Individual and Joint Action of Environmental Factors and Risk of MS
Section snippets
A causal pie model for multiple sclerosis
MS is a complex multifactorial disease wherein a variety of environmental and genetic factors interplay to manifest in the clinical disorder recognized by all neurologists. Rothman’s “Causal Pie Model”1 is a useful framework to understand this interplay of etiological factors, allowing a structure wherein individual components can act together to cause disease. These components may be simplified as “slices of a pie” (Fig. 1), with a given causal mechanism requiring the joint action of many
Epstein-Barr virus
Infections are usual suspects among potential etiological factors in autoimmune disease, thought to act by molecular mimicry, for example, Campylobacter and Guillain-Barré syndrome, or by passive changes in immune modulation. EBV is the only viral agent with convincing and consistent evidence for an association with MS onset. EBV is a member of the Herpesviridae group. Whereas primary EBV infection in childhood is normally asymptomatic, infection at or after adolescence often results in
Sun exposure/vitamin D
It has long been recognized that MS has a distinct geographic variability in its distribution, with the frequency of MS increasing with increasing latitude,29, 30 and this gradient has been borne out in meta-analyses of MS prevalence and incidence.31, 32 Of interest, a recent study conducted in Australia found a latitudinal gradient in the incidence of first demyelinating events, with the incidence rate increasing by 9.55% per degree increase in latitude.33 Although differences in allele
Smoking
A large number of studies, including prospective studies,98, 99, 100, 101 have found a positive association between smoking and MS. The results have been very consistent in that few have reported a null finding and none an inverse association. The magnitude of effect is modest, with a 2007 meta-analysis of 6 epidemiologic studies finding a pooled estimate for ever smoking versus never smoking of 1.34 (1.17–1.54).102 Of note, the 3 retrospective studies provided a slightly stronger risk estimate
Infections as a protective factor
Infections might also play a protective role. Bach119 demonstrated that the increased incidence over time of autoimmune and allergic diseases such as MS, type 1 diabetes, Crohn disease, and asthma coincided with the decrease in incidence of measles, mumps, rheumatic fever, hepatitis A, and tuberculosis. These observations might be related to infection load during early childhood. In atopic disease, there is evidence for the so-called Hygiene Hypothesis, where increased hygiene and smaller
Other factors
Several studies have investigated the relationship between human herpes virus (HHV)-6 and MS, but the results have been mixed. A systematic review of the literature between 1965 and 2001, which included 28 studies of serum, CSF, and/or pathology for the presence and quantity of serologic and/or direct evidence of HHV-6 infection, found no conclusive evidence of a difference in HHV-6 infection between cases and controls and thus, no association between HHV-6 and MS.126 Subsequent studies have
The joint action of risk factors
Recently, an increasing number of research groups has examined the combined action of 2 or more risk factors. In the most general sense, two risk factors are said to interact with one another if the effect of the first factor on disease risk depends on the level of the second factor, and vice versa. For gene-environment interaction, attention has largely focused on the major genetic risk factor HLA-DR15. Thus, the effect of an environmental exposure on MS might depend on whether a person is
Summary
The etiology of MS is a complex story with multiple factors playing a role at different times during life, interacting with each other to ultimately manifest in MS. Using the Rothman Causal Pie Model helps demonstrate that the way these factors come together to cause disease is somewhat idiosyncratic, with different individuals having different paths to disease; this complicates the task of epidemiologists. Defining causal associations is only a part of the whole equation. Knowing how causal
References (171)
- et al.
Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study
Lancet Neurol
(2007) Preventing and curing multiple sclerosis by controlling Epstein-Barr virus infection
Autoimmun Rev
(2009)- et al.
Maternal vitamin D3 deprivation and the regulation of apoptosis and cell cycle during rat brain development
Brain Res Dev Brain Res
(2004) - et al.
Maternal vitamin D depletion alters neurogenesis in the developing rat brain
Int J Dev Neurosci
(2007) - et al.
Vitamin D3 and brain development
Neuroscience
(2003) - et al.
Developmental vitamin D3 deficiency alters the adult rat brain
Brain Res Bull
(2005) - et al.
Developmental vitamin D deficiency causes abnormal brain development
Psychoneuroendocrinology
(2009) - et al.
Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring
Psychoneuroendocrinology
(2007) - et al.
Differential effects of 1,25-dihydroxyvitamin D3 on human lymphocytes and monocyte/macrophages: inhibition of interleukin-2 and augmentation of interleukin-1 production
Cell Immunol
(1986) Immunomodulatory actions of 1,25-dihydroxyvitamin D3
J Steroid Biochem Mol Biol
(1995)
1,25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR
Cell Immunol
Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D(3) in the immune system
J Steroid Biochem Mol Biol
Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory
Diabetes Res Clin Pract
1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis
Brain Res Mol Brain Res
Peripheral blood regulatory T cell measurements correlate with serum vitamin D levels in patients with multiple sclerosis
J Neuroimmunol
Regulatory T cell function correlates with serum 25-hydroxyvitamin D, but not with 1,25-dihydroxyvitamin D, parathyroid hormone and calcium levels in patients with relapsing remitting multiple sclerosis
J Steroid Biochem Mol Biol
Effects of UV on the migration and function of epidermal antigen presenting cells
Mutat Res
Causation and causal inference in epidemiology
Am J Public Health
The environment and disease: association or causation?
Proc R Soc Med
Epstein-Barr virus: exploiting the immune system
Nat Rev Immunol
Multiple sclerosis is linked to Epstein-Barr virus infection
Rev Med Virol
Environmental risk factors for multiple sclerosis. Part I: the role of infection
Ann Neurol
Epstein-Barr virus and multiple sclerosis
Epidemiology
Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis
Ann Neurol
Selective association of multiple sclerosis with infectious mononucleosis
Mult Scler
Multiple sclerosis after infectious mononucleosis
Arch Neurol
Association of infectious mononucleosis with multiple sclerosis. A population-based study
Neuroepidemiology
Multiple sclerosis and age at infection with common viruses
Epidemiology
Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study
JAMA
Multiple sclerosis and Epstein-Barr virus
JAMA
Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up
Arch Neurol
Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis
JAMA
An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study
Neurology
Demonstration of the Burkitt’s lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cells in vivo
Proc Natl Acad Sci U S A
Human leukocyte antigen-DR15, low infant sibling exposure and multiple sclerosis: gene-environment interaction
Ann Neurol
High seroprevalence of Epstein-Barr virus in children with multiple sclerosis
Neurology
Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis
Clin Exp Immunol
Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis
Brain
Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis
J Clin Invest
EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2
J Exp Med
Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain
J Exp Med
Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain
Brain
Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis
Neurology
Epidemiology of multiple sclerosis in Australia. With NSW and SA survey results
Med J Aust
Geography in multiple sclerosis
J Neurol
The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. A meta-analysis study
Neuroepidemiology
Temporal trends in the incidence of multiple sclerosis: a systematic review
Neurology
Latitudinal variation in incidence and type of first central nervous system demyelinating events
Mult Scler
Population frequency of HLA haplotypes contributes to the prevalence difference of multiple sclerosis in Ireland
J Neurol
Genetic and environmental factors and the distribution of multiple sclerosis in Europe
Eur J Neurol
Cited by (59)
Geochemistry of multiple sclerosis in Finland
2022, Science of the Total EnvironmentDistinguishing CNS neurosarcoidosis from multiple sclerosis and an approach to “overlap” cases
2022, Journal of NeuroimmunologyCitation Excerpt :The risks underlying the development of either condition are not completely understood. MS and sarcoidosis both arise due to a complex interplay between polygenetic mechanisms and environmental factors, with low vitamin D and previous Epstein-Barr virus infection particularly associated with the development of MS (Van der Mei et al., 2011; Bjornevik et al., 2022). Sarcoidosis is characterized by T cell-driven primarily non-necrotizing granulomatous inflammation, although the inciting specific antigens or micro-organism have not been identified to date, and currently no pathognomonic diagnostic markers exist (Smith et al., 2008; van der Mei et al., 2011; Grunewald et al., 2019; Sève et al., 2021).
Multiple Sclerosis and Smoking
2020, American Journal of MedicineCitation Excerpt :In addition, smoking can affect the levels of interleukin-1 and interleukin-6 in the body. The entry of these mediators into the central nervous system and their interaction with other inflammatory markers affecting the autoimmune response can influence the development of MS.65,66 Furthermore, chemicals such as nicotine and acrolein have been linked to immunomodulatory effects that influence MS; these substances can hinder the T-cell response and the function of different antigen-presenting cells in the body.11,67 In addition, tobacco can increase Fas expression in CD4+ T lymphocytes.11
Cigarette smoking and nicotine: Effects on multiple sclerosis
2019, Neuroscience of Nicotine: Mechanisms and TreatmentFactors associated with onset, relapses or progression in multiple sclerosis: A systematic review
2017, NeuroToxicologyCitation Excerpt :Although a recent study has questioned whether the season/month of birth effect in diseases such as MS is actually an artifact, or chance finding, related to natural variation in both regional and temporal months of birth in any underlying (control) population (Fiddes et al., 2013). Much discussion has surrounded the possible timing of environmental exposures after birth which might trigger MS onset, with no definitive answers (Handel et al., 2010b; van der Mei et al., 2011). Evidence from studies included in our review suggested that early childhood through until adolescence represent ‘at risk’ periods, with increased sun exposure, vitamin D intake or exposure to infant siblings during these times associated with a reduced risk of multiple sclerosis (Islam et al., 2007; Dalmay et al., 2010; van der Mei et al., 2003; Ponsonby et al., 2005; McDowell et al., 2010).
Financial disclosures and/or conflicts of interest: The authors have nothing to disclose.