Genetics of Multiple Sclerosis: An Overview and New Directions

Patsopoulos, Nikolaos A.

doi:10.1101/cshperspect.a028951

Cited by 131 publications

(86 citation statements)

References 113 publications

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“…A complex interplay between genetic and environmental factors is necessary for the development of autoimmunity. In MS, genetically predisposing factors have been recognized, with specific polymorphisms of the major histocompatibility complex (MHC), namely the human leukocyte antigen (HLA) system, to be the factors accounting for the majority of cases [10]. For instance, beta chain of HLA (HLA-DRB1 ) and DQ beta 1 chain of HLA (HLA-DQB1)polymorphisms have been implicated in MS predisposition in Caucasians.…”

Section: The Environmental Factor In Autoimmune Diseasementioning

confidence: 99%

“…In addition, more than 130 single nucleotide polymorphisms (SNPs) implicated in various responses of the innate and adaptive immune system, as well as in cell survival and/or pathways of cellular death, have been recognized. However, even by considering the cumulative effect of these polymorphisms, the effect of the genetic factor itself does not account for more than 30% of MS cases [10]. Environmental factors have long been implicated in MS pathogenesis, and they include lifestyle conditions, such as smoking and the level of physical exercise, as well as the type of overall diet (e.g., Western, Eastern, or Mediterranean) and/or specific dietary parameters, such as vitamin D and salt intake [11,12].…”

Section: The Environmental Factor In Autoimmune Diseasementioning

confidence: 99%

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Microbiome in Multiple Sclerosis: Where Are We, What We Know and Do Not Know

et al. 2020

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An increase of multiple sclerosis (MS) incidence has been reported during the last decade, and this may be connected to environmental factors. This review article aims to encapsulate the current advances targeting the study of the gut–brain axis, which mediates the communication between the central nervous system and the gut microbiome. Clinical data arising from many research studies, which have assessed the effects of administered disease-modifying treatments in MS patients to the gut microbiome, are also recapitulated.

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Section: The Environmental Factor In Autoimmune Diseasementioning

confidence: 99%

Section: The Environmental Factor In Autoimmune Diseasementioning

confidence: 99%

Microbiome in Multiple Sclerosis: Where Are We, What We Know and Do Not Know

et al. 2020

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“…CD4 + T cells can be thought of as master regulators of the immune response during MS, whereas perivascular CD8 + T cells, microglial cells, macrophages, and even neutrophils largely mediate white matter damage [2]. Genome-wide association studies (GWAS) pinpoint the major histocompatibility complex (MHC) genes located in the human leukocyte antigen (HLA) region as having the strongest influence on disease, further emphasizing the importance of T cells in MS pathophysiology [3].…”

Section: Introductionmentioning

confidence: 99%

T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response

Kim

Dickey

Stone

et al. 2019

J Neuroinflammation

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Background Treatments for autoimmune diseases aim to dampen autoreactivity while preserving normal immune function. In CD4 + T cells, the transcription factor Oct1/Pou2f1 is a dispensable transcription factor for T cell development and response to primary infection, but promotes expression of target genes, including Il2 and Ifng , under conditions of antigen reencounter. As a result, they are more strongly expressed upon secondary stimulation. Such repeated antigen encounters occur in memory recall responses, in autoimmunity where self-antigen can be recognized multiple times, and in chronic infection where foreign antigen is persistent. Based on these previous findings, we hypothesized that Oct1 loss would protect animals from autoimmunity but maintain normal responses to pathogens in the CNS. Objective We used a conditional mouse Oct1 ( Pou2f1 ) allele and a CD4-Cre driver to determine the effect of T cell-specific Oct1 loss on autoimmune- and viral-induced neuroinflammation using an autoantigen-driven EAE model of autoimmunity and a JHMV model of viral infection. Results Oct1 conditional deletion mitigated clinical scores and reduced infiltrating T cells and cytokine production in the EAE model. Consistently, Oct1-deficient CD4 + T cells stimulated in vitro showed increased expression of markers associated with T cell anergy, particularly in the absence of co-stimulatory signals. In contrast, anti-viral T cell effector functions are intact in the absence of Oct1, with no changes in neuroinflammation, infiltrating T cells or cytokine production. Conclusion Our findings uncover a significant difference between the effect of Oct1 loss on autoimmune and anti-pathogen responses, which potentially could be exploited for therapeutic benefit. Electronic supplementary material The online version of this article (10.1186/s12974-019-1523-3) contains supplementary material, which is available to authorized users.

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“…According to the report provided by Atlas of MS in 2013, the number of individuals affected by MS is about 2.3 million [ 4 ]. Previous Genome-wide association studies (GWAS) uncovered that about 200 variants in the human genome are associated with MS and they mainly affect immunological process related genes and lie in their regulatory regions [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variant rs755622 Regulates Expression of the Multiple Sclerosis Severity Modifier D-Dopachrome Tautomerase in a Sex-Specific Way

Han

Zhao

et al. 2018

BioMed Research International

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Multiple sclerosis (MS) is a sex-specific autoimmune disease involving central nervous system. Previous studies determined that macrophage migration inhibitory factor (MIF) and its homologue D-dopachrome tautomerase (DDT) sex-specifically affect MS progression. Moreover, other studies reported that rs755622 polymorphism in promoter region of MIF gene is associated with risk of MS and affects the promoter activity to regulate MIF expression in a sex-specific way. Given that MIF and DDT share a part of promoter sequence, we surmise that rs755622 can also regulate DDT expression in a sex-specific way. However, this has not yet been studied. Here, we used five large-scale expression quantitative trait loci (eQTLs) and two RNA-seq datasets from brain and blood to assess the potential influence of rs755622 variant on expression of DDT in different genders by the linear regression and differential expression analysis. The results show that the minor allele frequency of rs755622 and expression of DDT are significantly increased in males for MS subjects and this minor allele variant can significantly upregulate DDT expression for males but not females, which suggests that the regulation of DDT expression level by rs755622 can affect MS progression in males. These findings further support and expand conclusions of previous studies and may help to better understand the mechanisms of MS.

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Genetics of Multiple Sclerosis: An Overview and New Directions

Cited by 131 publications

References 113 publications

Microbiome in Multiple Sclerosis: Where Are We, What We Know and Do Not Know

Microbiome in Multiple Sclerosis: Where Are We, What We Know and Do Not Know

T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response

Genetic Variant rs755622 Regulates Expression of the Multiple Sclerosis Severity Modifier D-Dopachrome Tautomerase in a Sex-Specific Way

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