Virus-Induced Autoimmune Diabetes in the LEW.1WR1 Rat Requires Iddm14 and a Genetic Locus Proximal to the Major Histocompatibility Complex

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 12; pp. 2930 - 2938
• Main Authors: BLANKENHORN, Elizabeth P, CORT, Laura, GREINER, Dale L, GUBERSKI, Dennis L, MORDES, John P
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2009
• Subjects: Animals; Autoimmunity; Biological and medical sciences; Chromosome Mapping; Complications and side effects; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - virology; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Disease susceptibility; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene loci; Genetic aspects; Genetic Linkage; Genetic Predisposition to Disease; Genomes; Genotype; Health aspects; Infections; Laboratory animals; Ligands; Major histocompatibility complex; Major Histocompatibility Complex - genetics; Medical sciences; Original; Parvoviridae Infections - complications; Parvovirus; Poly I-C; Polymorphism, Single Nucleotide; Rats; Rats, Inbred Strains; Research design; Risk factors; Type 1 diabetes; Viral infections; Virus diseases; Viruses; United States; United States > US; Massachusetts; Endocrinopathy; Autoimmunity; Vertebrata; Mammalia; Rat; Animal; Diabetes mellitus; Major histocompatibility system; Rodentia; Genetics; Locus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-0387

Virus-Induced Autoimmune Diabetes in the LEW.1WR1 Rat Requires Iddm14 and a Genetic Locus Proximal to the Major Histocompatibility Complex Elizabeth P. Blankenhorn 1 , Laura Cort 1 , Dale L. Greiner 2 , Dennis L. Guberski 3 and John P. Mordes 2 1 Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, Pennsylvania; 2 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; 3 Biomedical Research Models, Worcester, Massachusetts. Corresponding author: Elizabeth P. Blankenhorn, eblanken{at}drexelmed.edu . Abstract OBJECTIVE To identify genes that confer susceptibility to autoimmune diabetes following viral infection in the LEW.1WR1 rat. RESEARCH DESIGN AND METHODS About 2% of LEW.1WR1 rats develop spontaneous autoimmune diabetes. Immunological perturbants including viral infection increase both the frequency and tempo of diabetes onset. To identify diabetes susceptibility genes (LEW.1WR1 × WF), F2 rats were infected with Kilham rat virus following brief pretreatment with polyinosinic:polycytidylic acid. This treatment induces diabetes in 100% of parental LEW.1WR1 rats and 0% of parental WF rats. Linkage to diabetes was analyzed by genome-wide scanning. RESULTS Among 182 F2 rats, 57 (31%) developed autoimmune diabetes after a mean latency of 16 days. All diabetic animals and ∼20% of nondiabetic animals exhibited pancreatic insulitis. Genome-wide scanning revealed a requirement for the Iddm14 locus, long known to be required for diabetes in the BB rat. In addition, a new locus near the RT1 major histocompatibility complex (MHC) was found to be a major determinant of disease susceptibility. Interestingly, one gene linked to autoimmune diabetes in mouse and human, UBD , lies within this region. CONCLUSIONS The Iddm14 diabetes locus in the rat is a powerful determinant of disease penetrance in the LEW.1WR1 rat following viral infection. In addition, a locus near the MHC ( Iddm37 ) conditions diabetes susceptibility in these animals. Other, as-yet-unidentified genes are required to convert latent susceptibility to overt diabetes. These data provide insight into the polygenic nature of autoimmune diabetes in the rat and the interplay of genetic and environmental factors underlying disease expression. Footnotes The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received March 17, 2009. Accepted August 26, 2009. © 2009 American Diabetes Association