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Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0002-5415-6567
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0003-3994-2305
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0002-9205-0771
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
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2024 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 147, no 1, p. 177-185Article in journal (Refereed) Published
Abstract [en]

Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A.

A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI).

Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis).

In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.

Place, publisher, year, edition, pages
Oxford University Press, 2024. Vol. 147, no 1, p. 177-185
Keywords [en]
axonal injury, Epstein-Barr virus, human herpesvirus 6-A, multiple sclerosis, neurofilament light chain
National Category
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-219831DOI: 10.1093/brain/awad374ISI: 001129461500001PubMedID: 37930324Scopus ID: 2-s2.0-85181761078OAI: oai:DiVA.org:umu-219831DiVA, id: diva2:1830096
Funder
Swedish Research Council, 2015-02419Visare NorrRegion Jämtland Härjedalen, JLL-967380The Swedish Brain FoundationEU, Horizon 2020, 733161Swedish Research Council, 2017-00915Swedish Research Council, 2022-00732Available from: 2024-01-22 Created: 2024-01-22 Last updated: 2024-07-02Bibliographically approved
In thesis
1. Exposures associated with multiple sclerosis development: presymptomatic case-control studies
Open this publication in new window or tab >>Exposures associated with multiple sclerosis development: presymptomatic case-control studies
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Exponeringar associerade med multipel skleros : presymptomatiska fall-kontrollstudier
Abstract [en]

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease affecting the central nervous system. The current view is that MS is caused by a complex interplay of several environmental factors, eliciting an immune reaction in genetically susceptible individuals. Most previous studies of MS aetiology were retrospective, conferring the risk of reverse causation or recall bias. Few studies have been performed on data collected before the onset of the disease. The objective of this project was to identify risk factors for MS by analysing markers of exposure in samples collected before the clinical onset of MS.

Method: A series of nested case-control studies were performed by cross-linking Swedish MS registries with Swedish biobanks, thereby identifying serum or plasma samples from up to 837 cases who later developed MS. For each case, up to two matched controls were selected. The following environmental risk factors were assessed: Antibodies against herpesviruses Epstein-Barr virus (EBV), Human herpesvirus 6A (HHV-6A) and Cytomegalovirus (CMV); Free Vitamin D3 Index and Vitamin D Binding Protein (DBP); and C-reactive Protein (CRP). Early signs of neural injury were assessed by measuring the concentration of neurofilament light chain in serum (sNfL). The associations between the environmental factors and future development of MS were analysed with conditional logistic regression, calculating odds ratios (OR) with 95% confidence intervals (CI). Interactions were analysed on the multiplicative and additive scales. The temporal relation of HHV-6A serostatus and axonal injury was analysed with locally estimated scatterplot smoothing regression.

Results: Serological evidence of CMV infection was associated with a lower risk of MS development (OR = 0.70, 95% CI 0.56–0.88). Antagonistic interactions were observed between serological signs of CMV, HHV-6A, and EBV infection. Antibodies against HHV-6A were associated with a higher level of sNfL. In MS cases, increasing levels of HHV-6A antibodies were detected several years before increasing sNfL. Among young individuals, high levels of Free Vitamin D3 Index were associated with a lower MS risk (OR = 0.37, 95% CI 0.15–0.91). In older individuals, high levels of DBP were associated with a lower risk of developing MS (OR = 0.36, 95% CI 0.15–0.85). Elevated levels of CRP were not associated with MS risk.

Conclusions: These results strengthen the evidence for HHV-6A and EBV in MS aetiology. They also support the hypothesis that CMV infection and a high level of free Vitamin D3 during childhood and adolescence are associated with a lower risk of MS later in life. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 86
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2289
Keywords
multiple sclerosis, risk factors, epidemiology, nested case-control study, Cytomegalovirus, Human herpesvirus 6A, Epstein-Barr virus, systemic inflammation, vitamin D, Vitamin D binding protein
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-224589 (URN)9789180703109 (ISBN)9789180703116 (ISBN)
Public defence
2024-06-14, Hörsal B, våning 9, byggnad 1D, Norrlands universitetssjukhus, Umeå, 13:00 (English)
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Supervisors
Available from: 2024-05-24 Created: 2024-05-20 Last updated: 2024-05-21Bibliographically approved

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Grut, ViktorBiström, MartinSalzer, JonatanLindam, AnnaSundström, Peter

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