Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans

Ban, Masashi; Booth, David R.; Heard, Robert; Stewart, Graeme J.; Vandenbroeck, Koen; Dubois, Bénédicte; Laaksonen, Mikko; Ilonen, Jorma; Alizadeh, Mehdi; Edan, Gilles; Babron, Marie‐Claude; Brassat, David; Clanet, Michael; Cournu-Rebeix, Isabelle; Fontaine, Bertrand; Sémana, G.; Goedde, René; Epplen, Jörg T.; Weber, Alexandra; Infante-Duarte, Carmen; Zipp, Frauke; Rajda, Cecília; Bencsik, Krisztina; Vécsei, László; Heggarty, Shirley; Graham, Colin A.; Hawkins, Stanley; Liguori, Maria; Momigliano–Richiardi, Patricia; Caputo, Domenico; Grimaldi, Luigi Maria Edoardo; Leone, Maurizio; Massacesi, Luca; Milanese, C.; Salvetti, Marco; Savettieri, G; Trojano, María; Bielecki, Bartosz; Mycko, Marcin P.; Selmaj, Krzysztof; Santos, Mónica; Maciel, Patrı́cia; Pereira, Clara; Silva, Ana; Silva, Ana Martins; Coraddu, Francesca; Marrosu, Maria Giovanna; Åkesson, Eva; Hillert, Jan; Datta, Pameli; Oturai, Annette Bang; Harbo, Hanne F.; Spurkland, Anne; Goertsches, Robert; Villoslada, Pablo; Eraksoy, Mefküre; Hensiek, Anke; Compston, Alastair; Setakis, Efrosini; Gray, Julia; Yeo, Tai Wai; Sawcer, Stephen

doi:10.1016/j.jneuroim.2006.06.003

Cited by 28 publications

(6 citation statements)

References 42 publications

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“…Jagged-1 has been found to be highly expressed in hypertrophic astrocytes within and around active MScl plaques lacking remyelination, while, in contrast, there was negligible jagged-1 expression in remyelinated lesions suggesting involvement of the Notch pathway in remyelination in MScl [21]. Later, linkage equilibrium screening implicated a number of genes, including the jagged-1 gene, as susceptibility genes for MScl in a large contingent of Europeans [22]. It has also been suggested that jagged-1 has therapeutic potential in the treatment of CD8 + T cell mediated diseases, due to it's ability to deliver indirect negative signals into CD8 + T cells in vivo [23].…”

Section: Discussionmentioning

confidence: 99%

Proteomics Comparison of Cerebrospinal Fluid of Relapsing Remitting and Primary Progressive Multiple Sclerosis

Stoop¹,

Singh²,

Dekker³

et al. 2010

PLoS ONE

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BackgroundBased on clinical representation of disease symptoms multiple sclerosis (MScl) patients can be divided into two major subtypes; relapsing remitting (RR) MScl (85–90%) and primary progressive (PP) MScl (10–15%). Proteomics analysis of cerebrospinal fluid (CSF) has detected a number of proteins that were elevated in MScl patients. Here we specifically aimed to differentiate between the PP and RR subtypes of MScl by comparing CSF proteins.Methodology/Principal FindingsCSF samples (n = 31) were handled according to the same protocol for quantitative mass spectrometry measurements we reported previously. In the comparison of PP MScl versus RR MScl we observed a number of differentially abundant proteins, such as protein jagged-1 and vitamin D-binding protein. Protein jagged-1 was over three times less abundant in PP MScl compared to RR MScl. Vitamin D-binding protein was only detected in the RR MScl samples. These two proteins were validated by independent techniques (western blot and ELISA) as differentially abundant in the comparison between both MScl types.Conclusions/SignificanceThe main finding of this comparative study is the observation that the proteome profiles of CSF in PP and RR MScl patients overlap to a large extent. Still, a number of differences could be observed. Protein jagged-1 is a ligand for multiple Notch receptors and involved in the mediation of Notch signaling. It is suggested in literature that the Notch pathway is involved in the remyelination of MScl lesions. Aberration of normal homeostasis of Vitamin D, of which approximately 90% is bound to vitamin D-binding protein, has been widely implicated in MScl for some years now. Vitamin D directly and indirectly regulates the differentiation, activation of CD4+ T-lymphocytes and can prevent the development of autoimmune processes, and so it may be involved in neuroprotective elements in MScl.

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Section: Discussionmentioning

confidence: 99%

Proteomics Comparison of Cerebrospinal Fluid of Relapsing Remitting and Primary Progressive Multiple Sclerosis

Stoop¹,

Singh²,

Dekker³

et al. 2010

PLoS ONE

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“…The evidence from preclinical models that Notch signals play important roles in the regulation of physiological processes underlying MS is incontrovertible. Furthermore, a large-scale linkage disequilibrium screen of 13,896 individuals identified JAG1 as a susceptibility gene for MS in Europeans (Games Collaborative Group et al, 2006), and a network analysis of the human T-cell activation network also indicated JAG1 as a potential therapeutic target (Palacios et al, 2007).…”

Section: Oligodendrocytes and Msmentioning

confidence: 99%

The Notch pathway in CNS homeostasis and neurodegeneration

Artavanis‐Tsakonas

Louvi

2019

WIREs Developmental Biology

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The role of the Notch signaling pathway in neural development has been well established over many years. More recent studies, however, have demonstrated that Notch continues to be expressed and active throughout adulthood in many areas of the central nervous system. Notch signals have been implicated in adult neurogenesis, memory formation, and synaptic plasticity in the adult organism, as well as linked to acute brain trauma and chronic neurodegenerative conditions. NOTCH3 mutations are responsible for the most common form of hereditary stroke, the progressive disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Notch has also been associated with several progressive neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Although numerous studies link Notch activity with CNS homeostasis and neurodegenerative diseases, the data thus far are primarily correlative, rather than functional. Nevertheless, the evidence for Notch pathway activity in specific neural cellular contexts is strong, and certainly intriguing, and points to the possibility that the pathway carries therapeutic promise. This article is categorized under: Nervous System Development > Flies Signaling Pathways > Cell Fate Signaling Nervous System Development > Vertebrates: General Principles

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“…In contrast to Oct1, OCA-B whole-body knockouts are viable and fertile 26 . Polymorphisms in the Ocab (Pou2af1) locus are associated with autoimmune diseases, including MS 27,28 . Although its expression is 50-100 fold lower in T cells compared to B cells 29 , targeting either OCA-B by genetic deletion in T cells or its downstream pathways with a membrane-permeable peptide mimic suppresses type-1 diabetes 31 .…”

Section: Million Individuals Worldwide Suffer From Multiple Sclerosis...mentioning

confidence: 99%

OCA-B promotes pathogenic maturation of stem-like CD4⁺T cells and autoimmune demyelination

Hughes,

Syage,

Mehrabad

et al. 2023

Preprint

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SummaryStem-like T cell populations can selectively promote autoimmunity, but the activities that sustain these populations are incompletely understood. Here, we show that T cell-intrinsic loss of the transcription cofactor OCA-B protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to infection. In EAE models driven by antigen re-encounter, OCA-B deletion eliminates CNS infiltration, proinflammatory cytokine production and clinical disease. OCA-B-expressing CD4+T cells within the CNS of mice with EAE display a memory phenotype and preferentially confer disease. In a relapsing-remitting EAE model, OCA-B T cell-deficiency specifically protects mice from relapse. During remission, OCA-B promotes the expression ofTcf7,Slamf6, andSellin proliferating T cell populations. At relapse, OCA-B loss results in both the accumulation of an immunomodulatory CD4+T cell population expressingCcr9andBach2, and the loss of effector gene expression from Th17 cells. These results identify OCA-B as a driver of pathogenic stem-like T cells.

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Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans

Cited by 28 publications

References 42 publications

Proteomics Comparison of Cerebrospinal Fluid of Relapsing Remitting and Primary Progressive Multiple Sclerosis

Proteomics Comparison of Cerebrospinal Fluid of Relapsing Remitting and Primary Progressive Multiple Sclerosis

The Notch pathway in CNS homeostasis and neurodegeneration

OCA-B promotes pathogenic maturation of stem-like CD4⁺T cells and autoimmune demyelination

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Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans

Cited by 28 publications

References 42 publications

Proteomics Comparison of Cerebrospinal Fluid of Relapsing Remitting and Primary Progressive Multiple Sclerosis

Proteomics Comparison of Cerebrospinal Fluid of Relapsing Remitting and Primary Progressive Multiple Sclerosis

The Notch pathway in CNS homeostasis and neurodegeneration

OCA-B promotes pathogenic maturation of stem-like CD4+T cells and autoimmune demyelination

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Product

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OCA-B promotes pathogenic maturation of stem-like CD4⁺T cells and autoimmune demyelination