Abstract
BackgroundSjögren's syndrome (SS) shares many clinical and pathological similarities with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These autoimmune diseases mostly affect women. In this study, concept profile analysis (CPA) and gene expression meta-analysis were used to identify genes potentially involved in SS pathogenesis.MethodsHuman genes associated with SS, SLE, and RA were identified using the CPA tool, Anni 2.1. The differential mRNA expression of genes common to SS and SLE (SS-SLE) was determined in female peripheral blood mononuclear cells (PBMCs) using NCBI-GEO2R. Differentially expressed (DE) SS-SLE PBMC genes in common with the SS-SLE CPA-identified genes were analyzed for differential expression in salivary glands or synovial biopsies, and for genes common to SS and RA and SLE and RA, analyzing differential expression in salivary glands in SS, synovial fibroblasts in RA, and synovial fluid in SLE. Among common genes, DE genes found in salivary gland mRNA expression in patients with SS were used for gene enrichment and SS molecular network construction. Secondary analysis was performed to identify DE genes unique to the disease site tissues, by excluding PBMC and CPA common DE genes to complement the SS network.ResultsWe identified 22 DE genes in salivary gland datasets in SS that have not previously been clearly associated with SS pathogenesis. Among these, higher levels of checkpoint kinase 1 (CHEK1), V-Ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1), and lymphoid enhancer binding factor 1 (LEF1) were significantly correlated with higher matrix metalloproteinase 9 (MMP9) levels. Higher MMP9 levels have been implicated in degradation of salivary gland structural integrity, leading to hypo-salivation in patients with SS. Salivary gland mRNA expression of MMP9 and the expression of cytokine CXCL10 were higher in patients with SS. CXCL10 has been shown to increase MMP9 expression and therefore may also play an important role in SS pathogenesis.ConclusionUsing CPA and gene expression analysis, we identified factors targeting MMP9 expression and/or function, namely CHEK1, CXCL10, ETS1, LEF1, and tissue inhibitor of metalloproteinase 1; altered mRNA expression of these could increase expression/activity of MMP9 in a concerted manner, thereby potentially impacting SS pathogenesis.
Highlights
Sjögren's syndrome (SS) shares many clinical and pathological similarities with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)
In analysis 1, we derived genes associated with SS, SLE, and RA by using concept profile analysis (CPA) (i.e., Anni 2.1) and compared those genes to the differentially expressed (DE) genes of the SS, SLE, and RA Peripheral blood mononuclear cells (PBMC) datasets
Analysis 1 - phase 3: expression analysis of phase 2 candidate genes associated with SS, SLE, and RA in disease sites among female patients After comparative gene expression analysis of SS, SLE, and RA PBMCs, we investigated the fundamental role played by the DE genes individually and collectively, primarily in SS
Summary
Sjögren's syndrome (SS) shares many clinical and pathological similarities with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Autoimmune diseases often share common clinical and pathological features such as innate immune response activation, chronic inflammation, development of specific autoantibodies, and systemic dysfunction of multiple organs [1, 3, 4]. SS is most closely associated with the two autoimmune disorders, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [5]. RA affects more women than men but less drastically (ratio of 2-3 to 1) [9, 10]
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