Autoimmunity in narcolepsy

Bonvalet, Mélodie; Ollila, Hanna; Ambati, Aditya; Mignot, Emmanuel

doi:10.1097/mcp.0000000000000426

Cited by 44 publications

(34 citation statements)

References 74 publications

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“…Moreover, the lateral hypothalamus hosts neurons producing orexin, a neuropeptide of fundamental importance for arousal and vigilance. In narcolepsy, a disease with dramatically reduced vigilance, autoimmunological reactions against orexin-producing neurons strongly decrease orexin levels 65. This led to the hypothesis that less pronounced reductions of orexin might produce fatigue in MS. For example, hypothalamic lesions in MS could lead to partial depletion of orexin; alternatively, immunological processes could affect the synthesis and/or postsynaptic efficacy of orexin.…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis

Manjaly¹,

Harrison

Critchley

et al. 2019

J Neurol Neurosurg Psychiatry

221

231

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Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients’ quality of life. Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms. Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients. This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments.

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Section: Introductionmentioning

confidence: 99%

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis

Manjaly¹,

Harrison

Critchley

et al. 2019

J Neurol Neurosurg Psychiatry

221

231

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“…Molecular mimicry and the consequent potential cross-reactivity following infections have been repeatedly described in humans. [1][2][3][4][5][6][7][8][9][10][11][12] Such cross-reactivity is not evident in experimental infections of primates. 13 Actually, following preclinical studies performed in primates [14][15][16][17][18] as recommended by the Food and Drug Administration, 19 the reports declare that primate active immunization by pathogen vaccine administration is well tolerated and exempt of relevant events.…”

Section: Introductionmentioning

confidence: 99%

Medical, Genomic, and Evolutionary Aspects of the Peptide Sharing between Pathogens, Primates, and Humans

Kanduc

Shoenfeld

2020

Global Medical Genetics

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Comparing mammalian proteomes for molecular mimicry with infectious pathogens highlights the highest levels of heptapeptide sharing between pathogens and human, murine, and rat proteomes, while the peptide sharing level is minimal (or absent) with proteomes from nonhuman primates such as gorilla, chimpanzee, and rhesus macaque. From the medical point of view, the data might be useful to clinicians and vaccinologists to develop and evaluate immunomodulatory and immunotherapeutic approaches. As a matter of fact, primates seem to be unreliable animal models for revealing potential autoimmune events in preclinical testing of immunotherapies. In terms of genomics, the scarce or absent peptide sharing between pathogens and primates versus the massive peptide sharing existing between pathogens and humans lets foresee mechanisms of pathogen sequence insertion/deletion/alteration that have differently operated in mammals over evolutionary timescales. Why and how the human genome has been colonized by pathogen sequences and why and how primates escaped such a colonization appears to be the new scientific challenge in our efforts to understand not only the origin of Homo sapiens but also his autoimmune diseasome.

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“…Genome-wide association studies have revealed a strong association of narcolepsy with the T-cell receptor alpha locus ( Hallmayer et al, 2009 ) and especially with Major Histocompatibility Complex (MHC) class II DQB1*06:02 alleles ( Bonvalet et al, 2017 ; Tafti et al, 2014 ). DQB1*06:02 is present in approximately 30% of Finnish and Swedish populations ( Bomfim et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling

et al. 2018

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BackgroundNeuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive.MethodsHere we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3.FindingsOur data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1.InterpretationWe propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies.

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Autoimmunity in narcolepsy

Cited by 44 publications

References 74 publications

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis

Medical, Genomic, and Evolutionary Aspects of the Peptide Sharing between Pathogens, Primates, and Humans

Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling

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