Genetic control of pathogenic mechanisms in autoimmune demyelinating disease.

Multiple sclerosis is a disease of discrete phenotypes in different individuals. Animal models have been useful in identifying self-antigens that become the focus of autoimmune attack and genetic loci that control susceptibility to disease. We have previously demonstrated a role for Fas-dependent pathogenesis in the induction of EAE in B10.PL mice immunized with MBP. Others have indicated a Fas-independent mechanism predominates in SJL mice immunized with PLP. Here we compare the response of (B10.PLxSJL)F1 and parental mice under similar conditions for induction of EAE. The results indicate that immunodominance and dominant pathogenic mechanisms are both under genetic control, but can be inherited independently. The data also indicate that the dominant pathogenic mechanism can change during the course of disease in an individual. Elucidation of the genetic elements controlling pathogenesis during the course of disease would provide important information in designing therapeutic strategies for individuals in a heterogeneous patient population.