Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect... Show moreNarcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®. Show less
Seifinejad, A.; Ramosaj, M.; Shan, L.; Li, S.; Possovre, M.L.; Pfister, C.; ... ; Tafti, M. 2023
Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of... Show moreNarcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt,Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy. Show less
Kamp, I.; Honda, M.; Nomura, H.; Audard, M.; Fedele, D.; Waters, L.B.F.M.; ... ; Ysard, N. 2021
Context. The evolution of young massive protoplanetary disks toward planetary systems is expected to correspond to structural changes in observational appearance, which includes the formation of... Show moreContext. The evolution of young massive protoplanetary disks toward planetary systems is expected to correspond to structural changes in observational appearance, which includes the formation of gaps and the depletion of dust and gas. Aims: A special group of disks around Herbig Ae/Be stars do not show prominent silicate emission features, although they still bear signs of flaring disks, the presence of gas, and small grains. We focus our attention on four key Herbig Ae/Be stars to understand the structural properties responsible for the absence of silicate feature emission. Methods: We investigate Q- and N-band images taken with Subaru/COMICS, Gemini South/T-ReCS, and VLT/VISIR. We perform radiative transfer modeling to examine the radial distribution of dust and polycyclic aromatic hydrocarbons (PAHs). Our solutions require a separation of inner- and outer- disks by a large gap. From this, we characterize the radial density structure of dust and PAHs in the disk. Results: The inner edge of the outer disk has a high surface brightness and a typical temperature between ~{}100-150 K and therefore, dominates the emission in the Q-band. All four disks are characterized by large gaps. We derive radii of the inner edge of the outer disk of 34$_{-4}$$^{+4}$, 23$_{-5}$$^{+3}$, 30$_{-3}$$^{+5}$ and 63$_{-4}$$^{+4}$ AU for HD 97048, HD 169142, HD 135344 B, and Oph IRS 48, respectively. For HD 97048 this is the first detection of a disk gap. The large gaps deplete the entire population of silicate particles with temperatures suitable for prominent mid-infrared feature emission, while small carbonaceous grains and PAHs can still show prominent emission at mid-infrared wavelengths. The continuum emission in the N-band is not due to emission in the wings of PAHs. This continuum emission can be due to very small grains or to thermal emission from the inner disk. We find that PAH emission is not always dominated by PAHs on the surface of the outer disk. Conclusions: The absence of silicate emission features is due to the presence of large gaps in the critical temperature regime. Many, if not all Herbig disks with spectral energy distribution classification ''group I'', are disks with large gaps and can be characterized as (pre-) transitional. An evolutionary path from the observed group I to the observed group II sources seems no longer likely. Instead, both might derive from a common ancestor. Tables A.1-A.4 are only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/555/A64Show less
