The genetics of autoimmunity in the rat: The search for non-MHC-linked genes

Multiple sclerosis (MS) and insulin dependent diabetes mellitus (IDDM) are complex autoimmune diseases, where both genetic and environmental factors contribute to disease etiology. Because of the complex nature of both diseases, identification of non-MHC-linked genes has been difficult. The identification of non-MHC-linked genes in autoimmune diseases is the focus of this dissertation.;Lewis (LEW) rats are susceptible to the induction of experimental allergic encephalomyelitis (EAE), the rodent model for MS. The histocompatible Lewis-resistant (LER) is a sub-strain of LEW and is resistant to EAE induction. We have investigated genetic differences between these two rat strains. We conducted microsatellite analysis to identify polymorphisms between the two strains on a whole genome scale. Using microsatellite analysis, we have shown that the LER rat strain is derived from LEW rats and Buffalo rats. The linkage on chromosome 4 encompasses the TCRb gene locus and is linked to disease severity. This is of interest to us, given the fact that there are allelic differences in the TCR Vb8 gene between LEW and LER and that one of the LER-specific-clusters is also found in this region on chromosome 4.;The diabetic-prone Bio-breeding (DP-BB) rat is an excellent model for studying IDDM. DP-BB rats spontaneously develop IDDM at approximately 60--80 days of age. The Wistar Furth (WF) rat is MHC-compatible with DP-BB, but does not spontaneously develop IDDM. One of the genes controlling IDDM in the DP-BB rat is the lymphopenia (lyp) gene, which causes depletion of a regulatory (RT6+) subset of T cells in the periphery of DP-BB rats. Lyp is recessive, so to create homozygous lyp/ lyp progeny, previous genetic crosses have been generated in the direction of the susceptible DP-BB parent. Using an induction protocol that depletes peripheral RT6+ T cells, we have mimicked the activity of lyp and can induce IDDM in otherwise resistant F1 animals. We generated a (DP-BB x WF) F1 x WF backcross, and we show that IDDM segregates among the backcross progeny following the induction protocol. This has enabled the identification of novel genes that contribute to phenotypes related to IDDM.;To investigate the role of iddm4 and to determine that it is a different gene to lyp, we generated a backcross between the diabetic-resistant (DR)-BB rat and WF rat strain. DR-BB rats are a histocompatible sub-strain of the DP-BB rat. DR-BB rats share 85% of their genomic markers with DP-BB, but they express the wild type lyp gene and do not spontaneously develop IDDM. However, following the RT6+ T cell depletion protocol for IDDM induction, DR-BB rats develop diabetes. (Abstract shortened by UMI.).