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Differences in innate immune response between man and mouseZschaler, Josefin, Schlorke, Denise, Arnhold, Jürgen 20 June 2016 (has links) (PDF)
Mouse strains are frequently used to model human disease states, to test the efficiency of drugs and therapeutic principles. However, the direct translation of murine experimental data to human pathological events often fails due to sufficient differences in the organization of the immune system of both species. Here we give a short overview of the principle differences between mice and humans in defense strategies against pathogens and mechanisms involved in response to pathogenic microorganisms and other activators of the immune system. While in human blood mechanisms of immune resistance are highly prevailed, tolerance mechanisms dominate for the defense against pathogenic microorganisms in mouse blood. Further on, species-related differences of immune cells mainly involved in innate immune response as well as differences to maintain oxidative homeostasis are also considered. A number of disease scenarios in mice are critically reflected for their suitability to serve as a model for human pathologies. Due to setbacks in these studies, novel mouse models were created to bridge the immune system of both species: humanized mice. Accordingly, a special section of this review is devoted to new results applying humanized mouse models taking limitations and prospects into account.
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Differences in innate immune response between man and mouseZschaler, Josefin, Schlorke, Denise, Arnhold, Jürgen January 2014 (has links)
Mouse strains are frequently used to model human disease states, to test the efficiency of drugs and therapeutic principles. However, the direct translation of murine experimental data to human pathological events often fails due to sufficient differences in the organization of the immune system of both species. Here we give a short overview of the principle differences between mice and humans in defense strategies against pathogens and mechanisms involved in response to pathogenic microorganisms and other activators of the immune system. While in human blood mechanisms of immune resistance are highly prevailed, tolerance mechanisms dominate for the defense against pathogenic microorganisms in mouse blood. Further on, species-related differences of immune cells mainly involved in innate immune response as well as differences to maintain oxidative homeostasis are also considered. A number of disease scenarios in mice are critically reflected for their suitability to serve as a model for human pathologies. Due to setbacks in these studies, novel mouse models were created to bridge the immune system of both species: humanized mice. Accordingly, a special section of this review is devoted to new results applying humanized mouse models taking limitations and prospects into account.
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T-bet and RORa control lymph node formation by regulating embryonic innate lymphoid cell differentiationStehle, Christina 10 December 2021 (has links)
Angeborene lymphoide Zellen (ILCs) bilden eine Familie von Effektorzellen des angeborenen Immunsystems, denen somatisch rekombinierte Antigenrezeptoren fehlen und die in drei Hauptgruppen eingeteilt werden. In der Embryonalentwicklung spielen Typ 3 ILCs, sogenannte LTi (Lymphoid Tissue inducer) Zellen, eine zentrale Rolle in der Entwicklung von Lymphknoten. ILC3, einschließlich LTi Zellen sind abhängig von dem Master-Transkriptionsfaktor RORgt, was sich in RORgt-defizienten Mäuse durch die Abwesenheit aller ILC3, und auch durch fehlende Lymphknoten äußert.
Während postnatale Ko-expression der Transkriptionsfaktoren T-bet und RORgt in ILC3-Subpopulationen fest etabliert ist, ist der Einfluss von T-bet in fötalen ILC3 und auf die Generation von Lymphknoten noch unbekannt.
Um diese Mechanismen genau zu untersuchen, wurden fötale ILCs mittels Einzelzell-RNA-Sequenzierung charakterisiert, wodurch eine unerwartete Heterogenität innerhalb der ILC3 mit T-bet-exprimierenden Zellen aufgedeckt wurde. Außerdem wurden PLZF+ ILC-Vorläufer (ILCP) im sich entwickelnden Darm nachgewiesen.
Weiterhin, bestätigen diverse Mausmodelle eine Schlüsselrolle für T bet in der Regulation der ILC-Differenzierung und der Entstehung von Lymphknoten. Die zusätzliche genetische Ablation von T-bet in RORgt-defizienten Mäusen beeinflusste Differenzierungsentscheidungen in fötalen ILCP und ermöglichte die Akkumulation von ILCP mit LTi-Aktivität, wodurch die Organogenese von Lymphknoten, unabhängig von RORgt wiederhergestellt wurde. PLZF+ ILCP von RORgt/T-bet-Doppeldefizienten Mäusen bestanden bis ins Erwachsenenalter, wo diese Zellen die Darmbarrierefunktionen durch Produktion von IL-22 wiederherstellten. Darüber hinaus erwies sich RORa als entscheidend für die Entwicklung von PLZF+ ILCP und die damit verbundene Bildung von Lymphknoten. / Innate lymphoid cells (ILCs) represent a family of innate effector cells lacking rearranged antigen receptors, which are classified into three main groups based on their lineage-specifying transcription factors (TF) and effector functions. During embryonic development, the formation of lymphoid organs critically relies on a specific member of group 3 innate lymphoid cells (ILC3), expressing the master transcription factor RORgt and exhibiting lymphoid tissue inducer (LTi) functions. Accordingly, RORgt-deficient mice lack ILC3 and do not generate lymph nodes (LN).
While it is established that T-bet is co-expressed with RORgt in a subset of ILC3 emerging postnatally and influencing their differentiation, phenotype and functions, the effect of T-bet on fetal ILC3 biology and its impact on LN generation remains completely unknown.
In order to study the role of T-bet in fetal ILC3 differentiation and functions as well as in LN formation, single-cell RNA sequencing and flow cytometry were applied to characterize fetal ILC subsets revealing an unanticipated heterogeneity within embryonic ILC3 and identifying T-bet+ ILC3 subsets within the fetal intestine and mesenteric LN anlage for the first time.
Furthermore, PLZF+ ILC progenitors (ILCP) were exposed in the developing mouse intestine.
Importantly, using multiple mouse models, a key role for T-bet in regulating ILC differentiation and LN formation was discovered. Specifically, additional deficiency of T-bet in RORgt-deficient mice skewed lineage fate decisions in differentiating fetal ILCP and allowed accumulation of ILCP with LTi activity, thereby rescuing LN organogenesis in a RORgt-independent fashion. PLZF+ ILCP of RORgt/T-bet double deficient mice persisted into adulthood where these cells restored intestinal barrier functions through reinstalled IL-22 production. Moreover, RORa was found to be critical for the development of PLZF+ ILCP and associated LN formation.
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