the set of over-expressed genes, including pro-inflammatory cytokines, chemokines, granzymes, proteinases, and receptors for inflammatory mediators (IL1B, IL8, IL8RB, IL10RA, PTGDR,KLRC3,NKTR,GZMK, and multiple HLADR genes), as well as the master regulator of prostagladin synthesis, cyclo-oxygenase 2 (COX2/PTGS2). Additional indicators of immune cell activation that were over-expressed included the immediate-early response gene IER2, components of the insulin-like growth factor signaling pathway (IGF2R, IGFBP3), and activation-induced counter-regulators involved in pathway desensitization (TNFAIP, DUSP1, RGS1) and receptor shedding (MAN2C1, ADAM8, ARTS-1). GOstat bioinformatic analysis [44] confirmed the functional theme of a highly activated, proliferative phenotype in circulating leukocytes from socially isolated individuals by identifying over-representation of Gene Ontology (GO) annotations involving immune response and inflammation (GO:0009607, GO:0006952, GO:0006955; GO:0009613), stress response (GO: 0006950), antigen processing (GO:0019886, GO:0019884, GO:0045012), chemokine and cytokine activity (GO:0042379, GO:0008009, GO:0005125; GO:0001965), deoxyribonucleotide metabolism (GO:0009262), and nucleosome activity (GO:0000786) (all p < 0.05).
