Background/Purpose:

Lupus is a prototypic autoimmune disease characterized by B cell hyperactivity, autoantibody formation and resultant tissue damage. The mechanisms underlying tissue pathology in lupus are not completely understood. Analysis of gene expression in various tissues has been employed in an attempt to develop a better understanding of disease pathogenesis and tissue injury. The current experiments were undertaken to develop a more comprehensive understanding of molecular pathways involved in lupus organ pathogenesis by assessing gene expression profiles so that novel treatment candidates targeting commonly dysregulated cellular functions could be identified.

Methods:

Publicly available gene expression profiles were identified in GEO from lupus affected skin, synovium, and kidney. The raw data were downloaded, normalized, curated and assessed for differentially expressed (DE) genes. Correlation with clinical or histologic features was carried out by Weighted Gene Correlation Network Analysis (WGCNA) and variation in pathway activity was determined in individual samples and groups of samples by Gene Set Variation Analysis (GSVA).

Results:

More than 300 gene expression profiles from lupus patients and controls were analyzed to determine DE genes (8279 discoid lupus skin, 5465 synovium, 6381 kidney glomerulus WHO class 3/4, 5587 kidney tubulointerstitum WHO class 3/4). Notably, 45% of lupus tissue DE genes were detected in more than one tissue and 439 were differentially expressed in all tissues. Curated STRING-based protein-protein interaction analysis carried out using MCODE in Cytoscape of these 439 DE genes identified a number of gene clusters that were functionally characterized by both Biologically Informed Gene Cluster Analysis (BIG-C) and IPA. BIG-C identified 13 pathways that were abnormally expressed in all lupus tissues, whereas IPA identified 65 dysregulated pathways shared among these tissues. Using the the 45 BIG-C functional categories, GSVA separated lupus tissues from control tissues, identified commonly dysregulated functional pathways, documented individual tissue variation and also largely identified the same functional pathways that emerged from pathway construction generated from DE genes. WGCA identified a number of gene modules that correlated with clinical of histologic features. These modules contained nearly 85% of the DE genes. A number of approaches were employed to connect the dysregulated lupus organ pathways to potential drug candidates, including cross referencing to the Library of Integrated Network Based Cellular Signatures (LINCS). More than 75 potential drug candidates were identified.

Conclusion:

These results indicate that common cellular and molecular pathways can be identified in all of the affected lupus tissues, implying that related processes might be involved in the pathology of multiple organs in this autoimmune disease. Connectivity between lupus organ gene expression abnormalities and candidate drug induced changes in gene expression identified a number of potential novel treatments that could target the commonly dyregulated molecular pathways underlying lupus organ pathology.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/gene-expression-analysis-reveals-common-pathways-of-tissue-pathogenesis-in-lupus-organ-involvement/