@phdthesis{Yuan2023,
  author    = {Yuan, Xidi},
  title     = {Aging and inflammation in the peripheral nervous system},
  doi       = {10.25972/OPUS-23737},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237378},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Aging is known to be a risk factor for structural abnormalities and functional decline in the nervous system. Characterizing age-related changes is important to identify putative pathways to overcome deleterious effects and improve life quality for the elderly. In this study, the peripheral nervous system of 24-month-old aged C57BL/6 mice has been investigated and compared to 12-month-old adult mice. Aged mice showed pathological alterations in their peripheral nerves similar to nerve biopsies from elderly human individuals, with nerve fibers showing demyelination and axonal damage. Such changes were lacking in nerves of adult 12-month-old mice and adult, non-aged humans. Moreover, neuromuscular junctions of 24-month-old mice showed increased denervation compared to adult mice. These alterations were accompanied by elevated numbers of macrophages in the peripheral nerves of aged mice. The neuroinflammatory conditions were associated with impaired myelin integrity and with a decline of nerve conduction properties and muscle strength in aged mice. To determine the pathological impact of macrophages in the aging mice, macrophage depletion was performed in mice by oral administration of CSF-1R specific kinase (c-FMS) inhibitor PLX5622 (300 mg/kg body weight), which reduced the number of macrophages in the peripheral nerves by 70\%. The treated mice showed attenuated demyelination, less muscle denervation and preserved muscle strength. This indicates that macrophage-driven inflammation in the peripheral nerves is partially responsible for the age-related neuropathy in mice. Based on previous observations that systemic inflammation can accelerate disease progression in mouse models of neurodegenerative diseases, it was hypothesized that systemic inflammation can exacerbate the peripheral neuropathy found in aged mice. To investigate this hypothesis, aged C57BL/6 mice were intraperitoneally injected with a single dose of lipopolysaccharide (LPS; 500 μg/kg body weight) to induce systemic inflammation by mimicking bacterial infection, mostly via activation of Toll-like receptors (TLRs). Altered endoneurial macrophage activation, highlighted by Trem2 downregulation, was found in LPS injected aged mice one month after injection. This was accompanied by a so far rarely observed form of axonal perturbation, i.e., the occurrence of "dark axons" characterized by a damaged cytoskeleton and an increased overall electron density of the axoplasm. At the same time, however, LPS injection reduced demyelination and muscle denervation in aged mice. Interestingly, TREM2 deficiency in aged mice led to similar changes to LPS injection. This suggests that LPS injection likely mitigates aging-related demyelination and muscle denervation via Trem2 downregulation. Taken together, this study reveals the role of macrophage-driven inflammation as a pathogenic mediator in age-related peripheral neuropathy, and that targeting macrophages might be an option to mitigate peripheral neuropathies in aging individuals. Furthermore, this study shows that systemic inflammation may be an ambivalent modifier of age-related nerve damage, leading to a distinct type of axonal perturbation, but in addition to functionally counteracting, dampened demyelination and muscle denervation. Translationally, it is plausible to assume that tipping the balance of macrophage polarization to one direction or the other may determine the functional outcome in the aging peripheral nervous system of the elderly.},
  subject      = {Maus},
  language  = {en}
}
@phdthesis{Schreiber2019,
  author    = {Schreiber, David Lukas},
  title     = {CSF-1-Rezeptor Inhibitor als Therapieansatz in Mausmodellen f{\"u}r Charcot-Marie-Tooth Neuropathien Typ 1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174931},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Charcot-Marie-Tooth Neuropathien sind die h{\"a}ufigsten heredit{\"a}ren Erkrankungen des peripheren Nervensystems und dennoch bis heute nicht therapierbar. Die Lebensqualit{\"a}t der Patienten ist durch motorische und sensorische Defizite der Extremit{\"a}ten h{\"a}ufig stark eingeschr{\"a}nkt. Ursache k{\"o}nnen unter anderem Mutationen in Schwann-Zellen sein, die zu dem typischen Bild von Demyelinisierung und axonalem Schaden f{\"u}hren. In den letzten Jahren konnte in Mausmodellen das Immunsystem als wichtiger Mediator in der Pathogenese der CMT 1 Subtypen A, B und X identifiziert werden. Insbesondere Makrophagen spielen eine tragende Rolle bei dem Verlust der axonalen Integrit{\"a}t, bei der Sch{\"a}digung der Myelinscheiden, sowie bei der Dedifferenzierung von Schwann-Zellen. Entscheidender Faktor f{\"u}r Proliferation und Aktivierung der Makrophagen ist hierbei das Zytokin CSF-1, dessen korrespondierender Rezeptor auf Makrophagen exprimiert wird. Der CSF-1/CSF1R Signalweg bietet somit einen vielversprechenden Angriffspunkt. In der vorliegenden Arbeit wurden Mausmodelle der CMT 1 Subtypen A, B und X mit einem niedermolekularen CSF-1-Rezeptor Inhibitor behandelt. Anschließend erfolgte eine funktionelle und strukturelle Auswertung der peripheren Nerven. Das beste Ansprechen auf die Therapie zeigten Cx32def Mutanten. Strukturell fielen ein verringerter axonaler Schaden und eine verbesserte axonale Regenerationsf{\"a}higkeit sowie erhaltene neuromuskul{\"a}re Synapsen auf. Funktionell {\"a}ußerte sich dies in verbesserten elektrophysiologischen Parametern und einem Krafterhalt, welcher als klinischer Parameter die gr{\"o}ßte Relevanz f{\"u}r betroffene Patienten hat und somit besonders hervorzuheben ist. Auch P0het Mutanten zeigten Verbesserungen nach der CSF1RI Behandlung. Anders als bei Cx32def Tieren zeigte sich hier jedoch vor allem ein Erhalt der Myelinintegrit{\"a}t. Weiterhin wirkte sich die Therapie positiv auf elektrophysiologische Parameter und Krafttests aus. Vor allem besonders stark betroffene Individuen schienen hierbei von der CSF1RI Behandlung zu profitieren. Bei PMP22tg Mutanten hingegen konnten keine positiven Effekte der CSF1RI Behandlung nachgewiesen werden. Strukturelle und funktionelle Parameter behandelter Tiere unterschieden sich nicht von unbehandelten. Diese Ergebnisse unterstreichen die Relevanz der sekund{\"a}ren Entz{\"u}ndungsreaktion in CMT 1 Neuropathien als wichtigen Mediator in der Pathogenese. Weiterhin konnte gezeigt werden, dass eine Intervention im CSF-1/CSF1R Signalweg einen vielversprechenden m{\"o}glichen Ansatz f{\"u}r die Therapie der bisher nicht behandelbaren CMT 1 Subypen X und B darstellt. Unausweichlich ist hierbei ein m{\"o}glichst fr{\"u}her Therapiestart vor Auspr{\"a}gung der ersten molekularen und histologischen Ver{\"a}nderungen. Im Hinblick auf die nicht die Lebenserwartung reduzierende Erkrankung muss ferner eine Minimierung der Nebenwirkungen der Therapie gew{\"a}hrleistet sein. Besonders hervorzuheben ist hier die Verwendung eines Inhibitors, welcher nicht in das zentrale Nervensystem vordringen kann und somit die Funktion der Mikroglia nicht beeintr{\"a}chtigt.},
  subject      = {CSF-1},
  language  = {de}
}
@phdthesis{Klein2015,
  author    = {Klein, Dennis},
  title     = {The pathogenic role of endogenous antibodies in a mouse model for Charcot-Marie-Tooth 1B neuropathy},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121941},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2015},
  abstract  = {Charcot-Marie-Tooth (CMT) type 1 neuropathies are a genetically heterogeneous group of non-treatable inherited disorders affecting the peripheral nervous system that lead to sensory and motor dysfunction. Secondary low grade inflammation, implicating the innate and adaptive immune system, could previously be identified as a substantial disease modifier in two mouse models for CMT1, CMT1B and 1X, respectively. However, the exact mechanism how the adaptive immune system contributes to disease pathogenesis is not completely understood. Based on observations that the accumulation of endogenous antibodies to myelin components is important for rapid myelin clearance after nerve injury during Wallerian degeneration, a possibly similar mechanism was considered for endogenous antibodies as disease amplifier in mice heterozygously deficient for P0 (P0het), mimicking some typical features of CMT1B. In this study an increased antibody deposition was detected in the affected peripheral nerves of P0het myelin mutant mice. By crossbreeding P0het mutants with mice specifically lacking B-lymphocytes, and therefore antibodies (JHD-/-), a decline of endoneurial macrophages together with a substantially ameliorated demyelination could be demonstrated in 6-month-old mutant mice. Moreover, reconstitution with murine IgGs reverted the neuropathic phenotype, substantiating that endogenous antibodies are potentially pathogenic at this early stage of disease. Unexpectedly, in 12-months-old P0het mutants, JHD deficiency resulted in disease aggravation accompanied by an increased inflammatory reaction and M2-polarized macrophage response. These observations suggest that in a mouse model for CMT1B, the lack of endogenous antibodies has a dichotomous effect: ameliorating early macrophage-mediated demyelination, as opposed to increasing inflammatory reactions leading to disease aggravation at older ages.},
  subject      = {Maus},
  language  = {en}
}
@phdthesis{Schwab2009,
  author    = {Schwab, Nicholas},
  title     = {The importance of CD8\(^+\) T cells and antigen-presenting cells in the immune reaction of primary inflammatory versus degenerative diseases},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-37330},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {The bidirectional influence of parenchymal cells and cells of the immune system, especially of antigen-presenting and CD8\(^+\) T cells, in situations of putative auto- immune pathogenicity and degeneration was the main topic of this thesis. In the first part, the influence of human muscle cells on antigen-presenting cells was investigated. In inflammatory myopathies prominent infiltrates of immune cells containing T cells and antigen-presenting cells like macrophages and dendritic cells are present. The hypothesis was that human myoblasts have an inhibiting influence on these antigen-presenting cells under homeostatic conditions. A dysfunction or impairment under inflammatory circumstances might contribute to the development of myopathic conditions. The surface analysis of dendritic cells cocultured with myoblasts showed that immature dendritic cells could be driven into a reversible semi- mature state with significantly elevated levels of CD80. These dendritic cells were additionally characterized by their inhibiting function on T-cell proliferation. It was also shown that the lysates of healthy myoblasts could strongly enhance the phagocytic ability of macrophages, which could help with muscle regeneration and which might be disturbed in myositis patients. The second part of this thesis was about the clonal specificity of CD8\(^+\) T cells in a mouse model with genetically induced over-expression of PLP in oligodendrocytes. Here, we could show that the cytotoxic T lymphocytes, which had previously been shown to be pathogenic, were clonally expanded in the CNS of the transgenic mice. The amino acid sequences of the corresponding receptor chains were not identical, yet showed some similarities, which could mean that these clones recognize similar antigens (or epitopes of the same antigen). The knockout of PD-1 in this setting allowed for an analysis of the importance of tissue immune regulation. It became evident that the absence of PD-1 induced a larger number of clonal expansions in the CNS, hinting towards a reduced threshold for clonal disturbance and activation in these T cells. The expansions were, however, not pathogenic by themselves. Only in the presence of tissue damage and an antigenic stimulus (in our case the overexpression of PLP), the PD-1 limitation exacerbated the immune pathogenicity. Therefore, only in the presence of a "tissue damage signal", the dyshomeostasis of T cells lacking PD-1 achieved high pathogenetic relevance. Finally, we investigated the pathogenetic role of CD8 T cells in Rasmussen encephalitis, a rare and chronic neurological disease mainly affecting children. The analysis of the T-cell receptor repertoire in Rasmussen encephalitis patients in the peripheral CD4\(^+\) and CD8\(^+\) T-cell compartments as well as the brain revealed the involvement of T cells in the pathogenicity of this disease. Many clonal expansions in the brain matched CD8\(^+\) T-cell expansions in the periphery on the sequence level. These putatively pathogenic clones could be visualized by immunohistochemistry in the brain and were found in close proximity to astrocytes and neurons. Additionally, the expanded clones could be found in the periphery of patients for at least one year.},
  subject      = {T-Lymphozyt},
  language  = {en}
}