title: Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 (Cdcs1) locus.
abstract: Genetic modifier loci influence the phenotypic expression of many Mendelian traits; insight into disease pathogenesis gained from their identification in animal disease models may impact the treatment of human multigenic disorders. We previously described an innate immune-driven model of spontaneous ulcerative colitis in T-bet(-/-).Rag2(-/-) double-deficient mice that resembles human ulcerative colitis. On a BALB/c background, this disease is highly penetrant and results in the development of colorectal cancer. However, we observed that colitis in T-bet(-/-).Rag2(-/-) mice on a C57BL/6 background was significantly less severe. Quantitative trait locus analysis using an N2 backcross strategy revealed a single major quantitative trait locus on chromosome 3 that mapped to the Cdcs1 (cytokine deficiency-induced colitis susceptibility-1) locus previously identified in the Il10(-/-) and Gnai2(-/-) colitis models. Congenic introduction of the susceptible Cdcs1 interval from C3H/He into the C57BL/6 background restored colitis severity. Bone marrow reconstitution experiments further mapped the effect of host genetics on disease severity to the hematopoietic compartment. There were distinct differences in the expression of several Cdcs1 genes in bone marrow-derived dendritic cells from Cdcs1 congenic mice. We conclude that the Cdcs1 locus controls colitis severity in T-bet(-/-).Rag2(-/-) mice through innate immune cells.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joerg
authors.initials: J
authors.lastname: Ermann
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Garrett
authors.forename: Juhi
authors.initials: J
authors.lastname: Kuchroo
authors.forename: Khadija
authors.initials: K
authors.lastname: Rourida
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.forename: Andre
authors.initials: A
authors.lastname: Bleich
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D033481:Chromosomes, Mammalian / Q000235:genetics* / Q000276:immunology; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D040641:Quantitative Trait Loci / Q000235:genetics* / Q000276:immunology