Optic neuritis is a common manifestation of multiple sclerosis, an inflammatory demyelinating disease of the CNS. Although it is the presenting symptom in many cases, the initial events are currently ...unknown. However, in the earliest stages of autoimmune optic neuritis in rats, pathological changes are already apparent such as microglial activation and disturbances in myelin ultrastructure of the optic nerves. αB‐crystallin is a heat‐shock protein induced in cells undergoing cellular stress and has been reported to be up‐regulated in both multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Therefore, we wished to investigate the timing and localization of its expression in autoimmune optic neuritis. Although loss of oligodendrocytes was not observed until the later disease stages accompanying immune cell infiltration and demyelination, an increase in oligodendrocyte αB‐crystallin was observed during the preclinical stages. This was most pronounced within the optic nerve head and was associated with areas of IgG deposition. Since treatment of isolated oligodendrocytes with sera from myelin oligodendrocyte glycoprotein (MOG)‐immunized animals induced an increase in αB‐crystallin expression, as did passive transfer of sera from MOG‐immunized animals to unimmunized recipients, we propose that the partially permeable blood–brain barrier of the optic nerve head may present an opportunity for blood‐borne components such as anti‐MOG antibodies to come into contact with oligodendrocytes as one of the earliest events in disease development.
Main Points
αB‐crystallin is upregulated by oligodendrocytes during onset of autoimmune optic 3 neuritis.
Expression is greatest in optic nerve head and associated with IgG deposition.
Upregulation induced by EAE sera is dependent on anti‐MOG antibodies.
Proteolipid protein (PLP) is the most abundant integral membrane protein in central nervous system (CNS) myelin. Expression of the Plp‐gene in oligodendrocytes is not essential for the biosynthesis ...of myelin membranes but required to prevent axonal pathology. This raises the question whether the exceptionally high level of PLP in myelin is required later in life, or whether high‐level PLP expression becomes dispensable once myelin has been assembled. Both models require a better understanding of the turnover of PLP in myelin in vivo. Thus, we generated and characterized a novel line of tamoxifen‐inducible Plp‐mutant mice that allowed us to determine the rate of PLP turnover after developmental myelination has been completed, and to assess the possible impact of gradually decreasing amounts of PLP for myelin and axonal integrity. We found that 6 months after targeting the Plp‐gene the abundance of PLP in CNS myelin was about halved, probably reflecting that myelin is slowly turned over in the adult brain. Importantly, this reduction by 50% was sufficient to cause the entire spectrum of neuropathological changes previously associated with the developmental lack of PLP, including myelin outfoldings, lamellae splittings, and axonal spheroids. In comparison to axonopathy and gliosis, the infiltration of cytotoxic T‐cells was temporally delayed, suggesting a corresponding chronology also in the genetic disorders of PLP‐deficiency. High‐level abundance of PLP in myelin throughout adult life emerges as a requirement for the preservation of white matter integrity.
Main Points
The SPG2 disease gene Plp is deleted in adult mice.
Abundance of PLP in CNS myelin is halved 6 months later, reflecting its slow turnover. This suffices to impair myelin and axon integrity.
High PLP‐content of myelin is subject to selective pressure.
Background. The adaptive immune system has been considered to play a minimal role in the early host response during bacterial meningitis. Methods. We investigated the progression and outcome of ...pneumococcal meningitis in Ragl-/- mice lacking functional B and T cells by assessing overall and symptom-free survival, bacteriological and histological studies, as well as flow cytometry and measurements of proinflammatory mediators. Results. The intracerebral injection of S. pneumoniae D39 induced the recruitment of B and T cells (CD4⁺, γδ and natural killer) into the brain of wild-type mice. Mice with no functional B and T cells developed clinical symptoms and succumbed to the infection earlier than the wild-type group. In the CNS, Ragl-/- mice showed lower levels of interleukin 1β, reduced microglial proliferation, and impaired granulocyte recruitment with an earlier spread of pneumococci into the bloodstream, compared with wild-type mice. Lack of B and T cells resulted in a severe impairment of bacterial clearance in blood, spleen, and liver and an exaggerated systemic inflammatory response. Conclusions. B and T cells are important effector cells delaying the spread of pneumococci from the brain to the systemic circulation and shaping the immune response, thereby prolonging the survival of the host in the absence of antibiotic treatment.
Antidepressants are known to impact on the immune system. In this study, we examined the immunomodulatory properties of venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor (SNRI), in ...murine experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated CNS demyelinating disease model of multiple sclerosis. EAE was induced in SJL/J mice by adoptive transfer of myelin-specific T cells. Mice received different doses of venlafaxine before induction and after onset of disease. Sustained daily oral treatment with 6, 20 and 60 mg/kg significantly ameliorated the clinical symptoms of the disease compared to vehicle during both preventive and therapeutic intervention. Venlafaxine suppressed the generation of pro-inflammatory cytokines IL-12 p40, TNF-α and IFN-γ in encephalitogenic T-cell clones, splenocytes and peritoneal macrophages in vitro. It also diminished mRNA expression of a number of inflammatory genes in the inflamed CNS tissue, among them CD3, CD8, Granzyme B, IL-12 p40, IFN-γ, TNF-α and the chemokines Ccl2 and RANTES, whereas the expression of brain-derived neurotrophic factor was increased. These findings demonstrate the strong immunomodulatory property of the selective SNRI venlafaxine. Further studies are warranted to clarify whether venlafaxine may exert similar effects in humans.
Die Blumenuhr Inga Hilke Desch; Stefan Nessler; Dorothee Beez ...
Herausforderung Lehrer*innenbildung,
01/2020, Letnik:
3, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Vorgestellt wird eine 90-minütige Einführungssitzung in die Botanik mit Bezügen zu Chronobiologie, Evolution und Zoologie. Die Sitzung zeichnet sich durch einen hohen Eigenanteil der Studierenden ...aus, in dem diese mit Hilfe von rätselartigen, authentischen Problemstellungen botanische Grundkonzepte (Blattaufbau, Blütenaufbau, Wind- und Tierbestäubung) erarbeiten. Die bisherigen Erfahrungen bei der Durchführung der Einführungssitzung haben gezeigt, dass ein zumeist eher als uninteressant wahrgenommenes Thema in einem interessanten, authentischen und autonomieförderlichen Rahmen zu „verstecken“ möglich ist: Die Blumenuhr von Carl von Linné wirft die Fragen auf, woher Pflanzen wissen, wie spät es ist und wieso sich manche Blüten zu verschiedenen Zeiten öffnen und schließen. Der ersten Frage wird in einem kurzen Vortrag nachgegangen, in diesem werden auch die aktuellen Erkenntnisse zur Inneren Uhr von Drosophila (Nobelpreis 2017) vorgestellt, sowie die Unterschiede zwischen der Inneren Uhr und einer lichtinduzierten Reaktion bei Pflanzen. In der Gruppenarbeitsphase assistieren die Studierenden einem (ausgedachten) Schüler von Carl von Linné bei der Prüfung neuer Pflanzen für die Blumenuhr und erfahren so, dass das Öffnen und Schließen zu bestimmten Zeiten koevolutive Gründe hat, wieso sich hierfür keine windbestäubten Blüten eignen, was die Blüte überhaupt ist und wie der basale Bauplan der Pflanzen aussieht.
Prophylaxis with unmethylated cytosine phosphate guanidine (CpG) oligodeoxynucleotides (ODN) protects against several systemic experimental infections. Escherichia coli is a major cause of ...Gram-negative neonatal bacterial meningitis and also causes meningitis and meningoencephalitis in older and immunocompromised patients.
Wild-type (wt) and Toll-like receptor 9 (TLR9)-deficient mice were rendered neutropenic by intraperitoneal administration of the anti-Ly-6G monoclonal antibody. Immunocompetent and neutropenic mice received intraperitoneal CpG ODN or vehicle 72 h prior to induction of E. coli K1 meningoencephalitis.
Pre-treatment with CpG ODN significantly increased survival of neutropenic wt mice from 33% to 75% (P = 0.0003) but did not protect neutropenic TLR9-/- mice. The protective effect of CpG ODN was associated with an enhanced production of interleukin (IL)-12/IL-23p40 with sustained increased levels in serum and spleen at least for 17 days after conditioning compared to buffer-treated animals. CpG-treated neutropenic wt mice showed reduced bacterial concentrations and increased recruitment of Ly6ChighCCR2+ monocytes in brain and spleen 42 h after infection. The levels of macrophage inflammatory protein 1α (MIP-1α) and interferon gamma (IFN-γ) in spleen were higher 42 h after infection in CpG-treated compared to buffer-treated neutropenic animals. In immunocompetent mice, prophylaxis with CpG ODN did not significantly increase survival compared to the buffer group (60% vs. 45%, P = 0.2).
These findings suggest that systemic administration of CpG ODN may help to prevent bacterial CNS infections in immunocompromised individuals.
Active immunization with amyloid-β (Aβ) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, this ...treatment may also cause severe, life-threatening meningoencephalitis. Physiological responses to immunization with Aβ(1-42) are poorly understood. In this study, we characterized cognitive and immunological consequences of Aβ(1-42)/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55)/CFA or CFA alone, Aβ(1-42)/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Aβ(1-42)/CFA-immunized animals. In contrast to MOG(35-55)/CFA and PBS/CFA controls, the majority of infiltrating cells in Aβ(1-42)/CFA-immunized mice were CD11b(+)CD14(+) and CD45(high), indicating their blood-borne monocyte/macrophage origin. Immunization with Aβ(1-42)/CFA was significantly more potent than immunization with MOG(35-55)/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4-deficient mice revealed that the TLR2/4 pathway mediated the Aβ(1-42)-dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Aβ(1-42)/CFA. Thus, this study identifies adjuvant effects of Aβ(1-42), which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Aβ immunotherapy.
Abstract Here we demonstrate that miRNA regulation in marmoset ( Callithrix jacchus ) and C57/BL6 mouse EAE lesions largely resembles miRNA regulation in active human MS lesions. Detailed ...quantitative PCR analyses of the most up- and downregulated miRNAs of active human MS lesions in dissected lesions from marmoset EAE brains and inflamed spinal cords of EAE mice revealed that the conserved and highly regulated miRNAs, miRNA-155, miRNA-142-3p, miRNA-146a, miRNA-146b and miRNA-21, turned out to be similarly upregulated in marmoset and mouse EAE lesions.
PDF
