title: Iddm30 controls pancreatic expression of Ccl11 (Eotaxin) and the Th1/Th2 balance within the insulitic lesions.
abstract: The autoimmune diabetic syndrome of the BioBreeding diabetes-prone (BBDP) rat is a polygenic disease that resembles in many aspects human type 1 diabetes (T1D). A successful approach to gain insight into the mechanisms underlying genetic associations in autoimmune diseases has been to identify and map disease-related subphenotypes that are under simpler genetic control than the full-blown disease. In this study, we focused on the β cell overexpression of Ccl11 (Eotaxin), previously postulated to be diabetogenic in BBDR rats, a BBDP-related strain. We tested the hypothesis that this trait is genetically determined and contributes to the regulation of diabetes in BBDP rats. Similar to the BBDR strain, we observed a time-dependent, insulitis-independent pancreatic upregulation of Ccl11 in BBDP rats when compared with T1D-resistant ACI.1u.lyp animals. Through linkage analysis of a cross-intercross of these two parental strains, this trait was mapped to a region on chromosome 12 that overlaps Iddm30. Linkage results were confirmed by phenotypic assessment of a novel inbred BBDP.ACI-Iddm30 congenic line. As expected, the Iddm30 BBDP allele is associated with a significantly higher pancreatic expression of Ccl11; however, the same allele confers resistance to T1D. Analysis of islet-infiltrating T cells in Iddm30 congenic BBDP animals revealed that overexpression of pancreatic Ccl11, a prototypical Th2 chemokine, is associated with an enrichment in Th2 CD4+ T cells within the insulitic lesions. These results indicate that, in the BBDP rat, Iddm30 controls T1D susceptibility through both the regulation of Ccl11 expression in β cells and the subsequent Th1/Th2 balance within islet-infiltrating T lymphocytes.
authors.affiliation: Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada;
authors.forename: Gary Y C
authors.initials: GY
authors.lastname: Chao
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wallis
authors.forename: Leili
authors.initials: L
authors.lastname: Marandi
authors.forename: Terri
authors.initials: T
authors.lastname: Ning
authors.forename: Janice
authors.initials: J
authors.lastname: Sarmiento
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Philippe
authors.initials: P
authors.lastname: Poussier
mesh_terms: D000818:Animals; D001947:Breeding; D054413:Chemokine CCL11 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D056426:Genetic Loci / Q000235:genetics*; D005838:Genotype; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000276:immunology* / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D011913:Rats, Inbred BB; D058408:Th1-Th2 Balance; D014158:Transcription, Genetic
chemical_list: D054413:Chemokine CCL11