Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis

Abstract

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.

Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis

“…Antibodies to EBV peptides were consistently higher among individuals with MS than among controls, with little or no signal for antibody responses to other viruses. The serologic response to human herpesvirus 6A, for example, specifically to peptides within immediate-early protein 1, previously suggested to play a role in MS etiology, were also not significantly different in cases and controls …”

Cytomegalovirus, Epstein-Barr Virus, Herpes Simplex Virus, and Varicella Zoster Virus Infection Dynamics in People with Multiple Sclerosis from Northern Italy

“…VZV infection may be associated with the development of MS particularly in non-European regions with different virus transmission characteristics [ 52 ]. There is strong evidence [ 7 , 53 ] that another human herpesvirus—HHV6A—is also associated with the development of MS. We plan to investigate this association in a separate study. The events that combine for MS to develop may occur many years before the appearance of disease.…”

“…The association between past exposure to Epstein–Barr virus (EBV) and MS strongly suggests causation [ 5 ], although the definitive mechanisms responsible remain to be determined [ 6 ]. Infection with other human herpesviruses may also be associated with the development of MS. Human herpesvirus 6A infection has been associated with an increased risk of developing MS [ 7 ]. There is also evidence that varicella zoster virus (VZV) infection may be linked with the development of MS in certain geographical areas [ 8 ].…”

Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank

“…To elucidate the trajectory of GFAP and NfL levels preceding dementia diagnosis, a backward time scale was adopted, setting time 0 as either the point of dementia diagnosis or the end of follow-up. Data visualization was performed using ggplot2 package (version 3.4.2), applying loess regression with a 95% confidence interval [ 38 ]. Sensitivity analyses included subgroup analysis by age, sex, BMI, self-reported racial background, genetic background (AD-GRS, number of APOE*E4 alleles), and comorbidities for incident all-cause dementia by using Cox PH model.…”