The SNIB studies various aspects of the role of the hypothalamic pituitary adrenal (HPA) axis in susceptibility and resistance to autoimmune/inflammatory disease. The main experimental model involves 2 inbred strains of rats (LEW/N and F344/N rats) whose differential HPA axis responsiveness accounts at least in part for their differential inflammatory susceptibilities. Recent studies are aimed at identifying genes involved in determining differential susceptibility and resistance to autoimmune/ inflammatory diseases and differential corticotropin releasing hormone (CRH) responsiveness in these strains. Prior genetic linkage and segregation studies, now terminated, identified two linkage regions, one definite region on chromosome 10 and one probable region on chromosome 2, that linked with inflammatory susceptibility or resistance in these rat strains (LEW/N and F344/N rats). The large (approximately 16 cM) region between markers GH and R1710 on chromosome 10 that linked to inflammatory resistance in F344/N rats appears to be identical to the Cia5 and Oia3 linkage regions on chromosome 10 that is one of approximately 20 regions on 15 chromosomes and links to inflammatory arthritis in other rat intercrosses. It is also syntenic with a region on mouse chromosome 11 and human chromosome 17 that link with other autoimmune diseases in rodents and humans. Consistent with findings in other complex autoimmune inflammatory diseases, these genetic studies indicated that the genotypic contribution to the inflammatory phenotype was relatively low (approximately 35%), and the environmental variation was relatively high (approximately 65%). Several candidate genes within this region were sequenced because they are involved in both inflammation and HPA axis regulation (CRH-R1, ACE, STAT3, STAT5a and STAT5b). These genes showed significant coding region mutations and alone did not appear to contribute to the phenotype. Because of the relatively high environmental contribution to the trait, we examined early maternal-pup interactions as a possible early developmental environmental variable that could contribute to the differential inflammatory and HPA axis responsiveness in these strains in adulthood. These studies indicated that strain, gender and early maternal environment interact and contribute to the adult HPA axis responsiveness phenotype but not to the inflammatory trait. Evaluation of regulation of other genes in these strains using real-time PCR, in situ hybridization and immunohistochemistry indicate that other genes are dysregulated in the paraventricular nucleus of the hypothalamus, suggesting that a common cellular or signaling factor and not a single neurohormone gene account for the differential CRH responsiveness in these strains.
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