Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis—a presymptomatic case–control study

Grut, Viktor; Biström, Martin; Salzer, Jonatan; Stridh, Pernilla; Jons, Daniel; Gustafsson, Rasmus; Fogdell‐Hahn, Anna; Huang, Jesse; Brenner, Nicole; Butt, Julia; Bender, Noemi; Lindam, Anna; Alonso-Magdalena, Lucía; Gunnarsson, Martin; Vrethem, Magnus; Bergström, Tomas; Andersen, Oluf; Kockum, Ingrid; Waterboer, Tim; Olsson, Tomas; Sundström, Peter

doi:10.1111/ene.14961

Cited by 28 publications

(27 citation statements)

References 42 publications

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“…MS risk was lower among CMV-positive than among CMV-negative individuals (Fig. 2D), consistent with a previous report and with suggestions that the immune response to CMV attenuates the adverse effects of EBV ( 16 ).…”

supporting

confidence: 92%

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Bjørnevik

Cortese

Healy

et al. 2022

Science

1,125

827

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

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supporting

confidence: 92%

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Bjørnevik

Cortese

Healy

et al. 2022

Science

1,125

827

View full text Add to dashboard Cite

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Section: Discussionmentioning

confidence: 99%

“…The sharing of clones that are identical in amino acid but different in the nucleotide sequences has been attributed to the process known as convergent recombination of TCR 26 , 27 and this process can be explained by the redundancy of the genetic code. Cytomegalovirus (CMV) infection is also another environmental risk factor for MS, however in the contrary to EBV infection a previous infection with CMV protects against MS. 28 , 29 Here, we have also identified clones that are targeting CMV antigens, mainly phosphoprotein 65 (pp65). Interestingly, clones targeting one of the pp65 epitopes, RPHERNGFTVL, were recently reported being only present in Japanese MS patients compared to healthy controls and mainly in patients carrying HLA‐DRB1*04:05 and associated with a favorable disability progression.…”

Section: Discussionmentioning

confidence: 99%

Copy number variations across the blood–brain barrier in multiple sclerosis

Bedri

Evertsson

Khademi

et al. 2022

Ann Clin Transl Neurol

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Objective Multiple sclerosis (MS) is a neuroinflammatory disease where immune cells cross the blood–brain barrier (BBB) into the central nervous system (CNS). What predisposes these immune cells to cross the BBB is still unknown. Here, we examine the possibility that genomic rearrangements could predisposespecific immune cells in the peripheral blood to cross the BBB and form sub‐populations of cells involved in the inflammatory process in the CNS. Methods We compared copy number variations in paired peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells from MS patients. Thereafter, using next generation sequencing, we studied the T‐cell receptor beta (TRB) locus rearrangements and profiled the αβ T cell repertoire in peripheral CD4+ and CD8+ T cells and in the CSF. Results We identified deletions in the T‐cell receptor alpha/delta (TRA/D), gamma (TRG), and TRB loci in CSF cells compared to PBMCs. Further characterization revealed diversity of the TRB locus which was used to describe the character and clonal expansion of T cells in the CNS. T‐cell repertoire profiling from either side of the BBB concluded that the most frequent clones in the CSF samples are unique to an individual. Furthermore, we observed a difference in the proportion of expanded T‐cell clones when comparing samples from MS patients in relapse and remission with opposite trends in CSF and peripheral blood. Interpretation This study provides a characterization of the T cells in the CSF and might indicate a role of expanded clones in MS pathogenicity.

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“…High anti-HHV-6A levels interacted with high anti-EBV levels and aggravated the MS risk ( 65 ). When adding CMV to the model people with high levels of anti-HHV-6A and anti-EBV antibodies, and low levels of anti-CMV antibodies had 15 times higher risk of developing MS later in life compared to people with low levels of IE1A and EBV antibodies and high levels of CMV ( 66 ).…”

Section: Hhv-6 In Msmentioning

confidence: 99%

Human Herpesvirus 6A Is a Risk Factor for Multiple Sclerosis

Lundström

Gustafsson

2022

Front. Immunol.

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The role for human herpesvirus (HHV)-6A or HHV-6B in multiple sclerosis (MS) pathogenesis has been controversial. Possibly because the damage of the virus infection may occur before onset of clinical symptoms and because it has been difficult to detect active infection and separate serological responses to HHV-6A or 6B. Recent studies report that in MS patients the serological response against HHV-6A is increased whereas it is decreased against HHV-6B. This effect seems to be even more pronounced in MS patients prior to diagnosis and supports previous studies postulating a predomination for HHV-6A in MS disease and suggests that the infection is important at early stages of the disease. Furthermore, HHV-6A infection interacts with other factors suspected of modulating MS susceptibility and progression such as infection with Epstein-Barr virus (EBV) and Cytomegalovirus (CMV), tobacco smoking, HLA alleles, UV irradiation and vitamin D levels. The multifactorial nature of MS and pathophysiological role for HHV-6A in inflammation and autoimmunity are discussed.

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Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis—a presymptomatic case–control study

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 28 publications

References 42 publications

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Copy number variations across the blood–brain barrier in multiple sclerosis

Human Herpesvirus 6A Is a Risk Factor for Multiple Sclerosis

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