title: Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways.
abstract: Monitoring genome-wide, cell-specific responses to human disease, although challenging, holds great promise for the future of medicine. Patients with injuries severe enough to develop multiple organ dysfunction syndrome have multiple immune derangements, including T cell apoptosis and anergy combined with depressed monocyte antigen presentation. Genome-wide expression analysis of highly enriched circulating leukocyte subpopulations, combined with cell-specific pathway analyses, offers an opportunity to discover leukocyte regulatory networks in critically injured patients. Severe injury induced significant changes in T cell (5,693 genes), monocyte (2,801 genes), and total leukocyte (3,437 genes) transcriptomes, with only 911 of these genes common to all three cell populations (12%). T cell-specific pathway analyses identified increased gene expression of several inhibitory receptors (PD-1, CD152, NRP-1, and Lag3) and concomitant decreases in stimulatory receptors (CD28, CD4, and IL-2Ralpha). Functional analysis of T cells and monocytes confirmed reduced T cell proliferation and increased cell surface expression of negative signaling receptors paired with decreased monocyte costimulation ligands. Thus, genome-wide expression from highly enriched cell populations combined with knowledge-based pathway analyses leads to the identification of regulatory networks differentially expressed in injured patients. Importantly, application of cell separation, genome-wide expression, and cell-specific pathway analyses can be used to discover pathway alterations in human disease.
authors.affiliation: Department of Surgery, University of Rochester School of Medicine, Rochester, NY 14642, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Laudanski
authors.forename: Carol
authors.initials: C
authors.lastname: Miller-Graziano
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Xiao
authors.forename: Michael N
authors.initials: MN
authors.lastname: Mindrinos
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Richards
authors.forename: Asit
authors.initials: A
authors.lastname: De
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Maier
authors.forename: Paul
authors.initials: P
authors.lastname: Bankey
authors.forename: Henry V
authors.initials: HV
authors.lastname: Baker
authors.forename: Bernard H
authors.initials: BH
authors.lastname: Brownstein
authors.forename: J Perren
authors.initials: JP
authors.lastname: Cobb
authors.forename: Steve E
authors.initials: SE
authors.lastname: Calvano
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Davis
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
mesh_terms: D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D009000:Monocytes / Q000502:physiology*; D009102:Multiple Organ Failure / Q000235:genetics / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D013601:T-Lymphocytes / Q000502:physiology*; D014947:Wounds and Injuries / Q000276:immunology*