Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin⁺ neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a “neo-self-antigen” specifically in hypothalamic orexin⁺ neurons (called Orex-HA), which were transferred with effector neo-self-antigen–specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin⁺ neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin⁺ neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin⁺ neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy. Significance Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness and sudden loss of muscle tone. These clinical manifestations are the result of selective loss of a neuronal population producing orexin. The etiology of the disease remains elusive, although converging evidence points to a key involvement of the immune system. We developed an animal model to study the autoimmune processes at play in narcolepsy. We demonstrate that cytotoxic CD8 T cells, but not Th1 CD4 cells, are able to target and destroy orexinergic neurons. This selective neuronal loss is responsible for clinical signs mimicking human narcolepsy. By identifying potential immune effectors of the immunopathological process in narcolepsy, these findings offer a rationale for the use of immunotherapies.

The network of NF‐κB‐dependent transcription that activates both pro‐ and anti‐inflammatory genes in mammals is still unclear. As NF‐κB factors are evolutionarily conserved, we used Drosophila to understand this network. The NF‐κB transcription factor Relish activates effector gene expression following Gram‐negative bacterial immune challenge. Here, we show, using a genome‐wide approach, that the conserved nuclear protein Akirin is a NF‐κB co‐factor required for the activation of a subset of Relish‐dependent genes correlating with the presence of H3K4ac epigenetic marks. A large‐scale unbiased proteomic analysis revealed that Akirin orchestrates NF‐κB transcriptional selectivity through the recruitment of the Osa‐containing‐SWI/SNF‐like Brahma complex (BAP). Immune challenge in Drosophila shows that Akirin is required for the transcription of a subset of effector genes, but dispensable for the transcription of genes that are negative regulators of the innate immune response. Therefore, Akirins act as molecular selectors specifying the choice between subsets of NF‐κB target genes. The discovery of this mechanism, conserved in mammals, paves the way for the establishment of more specific and less toxic anti‐inflammatory drugs targeting pro‐inflammatory genes. See also: [S Tartey et al ][1] (October 2014) ![][2] The nuclear factor Akirin orchestrates NF‐κB transcriptional selectivity through the recruitment of the Osa‐containing‐SWI/SNF Brahma complex (BAP), by activating a subset of NF‐κB effector genes. The EMBO Journal (2014) 33: 2349–2362 [1]: http://dx.doi.org/10.15252/embj.201488447 [2]: pending:yes

Narcolepsy type 1 is a devastating neurological sleep disorder resulting from the destruction of orexin-producing neurons in the central nervous system (CNS). Despite its striking association with the HLA-DQB1*06:02 allele, the autoimmune etiology of narcolepsy has remained largely hypothetical. Here, we compared peripheral mononucleated cells from narcolepsy patients with HLA-DQB1*06:02-matched healthy controls using high-dimensional mass cytometry in combination with algorithm-guided data analysis. Narcolepsy patients displayed multifaceted immune activation in CD4+ and CD8+ T cells dominated by elevated levels of B cell–supporting cytokines. Additionally, T cells from narcolepsy patients showed increased production of the proinflammatory cytokines IL-2 and TNF. Although it remains to be established whether these changes are primary to an autoimmune process in narcolepsy or secondary to orexin deficiency, these findings are indicative of inflammatory processes in the pathogenesis of this enigmatic disease.

The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (T _RM ) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8 ⁺ T cells exhibit a T _RM -like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8 ⁺ T cells behind the blood-brain barrier adopt a characteristic T _RM differentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8 ⁺ T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8 ⁺ T cells. Consistently, a large fraction of autoreactive tissue-resident CD8 ⁺ T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8 ⁺ T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4 ⁺ T cells. Collectively, our results point to tissue-resident CD8 ⁺ T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.

Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild–moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1–95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6–15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7– 63.3) against any COVID-19, and 95.3% (80.5–98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease.