Raum-zeitliche Dynamik von primären Lymphoiden-Follikeln während der Organogenese und Lymphneogenese

Primary lymphoid follicles are structures which are important for adaptive immune responses in mammals. Within the follicles follicular dendritic cells (FDC) are maintained by constant stimuli provided by B cells. It is thought that the FDC are important for immune response. It is of interest to know how lymphoid follicles are regulated in order to understand their role in various autoimmune diseases in which these follicles are created ectopically. With the help of a tissue simulation relying on an agent-based cell model on top of a regular triangulation various scenarios suggested by the available experimental data have been investigated. In order to cope with the complexity in the simulation of immune tissue the regular triangulation has been implemented for the use on parallel computers. The algorithms for kinetic and dynamic regular triangulation have been created newly. Also the cell model underlying the simulation has been designed newly in many aspects. The simulations allowed to identify common factors that regulate the formation of lymphoid follicles normally during organogenesis in development and lymphneogenesis in the course of diseases. The generation of FDC from local stromal populations under the influence of B cell aggregates is shown to be possible with the given experimental parameters. The sequence of the organogenesis and lymphneogenesis can be described with regard to the morphology of the B and T zone. Tests for the stability of the primary lymphoid follicle system constraints the regulation of the B cell efflux. The required lymphatic vessels around the lymphoid follicle are shown to be negatively correlated with the FDC network. Moreover it is shown that the adjacent T zone consisting of its own stromal population and T cells has similar regulation principles. This easily explains the intermediate ring of B cells found around the T zone during development and certain signaling molecule deficiencies. A major result of this thesis is that the generation of FDC needs negative regulation while a number of other possible mechanisms is incompatible with the available experimental data. Moreover the observed microanatomy was brought into a functional relationship with data on the cellular level finally culminating in the proposal of new experiments that shed light on the dynamics of the primary lymphoid follicle. One conclusion is that the FDC directly or indirectly influence the angiogenesis and lymphangiogenesis processes in secondary lymphoid tissues. The work presented here may help to guide experiments with the help of computers in order to reduce the amount of experiments and design them in a way to maximize the amount of information about biological systems.In Säugetieren spielen primäre lymphoide Follikel eine wichtige Rolle bei der adaptiven Immunantwort. Innerhalb der Follikel werden follikuläre dendritische Zellen (FDZ) durch eine konstante Stimulation durch B-Zellen generiert und erhalten. Diese FDZ-Population is wichtig für bestimmte Immunreaktionen. Die Erzeugung und Regulierung der Follikel is interessant insbesondere im Hinblick auf ihre ektopische Erzeugung im Laufe von Autoimmunreaktionen. Mit Hilfe von Gewebesimulationen ausgehend von einem Individual-basierten Zellmodells, das auf einer Delaunay-Triangulation aufbaut, wurden verschiedene aus Experimenten generierter Szenarien untersucht. Zur Lösung des Komplexitäts-Problems der vielen zu simulierende Zellen des Gewebes wurde größtenteils neue Algorithmen zur parallelen Verarbeitung der Kinetik und Dynamik der Delaunay-Triangulation erstellt. Das darauf aufbauende Zellmodell ist ebenfalls der parallelen Verarbeitung angepaßt. Die Simulationen führten zur Identifizierung gemeinsamer Zusammenhänge der Regulation lymphoider Follikel währen der Organogenese und der krankheitsbedingten Lymphneogenese. Die Erzeugung von FDZ aus lokalen Populationen stromaler Zellen durch Aggregate von B-Lypmozyten ist im Bereich der experimentellen Parameter möglich. Die Sequenz der Musterbildung von B- und T-Zone des Follikels während Organogenese und Lymphneogenese kann simuliert werden. Stabilitätskriterien für das primäre lymphoide Follikel schränken die möglichen Mechanismen der Regulation des B-Lymphozyten-Efflux ein. Die dafür notwendigen lymphatischen Gefäße um das Follikel sind negativ mit den FDZ korreliert, um eine Position um das Follikel herum einzunehmen. Ebenso wird gezeigt, das die spezifischen stromalen Populationen der T-Zone zusammen mit den T-Lymphozyten ähnlichen Organisationsprinzipien gehorchen, wie das benachbarte Follikel. Dies erklärt auf einfache Weise, das Auftreten einer charakteristischen intermediären Morphologie des Follikels als B-Lymphozyten-Ring um die T-Zone sowohl während der normalen Entwicklung als auch als Resultat bestimmter Signalmolekül-Defizite. Ein zentrales Ergebnis dieser Arbeit ist, dass die Erzeugung der FDZ einer negativen Regulation unterliegen muss, während eine Reihe anderer denkbarer Mechanismen nicht mit den verfügbaren experimentellen Daten in Einklang zu bringen ist. Darüber hinaus konnten Morphologie und Funktion mit Daten der zellulären Ebene in Beziehung gesetzt werden. Daraus sind neue Experimente zur Dynamik primärer lymphoider Follikel abgeleitet worden. Ein Beispiel hierfü ist der Einfluss der FDZ auf die Angiogenese und Lymphangiogenese in sekundären lymphoiden Geweben. Die hier aufgeführte Arbeit stellt so einen Beitrag dar, Experimente mit Hilfe von Computer Simulationen zu entwerfen, um sowohl die Zahl der notwendigen Experimente zu reduzieren als auch deren Informationsgewinn über ein biologisches System zu maximieren

Integrating Signals from the T-Cell Receptor and the Interleukin-2 Receptor

T cells orchestrate the adaptive immune response, making them targets for immunotherapy. Although immunosuppressive therapies prevent disease progression, they also leave patients susceptible to opportunistic infections. To identify novel drug targets, we established a logical model describing T-cell receptor (TCR) signaling. However, to have a model that is able to predict new therapeutic approaches, the current drug targets must be included. Therefore, as a next step we generated the interleukin-2 receptor (IL-2R) signaling network and developed a tool to merge logical models. For IL-2R signaling, we show that STAT activation is independent of both Src- and PI3-kinases, while ERK activation depends upon both kinases and additionally requires novel PKCs. In addition, our merged model correctly predicted TCR-induced STAT activation. The combined network also allows information transfer from one receptor to add detail to another, thereby predicting that LAT mediates JNK activation in IL-2R signaling. In summary, the merged model not only enables us to unravel potential cross-talk, but it also suggests new experimental designs and provides a critical step towards designing strategies to reprogram T cells

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

10Kin1day: A Bottom-Up Neuroimaging Initiative.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain

Personalwirtschaft

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