Studies of Congenic Lines in the Brown Norway Rat Model of Th2-Mediated Immunopathological Disorders Show That the Aurothiopropanol Sulfonate-Induced Immunological Disorder (Aiid3) Locus on Chromosome 9 Plays a Major Role Compared toAiid2on Chromosome 10

Abstract

Brown Norway (BN) rats treated with aurothiopropanol-sulfonate (Atps) constitute a model of Th2-mediated immunological disorders associated with elevated IgE responses and renal IgG deposits. Using F2 offspring between Atps-susceptible BN and Atps-resistant Lewis rats, we had previously mapped three quantitative trait loci on chromosomes 9, 10, and 20 for which BN alleles increased susceptibility to Atps-induced immunological disorders (Aiid). In this study we have used congenic lines for the latter two quantitative trait loci, formerly called Atps2 and Atps3 and now named Aiid2 (chromosome 10) and Aiid3 (chromosome 9), for fine mapping and characterization of their impact on Atps-triggered reactions. In Aiid2 congenic lines, the gene(s) controlling part of the IgE response to Atps was mapped to an ∼7-cM region, which includes the IL-4 cytokine gene cluster. Two congenic lines in which the introgressed segments shared only a portion of this 7-cM region, showed an intermediate IgE response, indicating the involvement of several genes within this region. Results from BN rats congenic for the Lewis Aiid3 locus, which we mapped to a 1.2-cM interval, showed a stronger effect of this region. In this congenic line, the Atps-triggered IgE response was 10-fold lower than in the BN parental strain, and glomerular IgG deposits were either absent or dramatically reduced. Further genetic and functional dissections of these loci should provide insights into pathways that lead to Th2-adverse reactions.

A Role for VAV1 in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

“…Genotypes were determined by polymerase chain reaction (PCR) as described (10,17). We predicted the most probable marker order with 794 (DAxPVG.1AV1)G10 rats.…”

“…BN alleles at Eae4 confer less severe disease and a lower number of interferon-g (IFN-g) mRNAexpressing cells in the central nervous system (CNS) (10). This QTL colocalizes with a series of QTLs that regulate other immune-mediated diseases or phenotypes, such as arthritis (15,16), gold salt-triggered glomerulonephritis (17), immunoglobulin E response (18), and CD45RC T cell subsets (19,20), and so may plausibly control immune regulation.…”

“…The limits of the 117-kb region are indicated by arrows on the left. Arrows on the top and below indicate strain combinations in which there was evidence for a QTL in the Eae4 region(10,(15)(16)(17)(18)(19) (Fig. 1) and in which a QTL was not detected(11)(12)(13)(25)(26)(27)(28) (fig.…”

Functional and Genetic Analysis of Two CD8 T Cell Subsets Defined by the Level of CD45RC Expression in the Rat

“…Thereafter, additional markers on c9 and c20 were used to refine the quantitative trait loci (QTLs) found on these chromosomes. Congenic lines were developed by successive backcrosses on the BN genetic background as described (25) and subsequently maintained by brother-sister mating.…”

Gold causes genetically determined autoimmune and immunostimulatory responses in mice

“…In contrast, the Lewis strain is resistant to the effect of both gold and mercury [30]. Recently, quantitative trait factors for the gold-induced increase in IgE, development of autoantibodies and renal immune deposits were localized to chromosomes 9, 10 and 20 of the rat [31,32].…”