and spatially inhomogeneous process that is strongly influenced by turbulence and chemical reactions. Especially the heating of the structures due to hot gas flow and heat conduction may lead to hot surfaces which can act as ignition sources. Hence, various porous structures were investigated: First of all, their ability to relieve pressure and their stability concerning the maximum explosion pressure were examined. Their ability to avoid flame transmissions was determined by performing a standardized test for the non-transmission of an internal explosion. And, finally, the temperature and flow characteristics of these porous structures were investigated, too. Significant differences in flow resistance and heat conduction leading to different pressure relief and flame transmission behaviors were identified, depending on the specifics of the structure. In particular, the internal structure of the examined porous media, which results from porosity and pore size distribution as well as from the shape of the solid phase (matrix), affects these characteristics

Replacement of mouse Sox10 by the Drosophila ortholog Sox100B provides evidence for co-option of SoxE proteins into vertebrate-specific gene-regulatory networks through altered expression

AbstractNeural crest cells and oligodendrocytes as the myelinating glia of the central nervous system exist only in vertebrates. Their development is regulated by complex regulatory networks, of which the SoxE-type high-mobility-group domain transcription factors Sox8, Sox9 and Sox10 are essential components. Here we analyzed by in ovo electroporation in chicken and by gene replacement in the mouse whether the Drosophila ortholog Sox100B can functionally substitute for vertebrate SoxE proteins. Sox100B overexpression in the chicken neural tube led to the induction of neural crest cells as previously observed for vertebrate SoxE proteins. Furthermore, many aspects of neural crest and oligodendrocyte development were surprisingly normal in mice in which the Sox10 coding information was replaced by Sox100B arguing that Sox100B integrates well into the gene-regulatory networks that drive these processes. Our results therefore provide strong evidence for a model in which SoxE proteins were co-opted to these gene-regulatory networks mainly through the acquisition of novel expression patterns. However, later developmental defects in several neural crest derived lineages in mice homozygous for the Sox100B replacement allele indicate that some degree of functional specialization and adaptation of SoxE protein properties have taken place in addition to the co-option event

Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease

The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms—synaptic dysfunction, immune alterations, and gut–brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease

Analyse transkriptioneller Netzwerke während der Oligodendrozyten-Differenzierung und zentralnervöser Myelinisierung in der Maus

Viele Entwicklungsprozesse werden zur spezifischen Regulation nicht nur durch einzelne Transkriptionsfaktoren gesteuert, sondern vielmehr durch ein Zusammenspiel mehrerer Transkriptionsfaktoren. In der Entwicklung des zentralen Nervensystems der Wirbeltiere nimmt das SoxE-Protein Sox10 eine essentielle Rolle ein. Dies wurde in der Embryonalentwicklung bereits intensiv studiert. Jedoch wurde der Einfluss von Sox10 im postnatalen Rückenmark bisher wenig analysiert. Daher wurde in der vorliegenden Arbeit der postnatale Einfluss von Sox10 auf die Oligodendrozytenentwicklung mittels zentralnervöser Sox10-Deletion in der Maus untersucht. Sox10-defiziente Mäuse zeigten ab der zweiten Lebenswoche starke motorische Einschränkungen, und keines der Tiere überlebte den postnatalen Tag 24. Im Rückenmark dieser Mäuse lag kein Myelin vor, auch wenn einige Oligodendrozyten die Expression von Myelingenen induzieren und zumindest zeitweise aufrechterhalten konnten. Sobald neben Sox10 noch das nah verwandte SoxE-Gen Sox8 deletiert wurde, ging auch diese restliche Myelingenexpression verloren. Der Verlust von Sox10 führte dazu, dass Oligodendrozyten in ihrer Entwicklung nicht über das promyelinisierende Stadium hinauskamen. Dabei war der Verlust der Myrf-Expression der früheste in dieser Arbeit beobachtete Defekt. Myrf wurde als direktes Zielgen von Sox10 identifiziert, und besaß einen evolutionär konservierten Enhancer mit einer monomeren und einer dimeren Bindestelle für Sox10. Die spezifische Bindung von Sox10 an diese Region ließ sich durch Gelretardierungsexperimente, Chromatin-Immunpräzipitationen (ChIP) und Reportergenanalysen nachweisen. Zusätzlich wurde die Funktionalität der Sox10-Bindung durch die Mutagenese der Bindestellen in vitro und in vivo belegt. Durch Reportergen-Analysen in der Maus konnte dem Myrf-Enhancer in vivo Oligodendrozyten-spezifische Aktivität zugewiesen werden. Myrf interagierte mit Sox10 in vitro, und beide Transkriptionsfaktoren konnten Myelin-assoziierte Gene synergistisch aktivieren so dass davon auszugehen ist, dass Sox10 seine Wirkung im Rahmen der zentralnervösen Myelinisierung nach ähnlichen Prinzipien ausübt wie im peripheren Nervensystem