Gene regulation and immune mechanisms in multiple sclerosis experimental models

Abstract: Our strategy was to fine map and identify, in an unbiased way, genes or small regions that regulate myelin-oligodendrocyte glycoprotein-induced EAE (MOG-EAE). Such genes are important as they can then be tested for a role in MS. We focused on regions on rat chromosome 4 (RN04) and chromosome 15 (RN15), which were known to regulate neuroinflamation and are rich in immune-related genes. High resolution mapping of the two regions using data obtained from MOG-EAE experiments in the 7th (G7) and 10th (G10) generation of an advanced intercross line between susceptible DA and resistant, but MHC identical, PVG.AV1 strains confirmed their influence on MOG-EAE. Very narrow QTL confidence intervals with restricted sets of genes were demonstrated. Experiments in congenic strains confirmed the QTLs. Interaction analyses revealed interesting features within RN04. One QTL, Eae22, was only identified when epistasis was considered. Other QTLs, Eae24, Eae26 and Eae28 were linked to susceptibility phenotypes, whereas Eae24, Eae25, Eae26 and Eae27 were linked to severity phenotypes. Anti-MOG antibody levels for IgG1 were linked to Eae24. This is the first time that this immunological sub-phenotype has been linked to a locus that affects EAE. Studies of innate immunity aspects of MOG-EAE showed that induction of EAE requires MyD88-dependent signaling pathways. MyD88 was required for IL-6 and IL23 expression in mDC and the number of Th17 cells was reduced in MyD88-/- mice. Further, MOG-EAE was exacerbated in mice that lacked TLR4, TLR4 signaling decreased IL-6 and IL-23 production and TLR4-/- mice had a higher frequency of splenic Th17 cells and more sera IL-17. TLR9-/- mice developed more severe MOGEAE and higher IL-17 levels than WT mice, indicating that TLR9, like TLR4, regulates rather than promotes MOG-EAE. In conclusion, the fine mapping studies revealed restricted sets of candidate genes that regulate EAE and gene-gene interactions. Also, innate immunity signaling pathways affect EAE. The findings provide a basis for unraveling immune mechanisms in MS.