The major histocompatibility complex of the rat (RT1 complex) encodes two sets of class II molecules referred to as RT1.B and RT1.D. The complete structure of the RT1.D alpha u chain of the diabetes prone BB rat was determined by the isolation and characterization of a full size cDNA. Comparisons of the nucleotide and protein sequences of RT1.D alpha with the analogous molecules, H-2 I-E alpha and HLA DR alpha, revealed that these alpha chains have been highly conserved during evolution. Southern blot analysis indicated an association of the RT1 haplotypes, 'u' and 'l', with Bam H1 DNA bands of 9.8 kb and 11.7 kb, respectively. The BB rat develops insulin dependent diabetes as an autoimmune abnormality. Accumulating evidence suggests a cellular mediated etiology and the involvement of class II molecules. The steady state levels of RT1.D alpha mRNA were measured in splenic lymphocytes of diabetes prone BB rats and age matched histocompatible normal nondiabetic WF rats by a RNase protection assay. Compared to WF rats, elevated transcripts of RT1.D alpha were found in lymphocytes of young BB rats (approximately 4x and approximately 2.5x greater at 20-40 and 40-75 d, respectively). In lymphocytes of older diabetic and nondiabetic BB rats (greater than 75 d) the levels of RT1.D alpha mRNA were lower than in the young BB rats and were found at the WF control levels. The increased steady state RT1.D alpha mRNA levels in the young BB rats may reflect differences in the proportion of splenic lymphocytes expressing this gene (activated lymphocytes), and thus differences in splenic lymphocyte populations. The steady state RT1.D alpha mRNA levels in lymphocytes of the normal rats were found to be relatively similar at all ages examined. The increased class II gene transcripts found in lymphocytes of young BB rats indicates that they possess a highly activated immune system.
The BB rat spontaneously develops insulin-dependent diabetes mellitus (IDDM) as an autoimmune abnormality involving the class II molecules of the major histocompatibility complex (MHC). The rat MHC (RT1 complex) encodes two class II loci, RT1.B and RT1.D. The possibility that variant or unique class II MHC molecules may be associated with IDDM susceptibility was directly examined by determining the nucleotide sequences of class II mRNAs and/or cDNAs from the diabetes-prone (DP) BB rat, the diabetes-resistant (DR) BB rat, the normal histocompatible Wistar-Furth (WF) rat, and the Lewis rat. Sequence analysis indicates that the beta-chains of the RT1.B and RT1.D molecules of the u haplotype from DP-BB, DR-BB, and WF rats are identical but that they are different from other rat alleles and published mouse class II sequences. At the nucleotide level, the NH2-terminal domain of RT1.D beta of the BB and WF rats differs by a single silent nucleotide substitution. Comparisons with the sequences of the Lewis rat indicate hypervariable allelic differences and that the u and I haplotypes are remarkably similar. These findings establish that the class II molecules of the DP-BB rat are not variant or unique and that unaltered class II molecules of the u haplotype support the autoimmune response in the BB rat.
The BB rat spontaneously develops autoimmune abnormalities such as insulin-dependent diabetes mellitus and thyroiditis. The autoimmunity of the BB rat is controlled in part by genes of the major histocompatibility complex (MHC), known as the RT1 complex in the rat, and accumulating evidence suggests the involvement of MHC class II molecules. The RT1 complex specifies two types of class II molecules, which are encoded by the loci RT1.B and RT1.D. We have determined the relative steady-state mRNA levels of the class II genes RT1.B beta, RT1.D alpha, and RT1.D beta in splenic lymphocytes from individual autoimmune BB rats of various ages and from age-matched histocompatible normal Wistar-Furth (WF) rats. The relative steady-state mRNA levels of the RT1.D alpha and RT1.D beta genes, but not of the RT1.B beta gene, were elevated approximately 2.5-fold in lymphocytes of prediabetic BB rats 45-75 days old in comparison with age-matched normal WF rats and older BB rats greater than 75 days old. In the diabetic and nondiabetic BB rats greater than 75 days old, the RT1.D alpha and RT1.D beta transcripts were found at lower normal levels, similar to that of WF rats. In contrast, the RT1.B beta transcripts were found at comparable levels in lymphocytes of the BB and WF rats at all ages examined. The increased steady-state mRNA levels of the RT1.D alpha and RT1.D beta genes in the prediabetic BB rats may reflect differences in the proportion of lymphocytes expressing these genes and thus differences in splenic lymphocyte populations.(ABSTRACT TRUNCATED AT 250 WORDS)
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