Early pathogenic events associated with Sjögren's syndrome (SjS)-like disease of the nod mouse using microarray analysis

Abstract

Recently, we reported development of the C57BL/6.NOD-Aec1Aec2 mouse carrying two genetic intervals derived from the NOD mouse. These two genetic regions confer full Sjögren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. The current study was undertaken to apply microarray technology to define the molecular basis underlying onset of SjS-disease in C57BL/6.NOD-Aec1Aec2 mice. Using oligonucleotide microarrays, gene expression profiles of submandibular glands derived from 8- to 12-week-old C57BL/6.NOD-Aec1Aec2 mice and 8-week-old C57BL/6 mice were performed for comparison. Significant differential expressions were determined using the Mann-Whitney U test. Hybridizations using submandibular cDNA probes revealed 75 differentially expressed genes at 8 weeks and 105 differentially expressed genes at 12 weeks of age in C57BL/6.NOD-Aec1Aec2 mice compared to 8-week-old C57BL/6 mice. These genes were related generally to basic cellular activities such as transcription, translation, DNA replication, and protein folding. During the predisease phase, genes upregulated encode proteins associated with the IFN-gamma signal-transduction-pathway (Jak/Stat1), TLR-3 (Irf3 and Traf6) and apoptosis (casp11 and casp3), indicative of chronic proinflammatory stimuli, especially IL-1. Between 8 and 12 weeks of age, sets of clustered genes were upregulated that are associated with adaptive immune responses, especially B cell activation, proliferation and differentiation (Baffr, Taci, Bcma, Blys, April, CD70, CD40L, Traf1, Traf3, Pax5, c-Jun, Elk1 and Nf-kB), and neural receptors (Taj/Troy). Altered gene expressions of TLR3 and TNF-superfamily-receptors and ligands during this early phase of SjS suggest a possible viral etiology in the altered glandular homeostasis with an upregulated, possibly overstimulated, B-lymphocyte activation in the early autoimmune response present in the submandibular glands. The importance of NF-kappaB as a critical signal transduction pathway is also suggested but its link is not yet clear.

NOD Mice Exocrinopathy: Towards a Neuroimmune Link

“…Of note, we have described apoptotic images in histological slices of submandibular glands from 10-week-old NOD mice prior to the autoimmune response [7] . Similarly, inappropriate apoptosis in salivary glands was observed in NOD-scid mice [6] , and cas- pase -among other genes -appeared differentially expressed in submandibular glands of C57BL6/NODAec 1 Aec 2 mice, an SS-susceptible strain [19] , supporting the notion that early defects in the glands might predispose them to the autoimmune response.…”

Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases

“…Among the many chronic inflammatory conditions affecting the visual system, JAK/STAT pathway activation has been demonstrated to be involved in herpes-induced keratitis [147], experimental autoimmune-induced uveitis [EAU] [148], experimentally-induced Sjögren's-like syndrome in NOD mice [149], age-related macular degeneration [150], retinal angiogenesis in the context of diabetic retinopathy [151], lens injury produced by crystallins of the / superfamily [152] and in experimentally-induced acute ocular hypertension [153].…”

Gene expression and chromosomal location for susceptibility to Sjögren's syndrome

“…A few reports have described transcriptional profiles of whole LSG from SS patients [10][11][12]. A neglected aspect of these studies is that the amount of mononuclear infiltrate in LSG varies between SS patients [13].…”