Abstract 546: Systemic Transcriptional Alterations of Innate-Adaptive Immune Signaling Pathways in Atherosclerosis, Ischemic Stroke and Myocardial Infarction

Abstract

Objective: The immune system regulates inflammation associated with chronic cardiovascular disease. The primary aim of this study was to compare gene expression profiles of three innate and adaptive immune signaling pathways --the toll-like receptor (TLR), T-cell receptor (TCR), and B-cell receptor (BCR) signaling pathways in patients with subclinical atherosclerosis, acute ischemic stroke (IS), and myocardial infarction (MI). Methods: Peripheral blood gene expression profiles from human atherosclerotic diseases were downloaded from Gene Expression Omnibus (GEO): Atherosclerosis (GSE20129: 48 patients, 71 controls), IS (GSE16561: 39 patients - samples within 24 hours from symptom onset, 24 controls), and MI (GSE29111, 18 MI patients (7 and 30 days) samples after experiencing MI). Genes in the TLR (106 genes), TCR (104 genes), and BCR (72 genes) pathways were retrieved from the NCBI BioSystems database. Gene set enrichment analysis was used to evaluate the statistical significance of gene enrichment in each signaling pathway for each study. Weighted Gene Co-expression Network Analysis was used to identify gene modules and evaluate network connectivity across the disease states. Results: All three immune pathways significantly enriched differentially expressed genes in each disease state (P<0.01) - TLR (38% in atherosclerosis, 47% in IS, 30% in MI); TCR (51% in atherosclerosis, 54% in IS, and 53% in MI); BCR (57% in atherosclerosis; 60% in IS; 43% in MI). Transcriptional changes in the pathways are highly concordant across the diseases. The correlation of expression changes between any two diseases ranges from 0.53 to 0.76 (mean±SD: 0.66±0.09, P<0.00001). Although TLR genes were all up-regulated in each condition, network analysis revealed a striking down-regulation of gene modules in the TCR and BCR pathways. Of significance, the TCR-CD3 complex and CD79A/B were significantly down-regulated in patients of all three disease states. Conclusion: We found a strong overlap in expression between innate and adaptive immune pathways in three atherosclerotic related diseases. The down regulation of the TCR-CD3 complex suggests immune suppression is a common occurrence in either chronic or acute inflammation associated atherosclerotic disease.