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Reaction-diffusion networks underlying pattern formation of lymphoid tissue

Applicant Stein Jens Volker
Number 170969
Funding scheme Sinergia
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Interdisciplinary
Start/End 01.02.2017 - 31.01.2022
Approved amount 1'695'336.00
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All Disciplines (4)

Discipline
Interdisciplinary
Molecular Biology
Immunology, Immunopathology
Other disciplines of Engineering Sciences

Keywords (6)

Computer simulation; 3D organ imaging; Turing pattern; Single cell sequencing; Lymph node architecture; Reaction-diffusion network

Lay Summary (German)

Lead
In unserem Projekt haben sich ein Team von Immunologen, Bioinformatikern und Modellierern zusammengeschlossen, um die komplexe räumliche Anordnung von B-Zell-Follikeln in Lymphknoten besser zu verstehen. Dadurch erhoffen wir uns längerfristig neue Erkenntnisse zur verbesserten Impfung, vor allem bei immungeschwächten Personen.
Lay summary

Lymphknoten sind überall im Körper verteilte Ansammlungen von Lymphozyten, welche in allen Säugetieren für die Immunantworten gegen Viren und Bakterien verantwortlich sind. Lymphozyten werden wiederum unterschieden in T- und B-Zellen, wobei letztere die Herstellung von schützenden Antikörpern übernehmen, die geimpfte Menschen vor „echten“ Infektionen schützen. In Lymphknoten durchmischen sich T- und B-Zellen nicht nach einem Zufallsprinzip, sondern trennen sich in eigene Zonen auf. Insbesondere B-Zellen sammeln sich in mehreren Dutzend von „B-Zell Follikeln“, die in regelmässigen Abständen auf einer Seite des Lymphknotens zu finden sind. Oftmals ist diese Struktur in älteren oder immungeschwächten Personen beinträchtigt, was sich in geringerem Erfolg bei Grippeimpfungen u.ä. niederschlägt. Wie und warum diese auffällige Verteilung der B-Zellen reguliert ist, ist bisher nicht ausreichend untersucht.

In unserem Projekt haben sich ein Team von Immunologen, Bioinformatikern und Modellierern (d.h. Fachleute für „computer-based modelling“) zusammengeschlossen, um die komplexe räumliche Anordnung von B-Zell-Follikeln besser zu verstehen. Insbesondere prüfen wir, ob selbstorganisierende Musterbildung bei der Verteilung der Follikel eine Rolle spielt, ähnlich wie bei anderen entwicklungsbiologischen Vorgängen. Wir erhoffen uns dadurch längerfristig neue Erkenntnisse, wie diese spezifische Anordnung in Zukunft für verbesserte Impfstoffe zu nutzen sein könnte, beispielsweise indem die optimale Lymphknotenstruktur vor der Impfung widerhergestellt wird.
Direct link to Lay Summary Last update: 28.11.2016

Responsible applicant and co-applicants

Employees

Publications

Collaboration

Group / person Country
Types of collaboration
Prof. Mariagrazia Uguccioni, IRB Bellinzona Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Christopher Mueller/University of Strasbourg France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Shinichiro Sawa Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar University of Geneva Individual talk Lymphocyte trafficking in secondary lymphoid organs 16.11.2018 Geneva, Switzerland Stein Jens Volker;
Imaging the immune system Talk given at a conference Lymphocyte trafficking in secondary lymphoid organs 19.09.2018 Paris, France Abe Jun; Sivapatham Sujana; Wissmann Stefanie S; Barreto de Albuquerque Juliana; Stein Jens Volker; Ruef Nora Maria; Marcos Jimenez Ana;
From target to therapy Talk given at a conference Lymphocyte trafficking in secondary lymphoid organs 13.04.2018 Würzburg, Germany Stein Jens Volker;
Cytokine conference Poster Lymphocyte trafficking in secondary lymphoid organs 02.11.2017 Kanazawa, Japan Abe Jun; Stein Jens Volker;
STIMM seminar Uni Zurich Individual talk Lymphocyte trafficking in secondary lymphoid organs 07.07.2017 Zurich, Switzerland Stein Jens Volker;
SGAI meeting/conference chair Talk given at a conference Lymphocyte trafficking in secondary lymphoid organs 01.06.2017 St Gallen, Switzerland Stein Jens Volker; Abe Jun;
Seminar at institut Curie Individual talk Lymphocyte trafficking in secondary lymphoid organs 28.03.2017 Paris, France Stein Jens Volker;
Seminar RIA meeting Individual talk Lymphocyte trafficking in secondary lymphoid organs 08.03.2017 Bern, Switzerland Stein Jens Volker;


Associated projects

Number Title Start Funding scheme
172994 Immunology in context: Analyzing adaptive immunity through advanced microscopy 01.04.2017 Project funding (Div. I-III)

Abstract

Lymph nodes (LNs) are highly organized structures, where T and B cells congregate in separate microenvironments, the T cell area and B cell follicles containing follicular dendritic cells (FDCs). While it is well established that the FDC-secreted B cell chemoattractant CXCL13 attracts B cells into follicles, fundamental biological questions remain about how the striking geometric arrangement of follicles is achieved in the first place, and how it contributes to the efficient unfolding of humoral immune responses. Here, we will examine the hypothesis that a Turing network (a self-organizing reaction-diffusion system proposed by Alan Turing over 60 years ago) underlies periodic follicle patterning - a hypothesis which is suggested by the observed consistency of size and regular spacing of follicles in different sized LNs and other lymphoid organs. A Turing system requires at least two diffusible molecules, which are usually signaling ligands in biological cases; since CXCL13 is a cytokine and becomes expressed in a periodic pattern, it could be one of the Turing molecules. We will explore whether CXCL13 and other molecules drive the observed pattern by focusing on marginal reticular cells (MRCs), LN stromal precursors of FDCs. Our preliminary evidence suggests that MRCs contain CXCL13-expressing and non-expressing subsets to direct early B cell recruitment to spatially separated sites along the LN cortex where follicles will eventually form. Understanding the dynamics of Turing systems is often non-intuitive due to the dynamic feedbacks involved in the control circuit. We will therefore build a dynamical computer simulation of this hypothesis in 3D, driven by the molecular data obtained, to explore the various possible scenarios of follicle patterning. Combining novel transgenic reporter mice and single cell RNA-seq analysis with whole-organ imaging and computational modelling, we will investigate a potential reaction-diffusion mechanism underlying CXCL13 induction in MRC subsets and potentially other stromal cells. Our final goal is to interfere with this regulated formation to examine its impact on humoral responses. Our team combines complementary expertise in the fields of adaptive immunology, bioinformatics and modelling: quantitative 3D imaging of follicles in steady state and perturbed LNs and its correlation with adaptive immunity (Stein, UBERN); mathematical modeling of Turing models in multicellular tissue (Sharpe, CRG); and unbiased bioinformatic analysis of key cell populations to identify candidate components of follicle-inducing reaction-diffusion systems (Bruggmann, UBERN).
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