Multiple sclerosis twin study reveals distinct genetic, disease-specific, and psychometric impact on coping with critical life events.

Background: Critical life events challenge our competence to develop coping strategies. In people with multiple sclerosis (MS), the impact of genetics, disease-specific, and psychometric factors on coping strategies have not been explored to date.

Methods: In a unique cohort of 56 monozygotic twins discordant for MS, we applied comprehensive psychometric and clinical testing to measure factors influencing the psychosocial impact (including stressors and coping strategies) of a critical life event, exemplified by the COVID-19 pandemic (measured by the COVID-19 Pandemic Mental Health Questionnaire, CoPaQ).

Twin study identifies early immunological and metabolic dysregulation of CD8 T cells in multiple sclerosis.

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).

Multiple sclerosis and the intestine: Chasing the microbial offender.

Multiple sclerosis (MS) affects more than 2.8 million people worldwide but the distribution is not even. Although over 200 gene variants have been associated with susceptibility, studies of genetically identical monozygotic twin pairs suggest that the genetic make-up is responsible for only about 20%-30% of the risk to develop disease, while the rest is contributed by milieu factors.

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.

Twin study dissects CXCR3 memory B cells as non-heritable feature in multiple sclerosis.

Background: In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets.

Methods: In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data.

A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model.

Multiple sclerosis (MS) involves the infiltration of autoreactive T cells into the CNS, yet we lack a comprehensive understanding of the signaling pathways that regulate this process. Here, we conducted a genome-wide in vivo CRISPR screen in a rat MS model and identified 5 essential brakes and 18 essential facilitators of T cell migration to the CNS. While the transcription factor ETS1 limits entry to the CNS by controlling T cell responsiveness, three functional modules, centered around the adhesion molecule α4-integrin, the chemokine receptor CXCR3 and the GRK2 kinase, are required for CNS migration of autoreactive CD4 T cells.

Persistent virus-specific and clonally expanded antibody-secreting cells respond to induced self-antigen in the CNS.

B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality.

Broader Epstein-Barr virus-specific T cell receptor repertoire in patients with multiple sclerosis.

Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimer-confirmed, viral antigen-specific TCRβ sequences. We detected more MHC-I-restricted EBV-specific TCRβ sequences in MS patients.

Single-cell multiomics in neuroinflammation.

The central nervous system (CNS) is, more than other organs, particularly vulnerable to inflammation and immune responses must be tightly controlled in order to maintain host protection. Accordingly, neuroinflammation is an orchestrated process involving various cell types that may dramatically change their phenotypic and functional properties upon entering the CNS. Recent advances in single-cell multiomics offer the unique opportunity to resolve this cellular heterogeneity in a holistic fashion and reshape our understanding of the molecular and cellular processes during neuroinflammation.

Twin study reveals non-heritable immune perturbations in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions. Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations.

Multiple sclerosis and subclinical neuropathology in healthy individuals with familial risk: A scoping review of MRI studies.

Multiple genetic and non-heritable factors have been linked to the risk of multiple sclerosis (MS). These factors seem to contribute to disease pathogenesis before the onset of clinical symptoms, as suggested by incidental MRI evidence of subclinical MS neuropathology in individuals without clinical symptoms. Individuals with high familial risk for MS, such as first-degree relatives of patients with MS, can be studied by MRI to characterize the neuropathology during a subclinical period of MS.

Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABA receptor encephalitis.

Encephalitis associated with antibodies against the neuronal gamma-aminobutyric acid A receptor (GABA-R) is a rare form of autoimmune encephalitis. The pathogenesis is still unknown but autoimmune mechanisms were surmised. Here we identified a strongly expanded B cell clone in the cerebrospinal fluid of a patient with GABA-R encephalitis.

Plasma lipidomics of monozygotic twins discordant for multiple sclerosis.

Blood biomarkers of multiple sclerosis (MS) can provide a better understanding of pathophysiology and enable disease monitoring. Here, we performed quantitative shotgun lipidomics on the plasma of a unique cohort of 73 monozygotic twins discordant for MS. We analyzed 243 lipid species, evaluated lipid features such as fatty acyl chain length and number of acyl chain double bonds, and detected phospholipids that were significantly altered in the plasma of co-twins with MS compared to their non-affected siblings.

TSPO PET With 18F-GE-180 to Differentiate Variants of Multiple Sclerosis: Relapsing-Remitting Multiple Sclerosis, Tumefactive Demyelination, and Baló's Concentric Sclerosis.

PET targeting the translocator protein (TSPO) expression is an interesting approach to detect neuroinflammation, as TSPO is upregulated in activated macrophages and microglia. Considering the variable pathophysiology of multiple sclerosis (MS) variants, we compare TSPO PET using F-GE-180 in 3 different demyelinating diseases of the central nervous system: relapsing-remitting MS, tumefactive MS, and Baló's concentric sclerosis. Visualization of neuroinflammation and its PET patterns in addition to MRI may contribute to accurate distinction and monitoring of central nervous system demyelination.

Antibody signatures in patients with histopathologically defined multiple sclerosis patterns.

Early active multiple sclerosis (MS) lesions can be classified histologically into three main immunopathological patterns of demyelination (patterns I-III), which suggest pathogenic heterogeneity and may predict therapy response. Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody/complement deposition. In pattern III lesions, which include Baló's concentric sclerosis, primary oligodendrocyte damage was proposed.

Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis.

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.

The Glycosylation Site of Myelin Oligodendrocyte Glycoprotein Affects Autoantibody Recognition in a Large Proportion of Patients.

Autoantibodies to myelin oligodendrocytes glycoprotein (MOG) are found in a fraction of patients with inflammatory demyelination and are detected with MOG-transfected cells. While the prototype anti-MOG mAb 8-18C5 and polyclonal anti-MOG responses from different mouse strains largely recognize the FG loop of MOG, the human anti-MOG response is more heterogeneous and human MOG-Abs recognizing different epitopes were found to be pathogenic. The aim of this study was to get further insight into details of antigen-recognition by human MOG-Abs focusing on the impact of glycosylation.

DNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins, which strongly argues for involvement of epigenetic factors. We observe highly similar peripheral blood mononuclear cell-based methylomes in 45 MS-discordant monozygotic twins. Nevertheless, we identify seven MS-associated differentially methylated positions (DMPs) of which we validate two, including a region in the TMEM232 promoter and ZBTB16 enhancer.