Specific Class II Histocompatibility Gene Polymorphism in BB Rats

Abstract

SUMMARYThe BB rat spontaneously develops insulin-dependent diabetes mellitus of autoimmune etiology. From breeding studies, one of the genes necessary for the development of diabetes in these animals is linked to RT1, the rat major histocompatibility complex. To better define the BB rat's RT1 -linked diabetogenic gene (RT1-DM), we have used restriction endonucleases BamH1 and EcoR1 in conjunction with an I-A alpha (class II mouse major histocompatibility complex) gene probe to study RT1 class II gene polymorphisms among diabetes-prone BB rats and the related non-diabetesprone BBN rats. Both BB and BBN rats are indistinguishable RT1 U by serologic methods. Four polymorphic chromosome types (la, Ib, Ha, and lib) were recognized among the control BBN rats. In contrast, all BB rats were homozygous (lla/lla). From the multiple breeding programs involved, we hypothesize that the BB rat's RT1 -linked diabetogenic gene is linked to an I-A alpha-defined gene of the type Ha chromosome. The ability to split the RT1 U of BB rats will provide a powerful tool to localize and characterize RT1-DM. DIABETES 33:700-703, July 1984.T he BB rat strain was developed by Dr. Chappel and co-workers at BioBreeding Laboratories when diabetes mellitus spontaneously developed in an outbred commercial colony of Wistar-derived rats. Their diabetes is similar to type I diabetes of man. It is characterized by insulitis and pancreatic beta cell destruction leading to hypoinsulinemia and hyperglycemia that rapidly progress to ketoacidosis and death if not treated with ex- ogenous insulin. The type I diabetes of the BB rat is of autoimmune etiology. Diabetes can be transferred to immunodeficient rats with activated splenic lymphocytes from recently diabetic BB rats 2 and can be prevented or cured with multiple forms of immunotherapy. 3 The BB rat has a severe T-cell immunodeficiency, exhibiting an almost total lack of peripheral T-cells while having a grossly normal thymus. 4 We and others have recently reported that in crosses of BB rats with normal rat strains, there are at least two genes necessary for the development of diabetes.56 One determines the T-cell lymphopenia and is inherited by simple autosomal recessive genetics. The second is associated with RT1, the rat major histocompatibility complex (MHC). To further examine the BB rat's RT1-linked diabetogenic gene, termed RT1-DM, we have studied restriction fragment length polymorphisms using an I-A alpha probe (mouse class II MHC gene) in diabetes-prone BB rats and in control BBN rats, which are non-lymphopenic, non-diabetes prone, and derive from the same original colony as the BB rats. MATERIALS AND METHODSAnimals. In 1979 spontaneous diabetes was observed in a colony of outbred Wistar rats at BioBreeding, a commercial breeding facility. These diabetic rats were interbred and became known as BB rats. They were transferred to the animal facilities of the Department of National Health and Welfare, Ottawa, Canada, where they continue to be maintained by Dr. P. Thibert. These BB rats have bee...