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Supplementary material and methods

IV.1. a.i. Multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the CNS, which affected 2.5 million people worldwide in 2015, although its incidence varies greatly across world areas (Dendrou et al., 2015). The onset occurs usually in early- to mid-adulthood, and the prevalence is higher in women (Dendrou et al., 2015; Whitacre, 2001).

MS is a heterogeneous disease, with clinical characteristics that depend on the location of lesions within the CNS (Roman and Arnett, 2016). These lesions originate from an autoimmune attack against myelin, which is produced by oligodendrocytes and protects neuron fibers, leading to a rupture in neuron electric signals (Compston and Coles, 2008; Dendrou et al., 2015; Hemmer et al., 2015).

Patients are divided into three main clinical groups. About 85% of patients suffer from the relapsing-remitting form of MS (RRMS) at onset, which consists in acute relapses during several days, followed by remitting periods (Antel et al., 2012; Roman and Arnett, 2016). About 80% of the RRMS patients evolve towards a secondary progressive MS (SPMS) form, in which there is no remitting phase and that is associated with CNS atrophy and axonal loss. The remaining 20%

stay in the RRMS clinical form. Finally, about 15% of patients suffer from a primary progressive (PPMS) form, in which the disease is in constant progression since onset (Antel et al., 2012;

Roman and Arnett, 2016).

IV.1.a.ii. Causes

Although the causes of MS are not fully understood, the consensus points towards genetic susceptibilities, accounting for 30% of the pathogenesis, in combination with environmental factors, which account for 70% of the disease, with none of the genetic or environmental factors that could cause the disease alone (Brown, 2016; Compston and Coles, 2008; Olsson et al., 2017).

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Genetic susceptibilities

MS is not a hereditary disease. For instance, MS patient monozygotic twins do not necessarily develop the disease. Nonetheless, offsprings and siblings, especially monozygotic twins, of these patients are at higher risks, compared with the general population (Hemminki et al., 2009;

Wekerle, 2015). However, this is not due to one particular gene but rather linked with several genes, a majority of which being related to immune functions (Axisa and Hafler, 2016; Inshaw et al., 2018). Genome-wide association studies (GWAS) have lately revealed many variants associated with increased risks to develop MS. Major risk alleles are linked with MHC-II molecules, especially HLA-DRB1*1501 (Dendrou et al., 2018; International Multiple Sclerosis Genetics et al., 2007; International Multiple Sclerosis Genetics et al., 2011; Jersild et al., 1972;

Naito et al., 1972). In addition, many single nucleotide polymorphisms (SNPs) have been assigned to genes involved in various immune pathways such as adhesion molecules, cytokine production, central tolerance mechanisms, and T cell homeostasis, activation, proliferation and differentiation (Dendrou et al., 2015; International Multiple Sclerosis Genetics et al., 2013;

International Multiple Sclerosis Genetics et al., 2011).

Environmental factors

As above-mentioned, the incidence of MS varies greatly depending on world regions (Ascherio and Munger, 2007; Dendrou et al., 2015; Milo and Kahana, 2010). Immigration studies have shown that people emigrating from high to low incidence areas had decreased risks to develop MS, while the ones migrating in the opposite direction had the same risks as in their country of origin (Dean and Elian, 1997; Ebers, 2008; Gale and Martyn, 1995; Milo and Kahana, 2010).

These changes in the risk of developing MS were dependent on the ethnicity and on the age at immigration; exposure to environmental factors, such as infectious agents, before a certain age could be implicated (Dean and Elian, 1997; Ebers, 2008; Gale and Martyn, 1995; Milo and Kahana, 2010). This idea is linked with the hygiene hypothesis, which postulates that the reduced frequency of infections observed in the developed world is implicated in the increased frequency of autoimmune and allergic diseases (Ascherio and Munger, 2007; Bach, 2018; Gale and Martyn, 1995).

Two environmental factors are, in particular, thought to play a major role in MS pathogenesis:

low vitamin D levels and Epstein-Barr virus (EBV) infection (Brown, 2016; Milo and Kahana, 2010). Other factors such as cigarette smoking, obesity and low melatonin levels, as well as other viruses have been suggested to be implicated in the pathophysiology of MS, although their roles will not be detailed here (Bar-Or, 2016; Leibovitch et al., 2018; Olsson et al., 2017).

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Epstein-Barr virus

The role of infection by EBV, a herpes virus that is causing mononucleosis, has not been fully elucidated, but increasing evidence suggests it would be a causative agent of MS (Brown, 2016;

Geginat et al., 2017). Most of MS patients are infected by EBV, and have higher titers of antibodies directed towards EBV compared with infected individuals from the general population (Ascherio and Munger, 2007; Haahr and Hollsberg, 2006; Pender and Burrows, 2014). Of note, HLA-DRB1*1501 individuals with an infectious mononucleosis had higher risks to develop MS, these two factors having synergistic effects (Disanto et al., 2013). Different theories have been formulated regarding the impact of EBV infection on MS prevalence, including: molecular mimicry, i.e. T cell clone recognizing both EBV and myelin antigens, leading to the activation of myelin antigen-specific T cells following EBV infection; breakdown of tolerance and subsequent bystander activation of autoreactive T cells; and infection of B cells by EBV (B cells are the primary target of EBV), B cells being involved in the pathogenesis of MS, the role of which will be briefly described later in this section (Brown, 2016; Geginat et al., 2017; Lang et al., 2002; Li et al., 2018; Pender, 2003; Wucherpfennig and Strominger, 1995).

Vitamin D

The fact that MS incidence increases with the latitude could be due to differences in sunlight intensity (Milo and Kahana, 2010). Indeed, correlations have been found between a lack of sunlight exposure and increased risks to develop MS (Alonso et al., 2011; Dalmay et al., 2010;

Goldacre et al., 2004). A possible explanation for this latitude gradient of MS incidence might be the effects of ultra violet (UV) on vitamin D release, UV converting the precursor of Vitamin D into its active form. MS patient sera contain lower vitamin D levels, and low vitamin D serum levels correlate with higher risks to develop MS. However, reduced serum vitamin D levels in MS patients might not only be due to a lack of sunlight exposure, but also to polymorphisms for genes involved in vitamin D metabolism and diet (Ascherio et al., 2012; Brown, 2016;

Shaygannejad et al., 2010; Smolders et al., 2009). Dietary vitamin D uptake has been correlated with decreased risks to develop MS (Munger et al., 2004). Vitamin D can affect immune responses in many different ways and the link between a lack of vitamin D and increased risk of MS development might be due to the induction of immune tolerance by vitamin D, such as the induction of tolerogenic DCs and subsequent Treg generation (Adorini, 2003; Adorini and Penna, 2009; Griffin et al., 2001).

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