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  • 1
    Online Resource
    Online Resource
    The Royal Society ; 2021
    In:  Open Biology Vol. 11, No. 2 ( 2021-02)
    In: Open Biology, The Royal Society, Vol. 11, No. 2 ( 2021-02)
    Abstract: In vertebrates, the development of lymphocytes from undifferentiated haematopoietic precursors takes place in so-called primary lymphoid organs, such as the thymus. Therein, lymphocytes undergo a complex differentiation and selection process that culminates in the generation of a pool of mature T cells that collectively express a self-tolerant repertoire of somatically diversified antigen receptors. Throughout this entire process, the microenvironment of the thymus in large parts dictates the sequence and outcome of the lymphopoietic activity. In vertebrates, direct genetic evidence in some species and circumstantial evidence in others suggest that the formation of a functional thymic microenvironment is controlled by members of the Foxn1/4 family of transcription factors. In teleost fishes, both Foxn1 and Foxn4 contribute to thymopoietic activity, whereas Foxn1 is both necessary and sufficient in the mammalian thymus. The evolutionary history of Foxn1/4 genes suggests that an ancient Foxn4 gene lineage gave rise to the Foxn1 genes in early vertebrates, raising the question of the thymopoietic capacity of the ancestor common to all vertebrates. Recent attempts to reconstruct the early events in the evolution of thymopoietic tissues by replacement of the mouse Foxn1 gene by Foxn1 -like genes isolated from various chordate species suggest a plausible scenario. It appears that the primordial thymus was a bi-potent lymphoid organ, supporting both B cell and T cell development; however, during the course of vertebrate, evolution B cell development was gradually diminished converting the thymus into a site specialized in T cell development.
    Type of Medium: Online Resource
    ISSN: 2046-2441
    Language: English
    Publisher: The Royal Society
    Publication Date: 2021
    detail.hit.zdb_id: 2630944-0
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  • 2
    In: European Journal of Immunology, Wiley, Vol. 44, No. 10 ( 2014-10), p. 2893-2902
    Abstract: Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8–12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4 + T‐cell dependent, since old (40–50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age‐related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4 + T cells that promote ANA production were radioresistant. Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T‐cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T‐cell homeostasis may drive the onset of some autoimmune features.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1491907-2
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  • 3
    In: European Journal of Immunology, Wiley, Vol. 44, No. 5 ( 2014-05), p. 1299-1312
    Abstract: Autoimmune diseases develop when self‐specific T cells that escaped negative selection initiate a harmful immune response against self. However, factors, which influence the initiation and progression of an autoimmune response remain incompletely understood. By establishing a double‐transgenic BALB/c mouse system in which different amounts of a cell‐surface neo‐self‐antigen are expressed under the CD11c promoter, we demonstrate that antigen dose dramatically influences T‐cell tolerance mechanisms. Moderate antigen expression in both hematopoietic and nonhematopoietic cells favors the development of antigen‐specific Treg cells and the establishment of a tolerogenic environment. In marked contrast, a high dose of antigen expression results in very stringent negative selection, in poor development of antigen‐specific Treg cells and in the early onset of anemia and splenomegaly and the late development of arthritis and high titers of IgG auto Abs. Disease is initiated by autoreactive T cells, which escape negative selection by expressing a second TCR with a different specificity or an altered affinity. Transfer of Ag‐specific Treg cells ameliorates the early onset signs of disease but does not prevent the development of long‐term chronic pathologies. Altogether, our results suggest that Ag dose directly affects Treg‐cell generation and thus, the set‐up of T‐cell tolerance.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1491907-2
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  • 4
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-07-23)
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-07-23)
    Abstract: The numbers of thymic epithelial cells (TECs) and thymocytes steadily increase during embryogenesis. To examine this dynamic, we generated several TEC-specific transgenic mouse lines, which express fluorescent proteins in the nucleus, the cytosol and in the membranes under the control of the Foxn1 promoter. These tools enabled us to determine TEC numbers in tissue sections by confocal fluorescent microscopy, and in the intact organ by light-sheet microscopy. Compared to histological procedures, flow cytometric analysis of thymic cellularity is shown to underestimate the numbers of TECs by one order of magnitude; using enzymatic digestion of thymic tissue, the loss of cortical TECs (cTECs) is several fold greater than that of medullary TECs (mTECs), although different cTEC subsets appear to be still present in the final preparation. Novel reporter lines driven by Psmb11 and Prss16 promoters revealed the trajectory of differentiation of cTEC-like cells, and, owing to the additional facility of conditional cell ablation, allowed us to follow the recovery of such cells after their depletion during embryogenesis. Multiparametric histological analyses indicate that the new transgenic reporter lines not only reveal the unique morphologies of different TEC subsets, but are also conducive to the analysis of the complex cellular interactions in the thymus.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 5
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2022
    In:  Nature Vol. 606, No. 7912 ( 2022-06-02), p. 165-171
    In: Nature, Springer Science and Business Media LLC, Vol. 606, No. 7912 ( 2022-06-02), p. 165-171
    Abstract: T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age 1–10 . Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice 11–18 ; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved 1,12,16,17,19–27 . Here we combine scRNA-seq and a new CRISPR–Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    RVK:
    RVK:
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 6
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Advances Vol. 6, No. 48 ( 2020-11-27)
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 6, No. 48 ( 2020-11-27)
    Abstract: The onset of lymphocyte development in the vertebrate primordial thymus, about 500 million years ago, represents one of the foundational events of the emerging adaptive immune system. Here, we retrace the evolutionary trajectory of thymopoiesis, from early vertebrates to mammals, guided by members of the Foxn1/4 transcription factor gene family, which direct the differentiation of the thymic microenvironment. Molecular engineering in transgenic mice recapitulated a gene duplication event, exon replacements, and altered expression patterns. These changes predictably modified the lymphopoietic characteristics of the thymus, identifying molecular features contributing to conversion of a primordial bipotent lymphoid organ to a tissue specializing in T cell development. The phylogenetic reconstruction associates increasing efficiency of T cell generation with diminishing B cell–generating capacity of the thymus during jawed vertebrate evolution.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
    detail.hit.zdb_id: 2810933-8
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  • 7
    In: European Journal of Immunology, Wiley, Vol. 45, No. 3 ( 2015-03), p. 932-942
    Abstract: T‐cell lymphopenia following BM transplantation or diseases such as AIDS result in immunodeficiency. Novel approaches to ameliorate this situation are urgently required. Herein, we describe a novel stromal cell free culture system in which Lineage − Sca1 + c‐kit + BM hematopoietic progenitors very efficiently differentiate into pro‐T cells. This culture system consists of plate‐bound Delta‐like 4 Notch ligand and the cytokines SCF and IL‐7. The pro‐T cells developing in these cultures express CD25, CD117, and partially CD44; express cytoplasmic CD3ε; and have their TCRβ locus partially D–J rearranged. They could be expanded for over 3 months and used to reconstitute the T‐cell compartments of sublethally irradiated T‐cell‐deficient CD3ε −/− mice or lethally irradiated WT mice. Pro‐T cells generated in this system could partially correct the T‐cell lymphopenia of pre‐Tα −/− mice. However, reconstituted CD3ε −/− mice suffered from a wasting disease that was prevented by co‐injection of purified CD4 + CD25 high WT Treg cells. In a T‐cell‐sufficient or T‐lymphopenic setting, the development of disease was not observed. Thus, this in vitro culture system represents a powerful tool to generate large numbers of pro‐T cells for transplantation and possibly with clinical applications.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1491907-2
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  • 8
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2022
    In:  Communications Biology Vol. 5, No. 1 ( 2022-09-29)
    In: Communications Biology, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2022-09-29)
    Abstract: Few human tumours present with a recurrent pathognomonic mutation in a transcription factor. Thymomas are an exception, with the majority of some subtypes exhibiting a distinct somatically acquired missense mutation in the general transcription factor GTF2I. Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity. Phenotypic and molecular characterization of the mutant epithelium indicates that medullary differentiation is particularly affected as a result of impaired differentiation of bi-potent epithelial progenitors. The resulting gene expression signature is dominated by that of immature cortex-like thymic epithelial cells. TCR repertoire analysis of the cytopenic T cell compartment indicates efficient intrathymic selection; hence, despite marked homeostatic proliferation of T cell clones, autoimmunity is not observed. Thus, our transgenic mouse model recapitulates some aspects of the pathophysiology of a genetically defined type of human thymoma.
    Type of Medium: Online Resource
    ISSN: 2399-3642
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2919698-X
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  • 9
    Online Resource
    Online Resource
    American Chemical Society (ACS) ; 2014
    In:  Bioconjugate Chemistry Vol. 25, No. 5 ( 2014-05-21), p. 879-887
    In: Bioconjugate Chemistry, American Chemical Society (ACS), Vol. 25, No. 5 ( 2014-05-21), p. 879-887
    Type of Medium: Online Resource
    ISSN: 1043-1802 , 1520-4812
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2014
    detail.hit.zdb_id: 1500067-9
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  • 10
    In: BMC Musculoskeletal Disorders, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2021-12)
    Abstract: Total hip arthroplasty (THA) is an effective procedure for patients with end-stage hip osteoarthritis. However, whether or not pre-operatively existing functional deficits are persisting several years post-surgery in the affected limb has not been thoroughly researched. Therefore, the primary aim of this preliminary study was to include patients four to five years after undergoing THA and to investigate potential differences between the operated and non-operated leg in hip strength, range of motion (ROM), balance, and gait. The secondary aim was to compare these values from the operated leg of the patients to those of the legs of healthy subjects. Methods Sixteen patients (age: 65.20 ± 5.32 years) following unilateral THA (post-operation time: 4.7 ± 0.7 years) and ten, healthy, age-matched control subjects (age: 60.85 ± 7.57 years) were examined for maximum isometric hip muscle strength, active ROM of the hip joint, balance and gait on both limbs. Paired t-tests were used to assess the inter-limb differences in the THA group. Analyses of covariance (ANCOVA) were performed to compare groups, using age as a covariate. Results The analysis of inter-limb differences in patients following THA revealed significant deficits on the operated side for hip abduction strength ( p  = 0.02), for hip flexion ROM ( p   〈  0.01) and for balance in terms of the length of center of pressure (COP) ( p  = 0.04). Compared to values of the control subjects, the patients demonstrated significantly reduced hip strength in flexion, extension and abduction ( p   〈  0.05) on the operated leg as well as reduced ROM measures in hip flexion, extension and abduction ( p   〈  0.05). Conclusions The first results of this explorative study indicated that inter-limb differences as well as reduced hip strength and hip ROM compared with control subjects were still present four to five years after THA. These persisting asymmetries and deficits in patients following THA may be one explanation for the decrease in health-related quality of life (HRQoL) seen in patients over the years after surgery. Further studies are required to replicate these findings with a larger sample size. Trial registration DRKS, DRKS00016945. Registered 12 March 2019 – Retrospectively registered,
    Type of Medium: Online Resource
    ISSN: 1471-2474
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2041355-5
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