| An enormous body of knowledge has accumulated regarding the immunopathology of autoimmune diseases; from development of autoimmune lymphocyte repertoires to the variety of mechanisms effecting inflammation and destruction of self tissues. Little information, in contrast, is available regarding physiologic autoimmune triggers. An emerging hypothesis, which may help define triggers of autoimmunity, is that physiologic defects particular to the target tissue somehow provoke inflammation.; The NOD mouse is a model of autoimmunity which is subject to inflammation in a number of exocrine and endocrine tissues. The most prominent clinical consequence of these inflammatory phenomena, diabetes, results from the autoimmune destruction of pancreatic beta cells. Defects in NOD target organs are suggested by abnormalities in morphology, rates of apoptosis, and secretory function. In order to understand the molecular nature of these defects, we have examined the gene expression profiles of three such target organs on the NOD background: pancreas, submandibular gland, and lacrimal gland. Specifically, we have compared tissues from a lymphocyte-deficient derivative strain, NOD/scid, to a non-autoimmune-prone background (C57BL6/scid). Use of scid mice for these comparisons has allowed us to focus strictly on tissue-native differences in gene expression, rather than inflammation/lymphocyte-dependent ones. NOD/scid tissues show differential expression in genes governing metabolism, transcription, protein processing/trafficking, and immunity, among others. In addition, a number of genes consistently altered in NOD/scid tissues lie within reported diabetes susceptibility loci. Previously identified susceptibility genes in NOD show altered expression levels, thus identification of differentially expressed genes within susceptibility intervals suggests novel candidate genes for diabetogenesis.; Analysis of differentially expressed genes having metabolic function suggested insulin resistance, and indeed, NOD/scid mice are insulin resistant per insulin challenge. NOD/scid mice are also glucose tolerant and hyperinsulinemic. Despite insulin resistance, these mice have somewhat lower basal fed and fasted serum glucose levels. Given previous reports of hyperactive islets in NOD mice, insulin resistance in NOD may confer a metabolic stress on tissues, especially the pancreatic islets. Considering the nature and numbers of differentially expressed genes with respect to metabolism, we suggest specific metabolic stresses in collaboration with defects affecting tissue antigen exposure may constitute an autoimmunogenic milieu. |
