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

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.

MRD's approach: Ideally suited to support Future Earth research agenda in mountains

Both Future Earth and Mountain Research and Development (MRD) aim to support production and dissemination of knowledge for sustainable development. As shown in Future Earth’s Strategic Research Agenda 2014, the global research community has begun to acknowledge its societal role and the need for a new type of research in which scientists link disciplines and coproduce transformation knowledge with stakeholders. Future Earth has defined three research themes that conceptualize the issues to be dealt with at the same time as the way in which this should be done. In many ways, MRD’s policy has made the journal a forerunner of Future Earth’s stipulated “step-change in research”. Indeed, MRD’s section policies aim to support similar contents and ways of producing these forms of knowledge. MRD publishes “systems knowledge” in its MountainResearch section, “target knowledge” in its MountainAgenda section, and “transformation knowledge” in its MountainDevelopment section. Each of these sections has dedicated review criteria to assess and enhance the quality of the knowledge presented in the papers. In this poster, we provide examples from each of the three sections of what the knowledge types look like, how they are assessed, and how they contribute to the three Future Earth themes.