Figure 4.

Modulation of multiple sclerosis risk from conception to the time of disease triggering.

Note that (a) risk factors for MS are multiple, genetic and environmental (lower part of the figure), (b) opposite conditions or other factors may be protective from MS occurrence (upper part of the figure), (c) interactions are numerous between all these risk and protective factors and (d) may occur throughout the first part of life, from conception until MS triggering. Note also that the period from conception to adolescence is crucial for the maturation of the immune system and thymus and could be particularly important for the interactions of the different protective and risk factors. In these successive events or situations, the likely risk factors are (see text): (1) unfavourable genetics, (1’) including HLA-DRB1*1501; (2) EBV infection, which may be a crucial event for subsequent MS (years later), with particularly an increase in MS risk if (2’) the primo-infection occurs late and (2”) is followed by a high anti-EBNA1 level; (3) vitamin D insufficiency, also increasing MS risk, (3’) including conditions likely related to this insufficiency or to insufficient exposure to sun; and (4) smoking, also contributing to this risk, even if (4’) it is only passive in childhood (however, with only one study having been reported so far). Reverse or other conditions could be protective: (1p) favourable genetics, (1p’) including HLA-A*0201; (2p) absence of EBV infection; (3p) vitamin D sufficiency, (3p’) including conditions likely related to a normal vitamin D status or sufficient exposure to sun; and (4p) numerous infections during childhood (hygienic hypothesis), possibly protective from subsequent auto-immune diseases. EBV, Epstein–Barr virus; HLA, human leukocyte antigen system; MS, multiple sclerosis.