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The sequence of functional public and private antibody repertoire development in response to transient exposures to non-pathogenic intestinal microbes

English title The sequence of functional public and private antibody repertoire development in response to transient exposures to non-pathogenic intestinal microbes
Applicant Macpherson Andrew
Number 179479
Funding scheme Project funding (Div. I-III)
Research institution Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.10.2018 - 30.09.2022
Approved amount 1'300'701.00
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Keywords (6)

Gnotobiology; Reversible colonization; Antigen specificity; Immunoglobulin repertoire; Monoclonal antibody; Host-microbial mutualism

Lay Summary (German)

Lead
Mikrobiota-abhängige Entwicklung des Antikörperrepertoires:Mikrobiota, Infektionen und Lebensstil beeinflussen unser Immunsystem. In diesem Projekt untersuchen wir, wie sich diese Faktoren, insbesondere die Kolonisierung mit Mikroben nach der Geburt, auf das Antikörperrepertoire eines Individuums auswirken.
Lay summary

B-Zellen sind wichtige Zellen des adaptiven Immunsystems, welche Antikörper produzieren. Jede B-Zelle produziert einen Antikörper, welcher spezifisch für ein ganz bestimmtes Antigen ist. Nicht nur Infektionen mit Krankheitserregern, sondern auch die Besiedlung mit kommensaler Mikrobiota nach der Geburt führt zur Expansion des B-Zell-Kompartiments, welches eine sehr grosse Anzahl an verschiedenen Antikörpern produziert. Mikrobiota bezeichnet die Gesamtheit der Mikroorganismen, welche nach der Geburt die inneren und äusseren Körperoberflächen (z.B. Darm, Atemwege, Haut) von Säugetieren besiedeln. Da die Zusammensetzung der Mikrobiota sowohl von Tier zu Tier als auch innerhalb eines Tieres abhängig von Nahrung oder Infektionen über die Zeit hinweg schwankt, ist es wichtig zu verstehen, in wieweit sich dies im jeweiligen B-Zell-Repertoire des Individuums wiederspiegelt. Unser Ziel ist es mit Hilfe von Sequenzierung des B-Zell-Rezeptor-Gens als auch mit klassischen Affinitätsstudien, den Einfluss der Mikrobiota auf die Entwicklung des Antikörper-Repertoires zu verstehen. Insbesondere werden wir untersuchen wie die Besiedlung mit bestimmten kommensalen Bakterien im frühen Leben Einfluss auf das primäre Antikörperrepertoire nimmt und damit die Präsenz von Antikörpern spezifisch für Viren, Bakterien, Nahrungsbestandteile oder Selbstantigene bestimmt.
Unser Projekt wird zum Verständnis dessen beitragen wie bestimmte Bakterien der Mikrobiota das individuelle Präimmun-B-Zellrepertoire beeinflussen und damit nicht nur zum Wirt-Mikroben Mutualismus beisteuern, sondern auch die adaptive B-Zell-Immunantwort eines Individuums bestimmen.

Direct link to Lay Summary Last update: 05.04.2018

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
160262 Secretory IgA in host-microbial reciprocity 01.04.2015 Project funding (Div. I-III)

Abstract

Background and problem to be solved. We can now obtain unprecedented insight into the diversity and specificity of the B cell-derived immunoglobulin repertoire through high-throughput sequencing, and immune mechanisms that generate high affinity responses or tolerance have been well investigated. In contrast, the generation of the pre-immune primary repertoire and the reasons why this varies considerably between individuals are poorly understood. Animals become colonized with a microbiota in the intestine and on other body surfaces after birth, and this drives enormous expansion of the B cell compartment through antigen-specific and innate induction mechanisms. This microbiota varies qualitatively and quantitatively both from animal to animal, and over time through changes in diet and through infectious or non-infectious intestinal inflammation. How these differences in exposure to different taxa at different times shape an individual’s private immunoglobulin repertoire are not understood. This evolution of the primary repertoire needs to be characterised not only in terms of immunoglobulin sequence diversity, but also the functional portfolio of antigenic specificities and affinities bound by the main induced clonotypes.Aims. Our primary aims in this project are i) to use highly controlled sequences of transient colonization with different commensal intestinal microbes in post-weaning germ-free mice, to model how the primary repertoire is generated; and ii) to determine the binding and affinity of the main immunoglobulin clonotypes to bacterial, polyspecific, food or autoantigen targets that are induced as the microbial-induced repertoire is assembled. Secondary aims are iii) to appreciate how repertoire assembly is affected by subsequent polyclonal responses triggered by toxins or viruses; and iv) to relate specific microbiota-induced immunoglobulin clones to their functional role in preserving mucosal and systemic host-microbial mutualism.Feasibility and our distinct experimental approach. In preliminary experiments, we have discovered consistent B cell immunoglobulin repertoire signatures between replicate animals, induced by reversible dose-titrated bacterial colonization: these are distinct from the germ-free repertoire. This is oligoclonal (approximately 20 dominant clonotypes) but the oligoclonality is distinct, depending on the route of exposure, dose, and whether a toxin polyclonal response has been subsequently induced. This simplified situation allows us to address the private/public components of the immunoglobulin repertoire through high-throughput sequencing during its controlled evolution through state-of-the-art gnotobiology. Specific induction events will be characterised at different stages of B cell ontogeny and in different secondary lymphoid structures. These induced clonotypes from single cells will be expressed to define the monoclonal binding specificities and functional impact of individual induced immunoglobulins. This will link microbiota-related immunoglobulin sequences, structures, binding and whole animal functionality at unprecedented depth.Impact. Understanding the impact of defined taxa within the microbiota on the evolution of the primary immunoglobulin repertoire will address how personalized ‘preimmune’ (pre-infectious challenge) B cell adaptive immunity is established. The project will link the development of defined antigen binding repertoires to the trajectory and route of microbiota exposure to different taxa. It has the potential to tell us how mucosal and systemic priming events by the microbiota as an animal ages allow it to maintain functional host-microbial mutualism.
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