Virus-induced autoimmune diabetes in the LEW.1WR1 rat requires Iddm14 and a genetic locus proximal to the major histocompatibility complex.
OBJECTIVE
To identify genes that confer susceptibility to autoimmune diabetes following viral infection in the LEW.1WR1 rat.


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 x 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 approximately 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.
Blankenhorn
Elizabeth P
EP
Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA. eblanken@drexelmed.edu
Cort
Laura
L
Greiner
Dale L
DL
Guberski
Dennis L
DL
Mordes
John P
JP
D000818:Animals; D015551:Autoimmunity; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D004195:Disease Models, Animal; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D008285:Major Histocompatibility Complex / Q000235:genetics*; D010322:Parvoviridae Infections / Q000150:complications*; D017992:Parvovirus; D011070:Poly I-C; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D011919:Rats, Inbred Strains
D011070:Poly I-C