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The autoimmune basis of narcolepsy - PubMed

Review

The autoimmune basis of narcolepsy

Josh Mahlios et al. Curr Opin Neurobiol. 2013 Oct.

Abstract

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. Narcolepsy is caused by the loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus. Evidence, such as a strong association with HLA DQB1*06:02, strongly suggests an autoimmune basis targeting hypocretin neurons. Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, and the DNA methyltransferase DNMT1. Recently, attention has been raised regarding a spike in cases of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Europe. How the immune system may be involved in disease initiation and/or progression remains a challenge to researchers. Potential immunological pathways that could lead to the specific elimination of hypocretin producing neurons include molecular mimicry or bystander activation, and are likely a combination of genetic and environmental factors, such as upper airway infections.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

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Figures

Figure 1
Figure 1. Autoimmunity and hypocretin cell loss

[I] Following phagocytosis, APCs degrade H1N1 influenza virus in the lysosome, a process facilitated by cathepsin H. [II] Peptides from the virus are presented on the surface of APCs in the context of MHC class II (DQA1*01:02-DQB1*06:02) for cognate TCR recognition. [III] Hypocretin specific CD4+ T cells recognizes the presented antigen and is activated. After being activated, the CD4+ T cells upregulate the expression of OX40 which is an important costimulatory molecule recognized by APCs that express OX40L. [IV] Activated CD4+ T cells secrete IFN-γ, TNF-α and IL-2, which stimulate CD8+ T cells and drive a Th1 mediated immune response. IL-4 from activated CD4+ T cells promotes a humoral response leading to the production of Tribbles2 antibody by B cells. [V] Generation of super antigens as a result of streptococcus infection activates Th17 cells, facilitating the breakdown of the blood-brain barrier through the secretion of IL-17 and IL-22. Increased permeability allows for the migration of activated T cells, B cells, and TRIBBLES2 antibodies into the CNS. [VI] Migration of activated T cells and B cells through the BBB is followed by interaction with CNS APCs (microglia) that present autoantigens (hypocretin cell autoantigens) in the context of DQA1*01:02-DQB1*06:02 [VII and inset C] Reactivated T cells reach the hypothalamus and recognize hypocretin neurons, inducing effector functions such as the secretion of cytokines or cytotoxic compounds. Moreover, super-antigens from streptococcus cross-link the MHC and TCR molecules independent of antigen specificity activating the autoreactive T cell. This may lead to sensitization to hypocretin-specific antigens and form the basis for subsequent booster reactions of cross-reactive CD4+ T cells, a process that finally will end in an autoimmune reaction against hypocretin neurons. APC, antigen presenting cell; MCH, melanin concentrating hormone; MHC, major histocompatibility complex; TCR, T cell receptor.

Figure 2
Figure 2. Molecular mimicry between H1N1 peptides and hypocretin neuron autoantigens

Sequence and structural homology between foreign and self-peptides are required for molecular mimicry to occur. (A) The H1N1 virus is engulfed by an APC and the foreign antigenic material is digested into peptide fragments in the endosome/lysosome. (B) The invariant chain is digested and the MHC groove is ready for occupancy by the antigenic fragment. (C, D) The MHC binding groove selects the H1N1 fragment with a specific amino acid sequence in the context of DQA1*01:02-DQB1*06:02. (E) The vesicles move to the plasma membrane and the complex is displayed at the cell surface for TCR recognition. (F) The TCR recognizes a presented peptide with a specific amino acid sequence. (G, H) Activated CD4+ T cells cross-react and recognize hypocretin neuron autoantigens as foreign molecules, prompting an autoimmune response against hypocretin neurons. MHC, major histocompatibility complex; TCR, T-cell receptor.

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