Locatelli, G. et al. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nature Neurosci. 543-550

Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
Nature Neuroscience (Impact Factor: 16.1). 02/2012; 15(4):543-50. DOI: 10.1038/nn.3062
Source: PubMed


Anti-myelin immunity is commonly thought to drive multiple sclerosis, yet the initial trigger of this autoreactivity remains elusive. One of the proposed factors for initiating this disease is the primary death of oligodendrocytes. To specifically test such oligodendrocyte death as a trigger for anti-CNS immunity, we inducibly killed oligodendrocytes in an in vivo mouse model. Strong microglia-macrophage activation followed oligodendrocyte death, and myelin components in draining lymph nodes made CNS antigens available to lymphocytes. However, even conditions favoring autoimmunity-bystander activation, removal of regulatory T cells, presence of myelin-reactive T cells and application of demyelinating antibodies-did not result in the development of CNS inflammation after oligodendrocyte death. In addition, this lack of reactivity was not mediated by enhanced myelin-specific tolerance. Thus, in contrast with previously reported impairments of oligodendrocyte physiology, diffuse oligodendrocyte death alone or in conjunction with immune activation does not trigger anti-CNS immunity.

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    • "The numbers of Th 1 and Th 17 cells in peripheral lymphoid organs are unaltered, and the transfer of isolated splenocytes from Cupexposed animals to recipient mice does not result in immunemediated CNS inflammation. These results are in line with previous data presented byLocatelli et al. (2012). They showed that, even in a strong proinflammatory experimental setting, myelin antigens in CNS-draining lymph nodes failed to initiate anti- CNS immunity. "
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    ABSTRACT: we identify neurodegeneration as a potent trigger for peripheralimmunecell recruitment into the mouse forebrain. Female C57BL/6 mice were fed cuprizone for 3 weeks, followed by a period of 2 weeks on normal chow to induce the formation of lesion foci in the forebrain. Subsequent immunization with myelin oligodendrocyte glycoprotein 35–55 peptide, which induces myelin autoreactive T cells in the periphery, resulted in massive immune cell recruitment into the affected forebrain. Additional adoptive transfer experiments together with flow cytometry analysis underline the importance of brain-derived signals forimmunecell recruitment. This study clearly illustrates the significance of brain-intrinsic degenerative cascades for immune cell recruitment and MS lesion formation. Additional studies have to address the signaling cascades and mechanistic processes that form the top-down communication between the affected brain area, neurovascular unit, and peripheral immune cells.
    Full-text · Article · Dec 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "Transmission electron microscopy was performed as previously described (Locatelli et al., 2012). "
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    ABSTRACT: Although the importance of reactive astrocytes during CNS pathology is well established, the function of astroglia in adult CNS homeostasis is less well understood. With the use of conditional, astrocyte-restricted protein synthesis termination, we found that selective paralysis of GFAP(+) astrocytes in vivo led to rapid neuronal cell loss and severe motor deficits. This occurred while structural astroglial support still persisted and in the absence of any major microvascular damage. Whereas loss of astrocyte function did lead to microglial activation, this had no impact on the neuronal loss and clinical decline. Neuronal injury was caused by oxidative stress resulting from the reduced redox scavenging capability of dysfunctional astrocytes and could be prevented by the in vivo treatment with scavengers of reactive oxygen and nitrogen species (ROS/RNS). Our results suggest that the subpopulation of GFAP(+) astrocytes maintain neuronal health by controlling redox homeostasis in the adult CNS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell Reports
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    • "Alternatively, there are underlying signals from degenerating neurons and axons that cause T cell infiltration , which are therefore due to secondary axonal loss in myelin mutant mice. Among different models, the variability of axonal involvement differs and perturbations of myelin function (in Plp1 transgenic mice) may be more detrimental to axon survival than transient demyelination induced by diphtheria toxin ( Traka et al., 2010 ; Pohl et al., 2011 ; Locatelli et al., 2012 ). We note that, in contrast to oligodendrocytes, that the genetic ablation of adult hippocampal neurons in transgenic mice with an inducible diphtheria toxin gene causes significant infiltration of T cells ( Agarwal et al., 2012 ). "
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    ABSTRACT: Abstract Myelinating cells wrap axons with multilayered myelin sheaths for rapid impulse propagation. Dysfunctions of oligodendrocytes or Schwann cells are often associated with neuroinflammation, as observed in animal models of leukodystrophies and peripheral neuropathies, respectively. The neuroinflammatory response modulates the pathological changes, including demyelination and axonal injury, but also remyelination and repair. Here we discuss different immune mechanisms as well as factors released or exposed by myelinating glia in disease conditions. The spectrum of inflammatory mediators varies with different myelin disorders and has a major impact on the beneficial or detrimental role of immune cells in nervous system integrity.
    Full-text · Article · Aug 2013 · Biological Chemistry
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