Low sun exposure acts synergistically with high Epstein−Barr nuclear antigen 1 (EBNA‐1) antibody levels in multiple sclerosis etiology

Abstract

Background Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein‐Barr nuclear antigen 1 (EBNA‐1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein‐Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA‐1 antibody levels regarding MS risk. Methods We used a population‐based case−control study involving 2017 incident cases of MS and 2443 matched controls. We used logistic regression models to calculate the odds ratios of MS with 95% confidence intervals (CIs) in subjects with different sun exposure habits and EBNA‐1 status. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Results Low sun exposure acted synergistically with high EBNA‐1 antibody levels (AP 0.2, 95% CI 0.03–0.3) in its association to increased MS risk. The interaction was present regardless of HLA‐DRB1*15:01 status. Conclusions Low sun exposure may either directly, or indirectly by affecting vitamin D levels, synergistically reinforce pathogenic mechanisms, such as aspects of the adaptive immune response, related to MS risk conveyed by EBV infection.

Epstein–Barr virus infection, B‐cell dysfunction and other risk factors converge in gut‐associated lymphoid tissue to drive the immunopathogenesis of multiple sclerosis: a hypothesis

“…In a recent report, low sun exposure acted synergistically with high EBNA‐1 antibody levels in its association to increased MS risk 142 supporting the submitted hypothesis. The authors proposed that the two risk factors for MS (EBV infection and low sun exposure) re‐enforced the actions of each other.…”

“…[139][140][141] A recent study by our group suggested that narrowband UVB phototherapy primed the participant's B cells to be less responsive to activation through TLR7. 8 Direct induction of type I IFNs through sun exposure could be another mechanism of UVinduced immune modulation of MS. 138 In a recent report, low sun exposure acted synergistically with high EBNA-1 antibody levels in its association to increased MS risk 142 supporting the submitted hypothesis. The authors proposed that the two risk factors for MS (EBV infection and low sun exposure) re-enforced the actions of each other.…”

Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis

“…It is well established that Epstein-Barr virus (EBV) infection is associated with an increased risk of MS and is a prerequisite for disease development (4)(5)(6). In addition, aspects of EBV infection interact with both genetic and environmental risk factors, and combinations are associated with markedly increased MS risk (7)(8)(9)(10)(11). The exact mechanisms of these associations are not fully understood, and as more than 90% of the general population is infected with EBV, but only a few develop MS, other underlying mechanisms must be at play (4).…”

Adoptive T‐cell therapy targeting Epstein–Barr virus as a treatment for multiple sclerosis

“…Another important aspect of the link between EBV and MS is the molecular mimicry with cross‐reactive autoantibodies recognising EBV proteins and self‐antigens (Figure 2). 2 Of particular interest is the elevated levels of EBNA1‐specific antibodies in their serum and cerebrospinal fluid of MS patients 57–59 . These elevated levels of EBNA1‐specific antibodies have been recognised as a biomarker for an increased risk of MS 60 .…”

“… 2 Of particular interest is the elevated levels of EBNA1‐specific antibodies in their serum and cerebrospinal fluid of MS patients. 57 , 58 , 59 These elevated levels of EBNA1‐specific antibodies have been recognised as a biomarker for an increased risk of MS. 60 Furthermore, T cells specific for EBNA1 antigens have been shown to recognise myelin basic protein, anoctamin 2, α‐crystallin B chain and more recently glial cell adhesion molecule (GlialCAM). 2 , 61 , 62 , 63 Other EBV‐specific T cells directed to viral lytic antigens including BHRF1 and BPLF1 cross‐react with self‐antigen RASGRP2 which is expressed in the brain.…”