Susceptibility and resistance genes to insulin-dependent diabetes mellitus in the BB rat.
Insulin-dependent diabetes mellitus (IDDM, type I) is an autoimmune disorder exhibiting a strong association with particular haplotypes of the major histocompatibility complex (MHC). We have previously shown that the u haplotype of the rat MHC (RT1) is absolutely required for expression of IDDM in the BB rat model of the disease. To define the precise regions of the RT1 contributing to disease occurrence and to address the mechanism by which the associated haplotype participates in disease pathogenesis, we have transferred recombinant haplotypes bearing the IDDM-associated MHC in defined regions onto the BB rat genetic background. In this report, we present data from two breeding studies utilizing the r8 haplotype (RT1AaBuDuEuCu) that demonstrate that (1) the RT1A locus is not involved in the disease association, (2) the MHC genes determining disease susceptibility are not unique to the BB rat, and (3) IDDM resistance genes are found outside the MHC. We also present evidence that the immunoregulatory defect characteristic of BB rats enhances the incidence of IDDM although it is not absolutely required for disease expression. We were able to track the transmission of the recombinant haplotypes in diabetic progeny using a combination of monospecific alloantisera and restriction fragment length polymorphism analysis using locus-specific MHC gene probes.
Ono
S J
SJ
McGill Cancer Centre, Department of Medicine, McGill University Faculty of Medicine, Montreal, Que., Canada.
Fuks
A
A
Guttmann
R D
RD
Colle
E
E
D000818:Animals; D015342:DNA Probes; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D006239:Haplotypes; D006720:Homozygote; D008297:Male; D010641:Phenotype; D051381:Rats; D011913:Rats, Inbred BB
D015342:DNA Probes