Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Mitrovič, Mitja; Patsopoulos, Nikolaos A.; Beecham, Ashley; Dankowski, Theresa; Goris, An; Dubois, Bénédicte; D’hooghe, Marie B.; Lemmens, Robin; Damme, Philip Van; Søndergaard, Helle Bach; Sellebjerg, Finn; Sørensen, Per Soelberg; Ullum, Henrik; Thørner, Lise Wegner; Werge, Thomas; Saarela, Janna; Cournu-Rebeix, Isabelle; Damotte, Vincent; Fontaine, Bertrand; Guillot‐Noël, Léna; Lathrop, Mark; Vukusik, Sandra; Gourraud, Pierre‐Antoine; Andlauer, Till F. M.; Pongratz, Viola; Buck, Dorothea; Gasperi, Christiane; Bayas, Antonios; Heesen, Christoph; Kümpfel, Tania; Linker, Ralf A.; Paul, Friedemann; Stangel, Martin; Tackenberg, Björn; Bergh, Florian Then; Warnke, Clemens; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K.; Ziemann, Ulf; Tumani, Hayrettin; Gold, Ralf; Grummel, Verena; Hemmer, Bernhard; Knier, Benjamin; Lill, Christina M.; Luessi, Felix; Dardiotis, Efthimios; Agliardi, Cristina; Barizzone, Nadia; Mascia, Elisabetta; Bernardinelli, Luisa; Comi, Giancarlo; Cusi, Daniele; Esposito, Federica; Ferré, Laura; Comi, Cristoforo; Galimberti, Daniela; Leone, Maurizio; Sorosina, Melissa; Mescheriakova, Julia; Hintzen, Rogier Q.; Duijn, Cornelia M. van; Teunissen, Charlotte E.; Bos, Steffan Daniël; Myhr, Kjell–Morten; Celius, Elisabeth Gulowsen; Lie, Benedicte A.; Spurkland, Anne; Comabella, Manuel; Montalbán, Xavier; Alfredsson, Lars; Stridh, Pernilla; Hillert, Jan; Jagodic, Maja; Piehl, Fredrik; Jelčić, Ilijas; Martin, Roland; Sospedra, Mireia; Ban, Masashi; Hawkins, Clive; Hysi, Pirro G.; Kalra, Seema; Karpe, Fredrik; Khadake, Jyoti; Lachance, Geneviève; Neville, Matthew J.; Santaniello, Adam; Caillier, Stacy J.; Calabresi, Peter A.; Cree, Bruce A. C.; Cross, Anne H.; Davis, Mary F.; Haines, Jonathan L.; Bakker, Paul I. W. de; Delgado, Silvia; Dembele, Marieme; Edwards, Keith R.; Fitzgerald, Kathryn C.; Hákonarson, Hákon; Konidari, Ioanna; Lathi, Ellen; Manrique, Clara P.; Pericak‐Vance, Margaret A.; Piccio, Laura; Schaefer, Cathy; McCabe, Cristin; Weiner, Howard L.; Goldstein, Jacqueline I.; Olsson, Tomas; Hadjigeorgiou, Georgios M.; Taylor, Bruce; Tajouri, Lotti; Charlesworth, Jac; Booth, David R.; Harbo, Hanne F.; Ivinson, Adrian J.; Hauser, Stephen L.; Compston, Alastair; Stewart, Graeme J.; Zipp, Frauke; Barcellos, Lisa F.; Baranzini, Sergio E.; Boneschi, Filippo Martinelli; D’Alfonso, Sandra; Ziegler, Andreas; Oturai, Annette Bang; McCauley, Jacob L.; Sawcer, Stephen; Oksenberg, Jorge R.; Jager, Philip L. De; Kockum, Ingrid; Hafler, David A.; Cotsapas, Chris

doi:10.1016/j.cell.2018.09.049

Cited by 115 publications

(72 citation statements)

References 48 publications

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“…Furthermore, perforin and granzyme signaling pathways are also important for target cytotoxicity by predominantly CD8+ CTLs and natural killer cells. Recent work done by the IMSCG identified a coding variant in PFR1, the gene that encodes perforin, to be associated with the risk of getting MS 85 . This result underlines the potential importance of CD8+ cytotoxicity in MS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity

Kirby

Jin²,

Cardona

et al. 2018

Preprint

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Oligodendrocyte precursor cells (OPCs) are abundant in the adult CNS and can be recruited to form new oligodendrocytes and myelin in response to injury or disease. However, in multiple sclerosis (MS), oligodendrocyte regeneration and remyelination are often incomplete, suggesting that recruitment and maturation of OPCs is impaired. MS and the rodent model experimental autoimmune encephalomyelitis (EAE) are characterized by infiltration of activated T-cells into the CNS. To investigate the mechanisms by which this neuroinflammatory process influences OPC mobilization, we performed in vivo fate tracing in an inflammatory demyelinating animal model. Results of our studies showed that the OPC differentiation and myelin production are inhibited by either adoptive transfer of CNS infiltrating cytokine producing effector T-cells or CNS production of interferon gamma (IFNγ), using an astrocyte specific IFNγ transgene model. In both systems, IFNγ changes the profile of OPCs by inducing functional expression of the immunoproteasome and upregulation of MHC class I. OPCs exposed to IFNγ are shown to cross present exogenous antigen to cytotoxic CD8 T-cells, which then produce proteases and FasL that results in subsequent caspase 3/7 activation and OPC death, both in vitro and in vivo. Cross presentation by OPCs is dependent on the cytosolic processing pathway and can be inhibited by small molecules targeting MHC class I antigen processing and the immunoproteasome subunits. Finally, the immunoproteasome subunit, PSMB8, is shown to be markedly increased on Sox10 + oligodendrocyte lineage cells only in the demyelinated white matter lesions from patients with MS. These findings support the notion that OPCs have multiple functions beyond differentiation into myelinating cells and adapt to their microenvironment by responding to local cues. In MS, OPCs may be co-opted by the immune system to perpetuate the autoimmune response. Strategies aimed at inhibiting the aberrant immune activation pathways in OPCs may allow more efficient remyelination in MS.

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Section: Discussionmentioning

confidence: 99%

Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity

Kirby

Jin²,

Cardona

et al. 2018

Preprint

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“…Multiple sclerosis (MS) is an immune-mediated disease that affects the entire central nervous system (CNS) [1][2][3]. Magnetic resonance imaging (MRI) lesions are wellscattered at white matter (WM) and grey matter (GM) [4], while normal-appearing brain tissue in MRI also seems to be affected in pathological studies [4].…”

Section: Introductionmentioning

confidence: 99%

Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

Andravizou

Dardiotis

Artemiadis

et al. 2019

Autoimmun Highlights

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Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by focal or diffuse inflammation, demyelination, axonal loss and neurodegeneration. Brain atrophy can be seen in the earliest stages of MS, progresses faster compared to healthy adults, and is a reliable predictor of future physical and cognitive disability. In addition, it is widely accepted to be a valid, sensitive and reproducible measure of neurodegeneration in MS. Reducing the rate of brain atrophy has only recently been incorporated as a critical endpoint into the clinical trials of new or emerging disease modifying drugs (DMDs) in MS. With the advent of easily accessible neuroimaging softwares along with the accumulating evidence, clinicians may be able to use brain atrophy measures in their everyday clinical practice to monitor disease course and response to DMDs. In this review, we will describe the different mechanisms contributing to brain atrophy, their clinical relevance on disease presentation and course and the effect of current or emergent DMDs on brain atrophy and neuroprotection. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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“…GWAS results are derived from each common variant (signaled by a single nucleotide polymorphism (SNP)) that explains a small fraction of the risk/protection in a given population. The overall genetic risk is largely due to many common variants of small effect spread throughout the genome, except for loci lying in the HLA complex and a handful of rare gene variants that have recently been associated with MS [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis

Mechelli

Umeton

Manfrè

et al. 2020

Genes

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Genome-wide association studies have identified more than 200 multiple sclerosis (MS)-associated loci across the human genome over the last decade, suggesting complexity in the disease etiology. This complexity poses at least two challenges: the definition of an etiological model including the impact of nongenetic factors, and the clinical translation of genomic data that may be drivers for new druggable targets. We reviewed studies dealing with single genes of interest, to understand how MS-associated single nucleotide polymorphism (SNP) variants affect the expression and the function of those genes. We then surveyed studies on the bioinformatic reworking of genome-wide association studies (GWAS) data, with aggregate analyses of many GWAS loci, each contributing with a small effect to the overall disease predisposition. These investigations uncovered new information, especially when combined with nongenetic factors having possible roles in the disease etiology. In this context, the interactome approach, defined as “modules of genes whose products are known to physically interact with environmental or human factors with plausible relevance for MS pathogenesis”, will be reported in detail. For a future perspective, a polygenic risk score, defined as a cumulative risk derived from aggregating the contributions of many DNA variants associated with a complex trait, may be integrated with data on environmental factors affecting the disease risk or protection.

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Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Cited by 115 publications

References 48 publications

Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity

Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity

Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis

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