A Single Non-Synonymous Polymorphism of TLR2 Is responsible for Variability of Experimental Multiple Sclerosis in SJL and B6 Mice

Background: Multiple sclerosis is characterized by variability of course and lesions distribution. The complexity of its presentation may reflect differences in either environment or genetic. In rodents challenge with peptides of myelin drives distinct forms of EAE in each strain/peptide pair, but it is difficult to assess the relative role of genetic background and antigens in determining the course of the disease. In all EAE models the administration of mycobacterium –derived motives is essential for disease development. TLR2 is the main receptor recognizing motives from M tuberculosis. Methods: To study the contribution of TLR2 genetics to EAE, we crossed SJL (TLR2 83Ile) and B6 (TLR2 83Met) mice, generating F1 of SJLxB6wt (heterozygous for TLR2 Ile83Met) and F1 of SJLxB6tlr2- (TLR2 83Ile). We then immunized both groups of F1 mice with PLP139-151 and examined course and lesion distribution of EAE. Results: TLR2 83Ile increases secretion of IFN-γ (P = 0.043) and IL-17 (P = 0.041), whereas IL-13 and FoxP3 are similar in both groups. Consequently there are significant differences in the EAE. F1 mice of SJLxB6tlr2- display a more severe EAE (P = 0.0004) in the absence of PTx administration. SJLxB6wt mice are sensitive to PTx administration, whereas F1 mice of SJLxB6tlr2 are not. EAE developed in SJLxB6wt mice has a clear progressive/chronic clinical course, whereas that obtained in SJLxB6tlr2- mice often show incomplete and of short duration signs of remission.SJLxB6tlr2- mice frequently display inflammatory lesions and demyelination in the frontal lobes. Conclusions: Thus, a single polymorphism of TLR2 modifies significantly clinical and histology of EAE.