Is Hypovitaminosis D one of the Environmental Risk Factors for Multiple Sclerosis?

Charles Pierrot-Deseilligny; Jean-Claude Souberbielle


Brain. 2010;133(7):1869-1888. 

In This Article

Risk Factors for Multiple Sclerosis

Multiple sclerosis is considered to be an autoimmune disease, although its precise pathogenesis remains obscure. It is generally accepted that upstream to the disease different types of risk factors exist, even if we do not know exactly how these lead to the disease itself (Fig. 1). Among the risks, numerous genetic factors have been identified; in particular some susceptibility appears to exist in the histocompatibility complex of the human leucocyte antigen (HLA) (Sawcer and Compston, 2006; Compston and Coles, 2008; Chao et al., 2009; International Multiple Sclerosis Genetics Consortium, 2009; Ramagopalan et al., 2009a). Genetic factors will not be reviewed here, but we shall often refer to their actions, which appear to be of primary importance in influencing the risk of developing multiple sclerosis.

Figure 1.

Main risk and protective factors (arrows) for multiple sclerosis and arguments (bars) supporting a role of hypovitaminosis D among the environmental risk factors. Note that the mixing of all risk (and protective) factors is schematized in the orange ring surrounding multiple sclerosis.

Environmental risk factors are also strongly related to multiple sclerosis (Giovannani and Ebers, 2007; Ebers, 2008; Handel et al., 2010) (Fig. 1). The effects of latitude, climate and, most recently, hypovitaminosis D have successively been considered, even if the latter had previously been envisaged a long time ago (Goldberg, 1974). There are also infectious environmental risk factors, principally involving past infections with the Epstein-Barr—or related—virus (Bagert, 2009). Thus, after such infections and a variable but usually quite long latency, an immunological cascade could eventually trigger the disease, with a risk of multiple sclerosis multiplied by 20 or 30 if infectious mononucleosis is clinically expressed during adolescence (Thacker et al., 2006; Ascherio and Munger, 2007a, 2008; Zaadstra et al., 2008; Ramagolapan et al., 2009d). Furthermore, smoking could be both a premorbid risk factor and a deleterious factor influencing the course of the disease (Hernan et al., 2005; Ascherio and Munger, 2007a; Mikaeloff et al., 2007; Pittas et al., 2009). There may well be other, as yet undiscovered, environmental risk factors.

Moreover, it seems likely that a combination of several different risk factors is needed in order to trigger the disease (Compston and Coles, 2008; Goodin, 2009; Handel et al., 2010) (Fig. 1). For example, hypovitaminosis D (Hayes and Donald Acheson, 2008; Holmoy, 2008) or smoking (Simon et al., 2010) may potentiate the immunological stigmata of a past infection with Epstein-Barr virus and an increased susceptibility to the disease may result from the coexistence of some HLA groups with hypovitaminosis D (Niino et al., 2000; Ramagopalan et al., 2009c) or with the effects of a past infection with Epstein-Barr virus (De Jager et al., 2008, 2009; Sundström et al., 2008, 2009). Furthermore, protective genetic and environmental factors (Fig. 1) may counterbalance some of the deleterious effects of risk factors e.g. a climate offering a normal vitamin D status and, in the infectious field, the so-called 'hygiene' hypothesis, in which multiple infections occurring in early childhood (versus later in the life) could have a subsequent protective effect against autoimmune diseases (Ascherio and Munger, 2007a, 2008). Lastly, several crucial epochs for risk acquisition from the environment appear to exist (Ebers, 2009; Handel et al., 2010; McDowell et al., 2010). Environmental risk factors (i) could have affected previous generations, leaving a susceptibility for future generations via the HLA system (Chao et al., 2009); (ii) may also be present during pregnancy (see below influence of month of birth); (iii) may be important during childhood and adolescence (see below exposure to sun during this time of life); or (iv) could affect young adults (Munger et al., 2006), including after migrations (Ascherio and Munger, 2007b) (see below). Accordingly, generally speaking, it may be suggested that depending on the ethnic group, individual genetics, the familial environmental history, the month of birth, the latitude and climate of the country where a person has lived, the individual lifestyle in that country, infections that occurred in early childhood or during adolescence and other possible environmental factors, including smoking, multiple sclerosis will either start one day or never occur (Fig. 1). Finally, within the realm of all these risk factors, the potential pathogenic role of hypovitaminosis D appears to be relatively limited, possibly accounting for a significant effect at the scale of a population but not for the whole range of individual situations, in which genetics and several other environmental risk factors could interact in a very variable way without always requiring hypovitaminosis D to trigger the disease.


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