Genetic Susceptibility in Type 1 Diabetes and its Associated Autoimmune Disorders

Animal models of type 1 diabetes There are several animal models of type 1A diabetes (immune mediated). The first inbred animal model evolved from the discovery of diabetic animals in an outbred colony of Wistar rats maintained at the Bio Breeding Research Laboratories in Ottawa, Canada. The Bio Breeding (BB) rat develops spontaneous immune-mediated diabetes with at least four loci contributing to disease: the major histocompatibility complex (MHC, iddm2) on rat chromosome 20; the lymphopenic locus iddm1 on rat chromosome 4 [1], iddm3 on rat chromosome 2 [2], and a fourth locus on rat chromosome 15. The lymphopenic phenotype (iddm1 or lyp) locus has been mapped to a syntenic region of rat chromosome 4 [1,3]. Mutation at this locus in a homozygous state produces a severe T cell lymphopenia. Hornum and co-workers have mapped the gene to a 0.3-cM region between markers D4Got59 and Abp1 and constructed a 550-kb P1-derived artificial chromosome (PAC) contig covering the region [4]. They found a frameshift mutation in Immune-Associated Nucleotide4 (Ian4) gene which encodes a GTP-binding protein localized in the outer mitochondrial membrane [5]. This mutation results in a truncated gene product that lacks twothirds of the total protein. They hypothesized that Ian 4 is involved in the regulation of T-cell apoptosis, making it an excellent candidate for iddm1. The Ian4 gene product is anchored to the outer mitochondrial membrane, and this organelle is an important site for the regulation of cell death [6]. The same mutation was found by MacMurray and co-workers but they termed the gene Ian5 [7]. Some Ian genes are expressed in mature T cells and switched on during thymic T-cell development [8–10]. The Komeda diabetes-prone (KDP) rat [11], a diabetesprone substrain of the Long-Evans Tokushima lean (LETL) rat is characterized by autoimmune destruction of pancreatic β cells [12], rapid onset of overt diabetes with no sex difference, and no significant T cell lymphopenia. The gene Cblb (Casitus B-lineage lymphoma b, also known as Cas-Br-M murine ectropic retroviral transforming sequence b) was a potential candidate given its influence on immune function. Yokoi et al. [13] confirmed a C → T homozygous nonsense mutation (arginine to a stop at codon 455, Arg455X) that removes 484 amino acids, including the proline-rich region and leucine zipper domain. The mutation is specific to the KDP rat and its original LETL strain. Approximately 80% of the Iddm/kdp1 homozygous mutant animals develop diabetes with severe insulitis, and most of the remainder showed mild to moderate insulitis. Neither heterozygous nor wildtype animals developed diabetes. They demonstrated that Cblb is a important regulator of autoimmunity and Cblb is a major susceptibility gene for rat type 1 diabetes [14]. The non-obese diabetic mouse is the best studied spontaneous animal model of type 1 diabetes. Diabetes susceptibility in the NOD is polygenic, with a major influence of genes within the MHC. Linkage analyses have identified at least 19 susceptibility loci (Idd1-Idd19) that contribute to disease pathogenesis [15,16]. Lymphocytes mediate the specific destruction of insulin-producing β cells. These loci can either confer susceptibility or resistance to expression of insulin autoantibodies, insulitis and or disease development. Idd1 has been mapped to the MHC locus on mouse chromosome 17 [17,18]. Idd1 mapped to class II I-A and I-E regions as a gene complex [19], but the incidence of the disease is strongly affected by a gene or genes outside of this segment (Idd16). Variants of the beta-2 microglobulin gene is one of the first non-MHC genes to by clearly identified. Though neither the insulin 2 gene on chromosome 7 nor the insulin 1 gene on chromsome 19 show linkage to diabetes, in crosses with normal mouse strains, knockouts of either of these genes greatly influences the development of diabetes. Several new mouse models of human type 1 diabetes have been developed using transgenic mice. We found