title: The rat diabetes susceptibility locus Iddm4 and at least one additional gene are required for autoimmune diabetes induced by viral infection.
abstract: BBDR rats develop autoimmune diabetes only after challenge with environmental perturbants. These perturbants include polyinosinic:polycytidylic acid (poly I:C, a ligand of toll-like receptor 3), agents that deplete regulatory T-cell (Treg) populations, and a non-beta-cell cytopathic parvovirus (Kilham rat virus [KRV]). The dominant diabetes susceptibility locus Iddm4 is required for diabetes induced by treatment with poly I:C plus Treg depletion. Iddm4 is penetrant in congenic heterozygous rats on the resistant WF background and is 79% sensitive and 80% specific as a predictor of induced diabetes. Surprisingly, an analysis of 190 (BBDR x WF)F2 rats treated with KRV after brief exposure to poly I:C revealed that the BBDR-origin allele of Iddm4 is necessary but not entirely sufficient for diabetes expression. A genome scan identified a locus on chromosome 17, designated Iddm20, that is also required for susceptibility to diabetes after exposure to KRV and poly I:C (logarithm of odds score 3.7). These data suggest that the expression of autoimmune diabetes is a complex process that requires both major histocompatibility complex genes that confer susceptibility and additional genes such as Iddm4 and Iddm20 that operate only in the context of specific environmental perturbants, amplifying the immune response and the rate of disease progression.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Blankenhorn
authors.forename: Lucy
authors.initials: L
authors.lastname: Rodemich
authors.forename: Cristina
authors.initials: C
authors.lastname: Martin-Fernandez
authors.forename: Jean
authors.initials: J
authors.lastname: Leif
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
mesh_terms: D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D010322:Parvoviridae Infections / Q000150:complications; D011070:Poly I-C / Q000494:pharmacology; D051381:Rats; D011913:Rats, Inbred BB / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors
chemical_list: D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D011070:Poly I-C