Fig. 4

Proposed model explaining the loss of human salivary gland structural integrity in Sjögren’s syndrome (SS) based on the computational biosemantics analysis, gene expression and network analyses. a Major and minor salivary glands of the oral cavity. b Potential combinatorial factors may lead to SS. The current model involves multiple factors that together may play a role in the development of the disease. The primary factors include genetics, environmental factors, viruses, and retro-elements that may disrupt homeostasis. c Salivary unit portion showing individual acini. Acinar cells from these glands secrete water, salts and/or protein (major components of saliva) into the oral cavity. In SS, capillaries surrounding salivary tissue mediate the immune response by passing various interferons and chemokines produced by acinar cells into the bloodstream, which initiate the dendritic cell movement to the area. d Transcription factors ETS1 and LEF1 could directly upregulate (UR) matrix metalloproteinase 9 (MMP9) expression. MMP9, also known as gelatinase B, is involved in extracellular matrix degradation. e TLR7 is suggested to be a major player in the secretion of cytokines such as CXCL10 in systemic lupus erythematosus and other autoimmune diseases. MMP9 and CXCL10 feedback potentiate extracellular matrix (ECM) destruction. CXCL10, a cytokine, stimulates dendritic cell recruitment to a specific area while at the same time has been shown to increase MMP9 expression in a positive feedback-like mechanism. TIMP1, also known as tissue inhibitor of metalloproteinases, binds directly to metalloproteinases inhibiting their enzymatic activity. While MMP9 and TIMP1 are regulated in a ratio-specific manner, patients with SS have markedly UR levels of MMP9 and downregulated TIMP1, which might play a role in the progression of glandular destruction brought on by the disease