Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss? (original) (raw)

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11 Institute of Experimental Immunology, University Hospital Zurich, Zurich 8044, Switzerland

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22 Department of Neurology, Inselspital, University Hospital Berne, University Berne, Berne 3010, Switzerland

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33 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland

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11 Institute of Experimental Immunology, University Hospital Zurich, Zurich 8044, Switzerland

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11 Institute of Experimental Immunology, University Hospital Zurich, Zurich 8044, Switzerland

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44 Neurocenter of Southern Switzerland and Department of Neurology, University Hospital Zurich, Zurich 8091, Switzerland

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Received:

30 November 2009

Revision received:

23 March 2010

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Adriano Fontana, Heidemarie Gast, Walter Reith, Mike Recher, Thomas Birchler, Claudio L. Bassetti, Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss?, Brain, Volume 133, Issue 5, May 2010, Pages 1300–1311, https://doi.org/10.1093/brain/awq086
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Abstract

Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of narcolepsy being an immune-mediated disease. Narcolepsy is associated with polymorphisms of the genes encoding T cell receptor alpha chain, tumour necrosis factor alpha and tumour necrosis factor receptor II. Moreover the rate of streptococcal infection is increased at onset of narcolepsy. The hallmarks of anti-self reactions in the tissue—namely upregulation of major histocompatibility antigens and lymphocyte infiltrates—are missing in the hypothalamus. These findings are questionable because they were obtained by analyses performed many years after onset of disease. In some patients with narcolepsy autoantibodies to Tribbles homolog 2, which is expressed by hypocretin neurons, have been detected recently. Immune-mediated destruction of hypocretin producing neurons may be mediated by microglia/macrophages that become activated either by autoantigen specific CD4+ T cells or superantigen stimulated CD8+ T cells, or independent of T cells by activation of DQB1*0602 signalling. Activation of microglia and macrophages may lead to the release of neurotoxic molecules such as quinolinic acid, which has been shown to cause selective destruction of hypocretin neurons in the hypothalamus.

© The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Topic:

• polymorphism
• autoimmunity
• genes
• hypothalamus
• hla-dr2 antigen
• microglia
• narcolepsy
• neurons
• t-lymphocytes
• t-cell activation
• orexins
• molecule

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