Smoking and Epstein–Barr virus infection in multiple sclerosis development

Abstract

It is unclear whether smoking interacts with different aspects of Epstein-Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case-control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2-0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI − 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004-0.4), but not between past smoking and IM history (AP − 0.06, 95% CI − 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with underlying genetic and environmental factors. Smoking, high levels of EBNA-1 Immunoglobulin G (IgG), and infectious mononucleosis (IM) history have consistently been associated with increased MS risk 1-3. Previous studies on the interplay between smoking and aspects of EBV infection have used different study designs and statistical methods, and sample sizes have often been limited which may have contributed to conflicting results (Table 1). The first study observed a positive interaction on the multiplicative scale between smoking and elevated EBNA-1 IgG levels with regard to MS risk 4. Smoking was only observed to increase MS risk among subjects with high EBNA-1 IgG levels. These findings were not replicated in other studies 5-7. A recent study showed a trend towards a negative interaction among young adults and a trend towards a positive interaction among older subjects, as defined by age at EBV assessment, suggesting age may influence the interaction between smoking and EBNA-1 IgG levels 8. Results from previous studies on a possible interaction between smoking and IM history have also been conflicting. Two studies found no interaction between smoking and IM history 6,7 , whereas a recent study reported a negative interaction on the multiplicative scale regarding MS risk 9. Using two Swedish population-based case-control studies comprising 6,340 cases and 6,219 controls, we aimed to investigate the interplay between smoking and different aspects of EBV infection [elevated EBNA-1 IgG levels and infectious monon...

Epstein-Barr Virus and multiple sclerosis in a Spanish cohort: A two-years longitudinal study

“…After stratification by other predisposing factors for MS like HLA DRB1*15:01, vitamin D deficiency and smoking habit, EBNA-1 and VCA IgG prevalences and titers remained significantly higher in MS patients than in controls. A recent study with the Swedish cohort showed that smokers had higher EBNA-1 antibody levels than never smokers; authors suggested that smoking habit and EBNA-1 antibody levels could act synergistically to increase MS risk ( 16 ). Interestingly, we did not find a significant difference in EBNA-1 and VCA IgG prevalences between current smokers (MS patients and controls); a higher prevalence of both antibodies was found in the control group of current smokers than in the control group of no smokers, although this increase was not higher enough to be significantly different between both groups.…”

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

“…Smoking cigarettes is a well‐established risk factor for MS. 152 Recently, the impact of smoking on EBV reactivation and circulating levels of anti‐EBNA IgG and IgA has been investigated. 153 These and other studies 154 suggest that smoking may promote EBV reactivation and increase serum EBNA‐1 IgG antibody levels. Furthermore, a history of IM and smoking appears to interact to increase the risk of MS. 153 Cigarette smoking also affects the composition of the gut microbiome 155 and may interact with other factors affecting the gut microbiome in MS patients.…”

“… 153 These and other studies 154 suggest that smoking may promote EBV reactivation and increase serum EBNA‐1 IgG antibody levels. Furthermore, a history of IM and smoking appears to interact to increase the risk of MS. 153 Cigarette smoking also affects the composition of the gut microbiome 155 and may interact with other factors affecting the gut microbiome in MS patients. Smoking induces an expansion of circulating cMBCs, including IgA + cells, 156 , 157 but this effect may be transient because circulating B‐cell profiles are not different in smokers and non‐smokers.…”

Epstein-Barr Virus and Neurological Diseases

“…EBV infection can induce organismal immune disorders and promote the development of MS ( Hedstrom et al, 2020 ). The majority of adult patients with MS are EBV-positive before the onset of MS, indicating that EBV-seronegative individuals have a low risk of MS ( Drosu et al, 2021 ).…”