Multiple sclerosis (MS) is the major inflammatory disease of the central nervous system (CNS) in humans. Both environmental and genetic factors contribute to what is believed to be an autoimmune etiology. Although environmental factors are important in MS, they only exert their effects in genetically permissive hosts. Characterization of disease susceptibility genes in experimental allergic encephalomyelitis (EAE), the principal animal model of MS, will lead to a better understanding of the interplay between these factors. The long-term goal of the research proposed in this renewal is to characterize the genes controlling susceptibility to EAE in the mouse. To isolate these genes, we first precisely mapped them within the mouse genome during the previous funding period. We initiated breeding programs to generate B10.S/DvTe susceptible (B10.S.QTLSJL) and SJL/J resistant (SJL.QTLB10.S) phenotype-selected congenic lines possessing the minimal set of genes for susceptibility and resistance to EAE. The present application will continue this analysis by fixing these loci as single interval specific congenic lines, characterizing the component phenotypes regulated by each locus; and use positional-candidate gene cloning approach to identify the polymorphisms underlying the loci exhibiting the greatest phenotypic variation. In the companion aim, Bphs, an autoimmune disease susceptibility locus in EAE (eae27) and autoimmune orchitis, was shown by positional-candidate gene cloning to be the histamine H1 receptor (Hrh1/H1R). We will continue to characterize the role of H1R alleles in the pathogenesis of EAE by delineating the relative contribution of H1R signaling in CD4+ T-cells, antigen presenting cells and blood-brain-barrier endothelial cells, the 3 major cell types involved in the autoimmune inflammatory disease of the CNS.
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