Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis

Abstract

Experimental allergic encephalomyelitis (EAE) is the principal genetically determined animal model for multiple sclerosis (MS), the major inflammatory disease of the central nervous system (CNS). Although genetics clearly play a role in susceptibility to MS, attempts to identify the underlying genes have been disappointing. Considerable variation exists between MS patients with regard to the severity of clinical signs, mechanism of demyelination, and location of CNS lesions, confounding the interpretation of genetic data. A mouse-human synteny mapping approach may allow the identification of candidate susceptibility loci for MS based on the location of EAE susceptibility loci. To date, 16 regions of the mouse genome have been identified that control susceptibility or clinical signs of EAE. In this work, we examined the genetic control of histopathological lesions of EAE in an F2 intercross population generated from the EAE susceptible SJL/J and EAE resistant B10.S/DvTe mouse strains. Composite interval mapping was used to identify 10 quantitative trait loci (QTL), including seven newly identified loci controlling the distribution and severity of CNS lesions associated with murine EAE. QTL on chromosome 10 control lesions in the brain, whereas QTL on chromosomes 3, 7, and 12 control lesions in the spinal cord. Furthermore, sexually dimorphic QTL on chromosomes 2, 9, and 11 control CNS lesions in females, whereas QTL on chromosomes 10, 11, 12, 16, and 19 control lesions in males. Our results suggest that the severity and location of CNS lesions in EAE are genetically controlled, and that the genetic component controlling the character and severity of the lesions can be influenced by sex.

Figure 1.

CIM results for the combined (male + female) population. A solid line represents the plot of the LRT statistic for the brain whereas the broken line represents a plot of the LRT statistic for the SC. Tick marks on the x axis represent the positions of microsatellite markers. Permutation-derived significance cutoffs were based on 1000 permutations at α = 0.05. A–C: Composite interval maps with significant linkage for the trait, mononuclear cell infiltration. Significance cutoffs for this trait are LRT = 16.4 for the brain and 16.8 for the SC. D–E: Composite interval maps with significant linkage for demyelination. Significance cutoffs for this trait are LRT = 17.0 for the brain and 17.6 for the SC.

Figure 2.

CIM results for the female population. A solid line represents the plot of the LRT statistic for the brain whereas the broken line represents a plot of the LRT statistic for the SC. Tick marks on the x axis represent the positions of microsatellite markers. Permutation-derived significance cutoffs were based on 1000 permutations at α = 0.05. A: Composite interval map of chromosome 9 with significant linkage for acute inflammation in the SC. Significance cutoffs for this trait are LRT = 16.5 for the brain and 16.8 for the SC. B–C: Composite interval maps with significant linkage for mononuclear cell infiltration. Significance cutoffs for this trait are LRT = 16.4 for the brain and 16.55 for the SC.

Figure 3.

CIM results for the male population. A solid line represents the plot of the LRT statistic for the brain whereas the broken line represents a plot of the LRT statistic for the SC. Tick marks on the x axis represent the positions of microsatellite markers. Permutation-derived significance cutoffs were based on 1000 permutations at α = 0.05. A–C: Composite interval maps with significant linkage for the mononuclear cell infiltration. Significance cutoffs for this trait are LRT = 17.9 for the brain and 16.6 for the SC. D–E: Composite interval maps with significant linkage for demyelination. Significance cutoffs for this trait are LRT = 18.1 for the brain and 18.0 for the SC.