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Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8+ T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8+ T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8+ T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8+ T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease. Editor's summary: Multiple sclerosis (MS) is an inflammatory disease of the nervous system in which CD8 T cells are present in MS lesions, but their role in disease progression remains unclear. Kavaka et al. analyzed CD8 T cells from the blood and cerebrospinal fluid of monozygotic twins, where one twin had MS and the other showed no signs or subclinical signs of neuroinflammation (SCNI). CD8 T cells from individuals with MS and cotwins with SCNI exhibited proinflammatory immunological and metabolic features consistent with enhanced activation and migration. These findings were validated in a separate cohort of individuals with MS, providing insights into the role of CD8 T cells in MS progression. —Christiana Fogg [ABSTRACT FROM AUTHOR]

The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2%of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when we focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a disabling disease of the CNS. Inflammatory features of MS include lymphocyte accumulations in the CNS and cerebrospinal fluid (CSF). The preclinical events leading to established MS are still enigmatic. Here we compared gene expression patterns of CSF cells from MS-discordant monozygotic twin pairs. Six "healthy" co-twins, who carry a maximal familial risk for developing MS, showed subclinical neuroinflammation (SCNI) with small MRI lesions. Four of these subjects had oligoclonal bands (OCBs). By single-cell RNA sequencing of 2752 CSF cells, we identified clonally expanded CD8+ T cells, plasmablasts, and, to a lesser extent, CD4+ T cells not only from MS patients but also from subjects with SCNI. In contrast to nonexpanded T cells, clonally expanded T cells showed characteristics of activated tissue-resident memory T (TRM) cells. The TRM-like phenotype was detectable already in cells from SCNI subjects but more pronounced in cells from patients with definite MS. Expanded plasmablast clones were detected only in MS and SCNI subjects with OCBs. Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded TRM-like CD8+ cells. [ABSTRACT FROM AUTHOR]

Narcolepsy is a rare cause of hypersomnolence and may be associated or not with cataplexy, i.e. sudden muscle weakness. These forms are designated narcolepsy-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 strongly decreased levels of hypocretin-1 (synonym orexin-A) in the cerebrospinal fluid (CSF). The pathogenesis of narcolepsy is still not completely understood but the strong 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 CSF-cells from twelve NT1 and two NT2 patients by single cell RNAseq (scRNAseq). As controls, we used CSF cells from patients with multiple sclerosis, radiologically isolated syndrome, and idiopathic intracranial hypertension. From 27,255 CSF cells, we identified 20 clusters of different cell types and found significant differences in three CD4+ T cell and one monocyte clusters between narcolepsy and multiple sclerosis patients. Over 1000 genes were differentially regulated between patients with NT1 and other diseases. Surprisingly, the most strongly upregulated genes in narcolepsy patients as compared to controls were coding for the genome-encoded MTRNR2L12 and MTRNR2L8 peptides, which are homologous to the mitochondria-encoded HUMANIN peptide that is known playing a role in other neurological diseases including Alzheimer's disease. • Single cell RNAseq of cerebrospinal fluid (CSF) cells reveals 20 different cell clusters. • Gene expression in the CSF of narcoleptic patients differs from multiple sclerosis. • More than 1000 genes are differentially expressed in CSF CD4+ T cells from persons with narcolepsy. • -High expression of members of the HUMANIN gene family in CSF cells from persons with narcolepsy. [ABSTRACT FROM AUTHOR]