title: Minor genomic differences between related B6 and B10 mice affect severity of schistosome infection by governing the mode of dendritic cell activation.
abstract: Infection with the helminth Schistosoma mansoni results in hepatointestinal granulomatous inflammation mediated by CD4 T cells directed against parasite eggs. The severity of disease varies greatly in humans and mice; however, the genetic basis of such a heterogenous immune response remains poorly understood. Here we show that, despite their close genetic relationship, C57BL/10SnJ (B10) mice developed significantly more pronounced immunopathology and higher T helper 17 cell responses than C57BL/6J (B6) mice. Similarly, live egg-stimulated B10-derived dendritic cells (DCs) produced significantly more IL-1β and IL-23, resulting in higher IL-17 production by CD4 T cells. Gene expression analysis disclosed a heightened proinflammatory cytokine profile together with a strikingly lower expression of Ym1 in B10 versus B6 mice, consistent with failure of B10 DCs to attain alternative activation. To genetically dissect the differential response, we developed and analyzed congenic mouse strains that capture major regions of allelic variation, and found that the level of inflammation was controlled by a relatively small number of genes in a locus mapping to chromosome 4 117-143 MB. Our study has thus identified novel genomic regions that regulate the severity of the schistosome infection by way of controlling the mode of DC activation and consequent CD4 T-cell subset development.
authors.affiliation: Department of Integrative Physiology and Pathobiology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Smith
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sproule
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Philip
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Derry C
authors.initials: DC
authors.lastname: Roopenian
authors.affiliation: Department of Integrative Physiology and Pathobiology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Miguel J
authors.initials: MJ
authors.lastname: Stadecker
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D056426:Genetic Loci / Q000276:immunology*; D037102:Lectins / Q000235:genetics / Q000276:immunology; D051379:Mice; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology; D013045:Species Specificity; D058504:Th17 Cells / Q000276:immunology*; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D037102:Lectins; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases
keywords: B6/B10 mice; Dendritic cell activation; Genetics; Host/pathogen interactions; Schistosoma mansoni; Th17