Distinct genetic control of autoimmune neuropathy and diabetes in the non-obese diabetic background.

The non-obese diabetic (NOD) mouse is susceptible to the development of autoimmune diabetes but also multiple other autoimmune diseases. Over twenty susceptibility loci linked to diabetes have been identified in NOD mice and progress has been made in the definition of candidate genes at many of these loci (termed Idd for insulin-dependent diabetes). The susceptibility to multiple autoimmune diseases in the NOD background is a unique opportunity to examine susceptibility genes that confer a general propensity for autoimmunity versus susceptibility genes that control individual autoimmune diseases. We previously showed that NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) were protected from diabetes but spontaneously developed an autoimmune peripheral neuropathy. Here, we took advantage of multiple NOD mouse strains congenic for Idd loci to test the role of these Idd loci the development of neuropathy and determine if B6 alleles at Idd loci that are protective for diabetes will also be for neuropathy. Thus, we generated NOD-B7-2KO strains congenic at Idd loci and examined the development of neuritis and clinical neuropathy. We found that the NOD-H-2(g7) MHC region is necessary for development of neuropathy in NOD-B7-2KO mice. In contrast, other Idd loci that significantly protect from diabetes did not affect neuropathy when considered individually. However, we found potent genetic interactions of some Idd loci that provided almost complete protection from neuritis and clinical neuropathy. In addition, defective immunoregulation by Tregs could supersede protection by some, but not other, Idd loci in a tissue-specific manner in a model where neuropathy and diabetes occurred concomitantly. Thus, our study helps identify Idd loci that control tissue-specific disease or confer general susceptibility to autoimmunity, and brings insight to the Treg-dependence of autoimmune processes influenced by given Idd region in the NOD background.

Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity.

We originally discovered the serum and glucocorticoid inducible protein kinase, SGK, as a novel protein kinase that is under acute transcriptional control by serum and glucocorticoids. An expanding set of cell surface receptor, nuclear receptor, and cellular stress pathways has been shown to target SGK, which has implicated this regulated signaling molecule in a variety of biological functions. Compared to most other protein kinases, a distinguishing feature of SGK is the stringent stimulus-dependent regulation of its transcription, subcellular localization and enzymatic activity. In addition, SGK expression is regulated during discrete developmental stages, and during normal and abnormal physiological function. An analysis of the SGK promoter reveals many potential transcription factor sites that potentially account for the stimulus-dependent changes in SGK transcript expression observed in a variety of cell systems, although, the direct stimulus regulation of SGK promoter activity has been established only for glucocorticoids, p53 tumor suppressor protein, hyperosmotic stress and follicle stimulating hormone. In the systems tested to date, hormones, growth factors and environmental cues induce expression of a catalytically active SGK. It is now well established that the enzymatic activity of SGK is controlled by the PI 3-kinase cascade which produces a hyperphosphorylated active SGK. A critical third level of regulation is the stimulus-dependent control of SGK subcellular localization. The nuclear-cytoplasmic shuttling of SGK is regulated by a nuclear localization signal (NLS) that binds to the importin-alpha nuclear import receptor. Modeling of the 3-D structure of the central region of SGK that includes the kinase domain predicts that the NLS is located at an external surface of the molecule. Thus, multiple signal transduction pathways converge on SGK to control its availability, function and access to its substrates and non-substrate targets.