Methods: Using oligonucleotide microarrays, gene expression profiles of submandibular glands derived from 8 and 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.
Results: 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 pre-disease phase, genes up-regulated 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 up-regulated 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).
Conclusions: 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 up-regulated, possibly over-stimulated, B-lymphocyte activation in the early autoimmune response present in the submandibular glands. The importance of NF-kB as a critical signal transduction pathway is also suggested but its link is not yet clear.
Supported by NIH grant DE015152