Single cell transcriptomics of cerebrospinal fluid cells from patients with recent-onset narcolepsy.

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.

Risk of Major Types of Dementias Following Hospital-Diagnosed Infections and Autoimmune Diseases.

Background: Population-based studies have shown an increased risk of dementia after infections, but weaker links were reported for autoimmune diseases. Evidence is scarce for whether the links may be modified by the dementia or exposure subtype. Objective: We aimed to investigate the association between infections and/or autoimmune diseases and rates of major types of dementias in the short- and long terms. Methods: Nationwide nested case-control study of dementia cases (65+ years) diagnosed in Denmark 2016-2020 and dementia-free controls. Exposures were hospital-diagnosed infections and autoimmune diseases in the preceding 35 years. Two groups of dementia cases were those diagnosed in memory clinics (MC) and those diagnosed outside memory clinics (non-memory clinic cases, NMC). Results: In total, 26,738 individuals were MC and 12,534 were NMC cases. Following any infection, the incidence rate ratio (IRR) for MC cases was 1.23 (95% CI 1.20-1.27) and 1.70 for NMC cases (1.62-1.76). Long-term increased rates were seen for vascular dementia and NMC cases. IRRs for autoimmune diseases were overall statistically insignificant. Conclusions: Cases with vascular dementia and not Alzheimer's disease, and a subgroup of cases identified with poorer health have increased long-term risk following infections. Autoimmune diseases were not associated with any type of dementia. Notably increased risks (attributed to the short term) and for NMC cases may indicate that immunosenescence rather than de novo infection explains the links. Future focus on such groups and on the role of vascular pathology will explain the infection-dementia links, especially in the long term.

SLE serum induces altered goblet cell differentiation and leakiness in human intestinal organoids.

Human intestinal epithelial cells are the interface between luminal content and basally residing immune cells. They form a tight monolayer that constantly secretes mucus creating a multilayered protective barrier. Alterations in this barrier can lead to increased permeability which is common in systemic lupus erythematosus (SLE) patients. However, it remains unexplored how the barrier is affected. Here, we present an in vitro model specifically designed to examine the effects of SLE on epithelial cells. We utilize human colon organoids that are stimulated with serum from SLE patients. Combining transcriptomic with functional analyses revealed that SLE serum induced an expression profile marked by a reduction of goblet cell markers and changed mucus composition. In addition, organoids exhibited imbalanced cellular composition along with enhanced permeability, altered mitochondrial function, and an interferon gene signature. Similarly, transcriptomic analysis of SLE colon biopsies revealed a downregulation of secretory markers. Our work uncovers a crucial connection between SLE and intestinal homeostasis that might be promoted in vivo through the blood, offering insights into the causal connection of barrier dysfunction and autoimmune diseases.

Multiple sclerosis endophenotypes identified by high-dimensional blood signatures are associated with distinct disease trajectories.

One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible. Using two independent multicentric longitudinal cohorts of patients with early multiple sclerosis (n = 309 discovery and n = 232 validation), we were able to identify three distinct peripheral blood immunological endophenotypes by a combination of high-dimensional flow cytometry and serum proteomics, followed by unsupervised clustering. Longitudinal clinical and paraclinical follow-up data collected for the cohorts revealed that these endophenotypes were associated with disease trajectories of inflammation versus early structural damage. Investigating the capacity of immunotherapies to normalize endophenotype-specific immune signatures revealed discrete effect sizes as illustrated by the limited effect of interferon-ß on endophenotype 3-related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-ß exhibited higher disease progression and MRI activity over a 4-year follow-up compared with treatment with other therapies. We therefore propose that ascertaining a patient's blood immune signature before immunomodulatory treatment initiation may facilitate prediction of clinical disease trajectories and enable personalized treatment decisions based on pathobiological principles.