The Transcriptomic Profiling of Blood CD4 and CD8 T-cells in Narcolepsy Type I
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ABSTRACT:
PROVIDER: PRJNA1005567 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25643800_1.fastq.gz | Fastqsanger.gz | |||
| SRR25643800_2.fastq.gz | Fastqsanger.gz | |||
| SRR25643900_1.fastq.gz | Fastqsanger.gz | |||
| SRR25643900_2.fastq.gz | Fastqsanger.gz | |||
| SRR25644000_1.fastq.gz | Fastqsanger.gz |
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Project description:Background Narcolepsy Type I (NT1) is a rare, life-long sleep disorder arising as a consequence of the extensive destruction of orexin-producing hypothalamic neurons. The mechanisms involved in the destruction of orexin neurons are not yet elucidated but the association of narcolepsy with environmental triggers and genetic susceptibility (strong association with the HLA, TCRs and other immunologically-relevant loci) implicates an immuno-pathological process. Several studies in animal models and on human samples have suggested that T-cells are the main pathogenic culprits.Methods RNA sequencing was performed on four CD4 and CD8 T-cell subsets (naive, effector, effector memory and central memory) sorted by flow cytometry from peripheral blood mononuclear cells (PBMCs) of NT1 patients and HLA-matched healthy donors as well as (ageand sex-) matched individuals suffering from other sleep disorders (OSD). The RNAseq analysis was conducted by comparing the transcriptome of NT1 patients to that of healthy donors and other sleep disorder patients (collectively referred to as the non-narcolepsy controls) in order to identify narcolepsy- specific genes and pathways.We determined narcolepsy-specific differentially expressed genes, several of which are involved in tubulin arrangement found in CD4 (TBCB, CCT5, EML4, TPGS1, TPGS2) and CD8 (TTLL7) T cell subsets, which play a role in the immune synapse formation and TCR signaling. Furthermore, we identified genes (GZMB, LTB in CD4 and NLRP3, TRADD, IL6, CXCR1, FOXO3, FOXP3 in CD8) and pathways involved in various aspects of inflammation and inflammatory response. More specifically, the inflammatory profile was identified in the "naive" subset of CD4 and CD8 T-cell.We identified NT1-specific differentially expressed genes, providing a cell-type and subset specific catalog describing their functions in T-cells as well as their potential involvement in NT1. Several genes and pathways identified are involved in the formation of the immune synapse and TCR activation as well as inflammation and the inflammatory response.An inflammatory transcriptomic profile was detected in both "naive" CD4 and CD8 T-cell subsets suggesting their possible involvement in the development or progression of the narcoleptic process.
2023-11-13 | GSE240851 | GEO
Project description:Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found the associations of narcolepsy with human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor α (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. However, DQ6+ individuals generate DQ6-HCRT tetramer+/TRAJ24+ TCRs. Without a proof that an HCRT-reactive cell expressing such TCRs has expanded in vivo, T cell-mediated autoimmunity in narcolepsy remains speculative. Here, we isolated DQ6-HCRT tetramer+/CD4+ T cells (low frequency, <0.04%) from DQ6+ individuals with/without narcolepsy. Within 74 informative TRAJ24+ TCRαβ from 8/12 patients and 11/12 controls, we identified a conserved family of clonotypes shared by 2 patients and 2 controls using identical α/β genes. TRAJ24-G allele+ clonotypes only expanded in the two patients, whereas a TRAJ24-C allele+ clonotype expanded in a control. A representative tetramer+/G-allele+ TCR showed signaling reactivity to the physiologically modified form of the epitope HCRT87-97. Clonally expanded G-allele+ T cells also exhibited an unconventional effector phenotype. In vivo expansion of HCRT-reactive TRAJ24-G allele+ cells provides critical evidence for an autoimmune contribution to narcolepsy development.
2019-10-15 | GSE135852 | GEO
Project description:BackgroundNarcolepsy Type I (NT1) is a rare, life-long sleep disorder arising as a consequence of the extensive destruction of orexin-producing hypothalamic neurons. The mechanisms involved in the destruction of orexin neurons are not yet elucidated but the association of narcolepsy with environmental triggers and genetic susceptibility (strong association with the HLA, TCRs and other immunologically-relevant loci) implicates an immuno-pathological process. Several studies in animal models and on human samples have suggested that T-cells are the main pathogenic culprits.MethodsRNA sequencing was performed on four CD4 and CD8 T-cell subsets (naive, effector, effector memory and central memory) sorted by flow cytometry from peripheral blood mononuclear cells (PBMCs) of NT1 patients and HLA-matched healthy donors as well as (age- and sex-) matched individuals suffering from other sleep disorders (OSD). The RNAseq analysis was conducted by comparing the transcriptome of NT1 patients to that of healthy donors and other sleep disorder patients (collectively referred to as the non-narcolepsy controls) in order to identify NT1-specific genes and pathways.ResultsWe determined NT1-specific differentially expressed genes, several of which are involved in tubulin arrangement found in CD4 (TBCB, CCT5, EML4, TPGS1, TPGS2) and CD8 (TTLL7) T cell subsets, which play a role in the immune synapse formation and TCR signaling. Furthermore, we identified genes (GZMB, LTB in CD4 T-cells and NLRP3, TRADD, IL6, CXCR1, FOXO3, FOXP3 in CD8 T-cells) and pathways involved in various aspects of inflammation and inflammatory response. More specifically, the inflammatory profile was identified in the "naive" subset of CD4 and CD8 T-cell.ConclusionWe identified NT1-specific differentially expressed genes, providing a cell-type and subset specific catalog describing their functions in T-cells as well as their potential involvement in NT1. Several genes and pathways identified are involved in the formation of the immune synapse and TCR activation as well as inflammation and the inflammatory response. An inflammatory transcriptomic profile was detected in both "naive" CD4 and CD8 T-cell subsets suggesting their possible involvement in the development or progression of the narcoleptic process.
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Project description:Narcolepsy is a rare cause of excessive daytime sleepiness and may be associated or not with cataplexy, i.e. sudden muscle weakness. These forms are designated NAR-type 1 (NT1) and -type 2 (NT2), respectively. Notable characteristics of narcolepsy are that most patients carry the HLA-DQB1*06:02 allele and NT1-patients have highly decreased levels hypocretin-1 (synonym orexin-A) in the cerebrospinal fluid (CSF). The pathogenesis of narcolepsy is still enigmatic but the strung HLA-bias and increased frequencies of CD4+ T cells reactive to hypocretin in the peripheral blood suggest autoimmune processes in the hypothalamus. Here we analyzed the transcriptomes of single CSF-cells from 16 narcoleptic patients by mRNAseq. As controls, we used single cells from patients with multiple sclerosis, radiologically isolated syndrome, and idiopathic intracranial hypertension. We identified 20 clusters of different cell types and >1000 genes that were differentially regulated between the different diseases. Surprisingly, the strongest upregulation in narcolepsy patients as compared to controls were the genome-encoded MTRNR2L12 and MTRNR2L8 peptides, which are homologous to mitochondria-encoded HUMANIN peptide that is known playing a role in other neurological diseases.
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