Systems Biology Analysis of Sjogren’s Syndrome Pathogenesis: Human-Mouse Intersection Network

Objectives: Primary Sjogren’s syndrome (pSS) is an autoimmune disease with complex etiopathogenesis. Despite extensive studies using human samples and mouse models, the common biological pathways and key molecular targets remain elusive. To address this gap, we utilized a systems biology approach to identify disease-related gene-modules and signaling pathways that overlap between humans and mice.

Methods: Human parotid glands were harvested from 24 pSS and 16 non-pSS sicca patients following 2002 American-European Consensus Group criteria, and 25 matched controls. Mouse parotid, submandibular and sublingual glands were pooled from C57BL/6.NOD-Aec1Aec2 mice that developed SS-like disease. cRNA was hybridized to Affymetrix U133+2.0 arrays for human and GeneChip 430+2.0 arrays for mouse samples. The resulting gene expression data were subjected to weighted gene co-expression network analysis (WGCNA) that identified color-coded modules enriched with genes and functional pathways.

Results: Seven of the 19 gene-modules identified in humans were significantly different between pSS and control. A highly significant positive correlation was observed between disease status and Magenta (576 genes), Brown (2502 genes), Grey60 (216 genes) and Light-Cyan (349 genes) modules (r=0.67, p<2E-7; r=0.60, p<6E-6; r=0.47, p<8E-4; r=0.42, p<0.002, respectively), suggesting that these modules are comprised of genes that are overexpressed in pSS. Conversely, a highly significant negative correlation was observed with Turquoise (3981 genes), Grey (3011 genes) and Salmon (446 genes) modules (r=-0.52, p<E-4; r=-0.41, p<0.003; r=-0.28, p<0.005, respectively), suggesting that these are comprised of genes that are underexpressed in pSS. Strikingly, the human Magenta module was the most highly preserved module in mouse (p<E-18). This module was enriched with genes involved in immune and inflammatory response, and the IL-4 signaling pathway that has been implicated in pSS disease progression.

Conclusions: Systems biology analysis of human and mouse gene expression data identified common biological pathways and molecular targets underlying critical molecular alterations in pSS pathogenesis.