Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways

Krzysztof Laudanski, Carol Miller-Graziano, Wenzhong Xiao, Michael N. Mindrinos, Daniel R. Richards, Asit De, Lyle L. Moldawer, Ronald V. Maier, Paul Bankey, Henry V. Baker, Bernard H. Brownstein, J. Perren Cobb, Steve E. Galvano, Ronald W. Davis, Ronald G. Tompkins, Timothy R. Billiar, David Camp, Celeste Finnerty, George Casella, Irshad H. ChaudryMashkoor Choudhry, Constance Elson, Bradley Freeman, Richard L. Gamelli, Nicole S. Gibran, Brian G. Harbrecht, Douglas L. Hayden, David Herndon, Jureta W. Horton, William Hubbard, John Lee Hunt, Jeffrey Johnson, Matthew B. Klein, James A. Lederer, Tanya Logvinenko, Stephen F. Lowry, John A. Mannick, Philip H. Mason, Grace P. McDonald-Smith, Bruce A. McKinley, Joseph P. Minei, Ernest E. Moore, Frederick A. Moore, Avery B. Nathens, Grant E. O'Keefe, Laurence G. Rahme, Daniel G. Remick, David A. Schoenfeld, Michael B. Shapiro, Martin Schwacha, Geoffrey M. Silver, Richard D. Smith, John Storey, Mehmet Toner, H. Shaw Warren, Michael A. West

Research output: Contribution to journalArticle

83 Citations (Scopus)

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-2Rα). 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.

Original languageEnglish (US)
Pages (from-to)15564-15569
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number42
DOIs
StatePublished - Oct 17 2006

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Monocytes
T-Lymphocytes
Wounds and Injuries
Genome
Leukocytes
Genes
Programmed Cell Death 1 Receptor
CD4 Antigens
Multiple Organ Failure
Cell Separation
Antigen Presentation
Transcriptome
Population
Cell Proliferation
Medicine
Apoptosis
Ligands
Gene Expression

Keywords

  • Anergy
  • Apoptosis
  • Costimulatory receptors
  • Immunosuppression
  • Network analysis

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways. / Laudanski, Krzysztof; Miller-Graziano, Carol; Xiao, Wenzhong; Mindrinos, Michael N.; Richards, Daniel R.; De, Asit; Moldawer, Lyle L.; Maier, Ronald V.; Bankey, Paul; Baker, Henry V.; Brownstein, Bernard H.; Cobb, J. Perren; Galvano, Steve E.; Davis, Ronald W.; Tompkins, Ronald G.; Billiar, Timothy R.; Camp, David; Finnerty, Celeste; Casella, George; Chaudry, Irshad H.; Choudhry, Mashkoor; Elson, Constance; Freeman, Bradley; Gamelli, Richard L.; Gibran, Nicole S.; Harbrecht, Brian G.; Hayden, Douglas L.; Herndon, David; Horton, Jureta W.; Hubbard, William; Hunt, John Lee; Johnson, Jeffrey; Klein, Matthew B.; Lederer, James A.; Logvinenko, Tanya; Lowry, Stephen F.; Mannick, John A.; Mason, Philip H.; McDonald-Smith, Grace P.; McKinley, Bruce A.; Minei, Joseph P.; Moore, Ernest E.; Moore, Frederick A.; Nathens, Avery B.; O'Keefe, Grant E.; Rahme, Laurence G.; Remick, Daniel G.; Schoenfeld, David A.; Shapiro, Michael B.; Schwacha, Martin; Silver, Geoffrey M.; Smith, Richard D.; Storey, John; Toner, Mehmet; Warren, H. Shaw; West, Michael A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 42, 17.10.2006, p. 15564-15569.

Research output: Contribution to journalArticle

Laudanski, K, Miller-Graziano, C, Xiao, W, Mindrinos, MN, Richards, DR, De, A, Moldawer, LL, Maier, RV, Bankey, P, Baker, HV, Brownstein, BH, Cobb, JP, Galvano, SE, Davis, RW, Tompkins, RG, Billiar, TR, Camp, D, Finnerty, C, Casella, G, Chaudry, IH, Choudhry, M, Elson, C, Freeman, B, Gamelli, RL, Gibran, NS, Harbrecht, BG, Hayden, DL, Herndon, D, Horton, JW, Hubbard, W, Hunt, JL, Johnson, J, Klein, MB, Lederer, JA, Logvinenko, T, Lowry, SF, Mannick, JA, Mason, PH, McDonald-Smith, GP, McKinley, BA, Minei, JP, Moore, EE, Moore, FA, Nathens, AB, O'Keefe, GE, Rahme, LG, Remick, DG, Schoenfeld, DA, Shapiro, MB, Schwacha, M, Silver, GM, Smith, RD, Storey, J, Toner, M, Warren, HS & West, MA 2006, 'Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 42, pp. 15564-15569. https://doi.org/10.1073/pnas.0607028103
Laudanski, Krzysztof ; Miller-Graziano, Carol ; Xiao, Wenzhong ; Mindrinos, Michael N. ; Richards, Daniel R. ; De, Asit ; Moldawer, Lyle L. ; Maier, Ronald V. ; Bankey, Paul ; Baker, Henry V. ; Brownstein, Bernard H. ; Cobb, J. Perren ; Galvano, Steve E. ; Davis, Ronald W. ; Tompkins, Ronald G. ; Billiar, Timothy R. ; Camp, David ; Finnerty, Celeste ; Casella, George ; Chaudry, Irshad H. ; Choudhry, Mashkoor ; Elson, Constance ; Freeman, Bradley ; Gamelli, Richard L. ; Gibran, Nicole S. ; Harbrecht, Brian G. ; Hayden, Douglas L. ; Herndon, David ; Horton, Jureta W. ; Hubbard, William ; Hunt, John Lee ; Johnson, Jeffrey ; Klein, Matthew B. ; Lederer, James A. ; Logvinenko, Tanya ; Lowry, Stephen F. ; Mannick, John A. ; Mason, Philip H. ; McDonald-Smith, Grace P. ; McKinley, Bruce A. ; Minei, Joseph P. ; Moore, Ernest E. ; Moore, Frederick A. ; Nathens, Avery B. ; O'Keefe, Grant E. ; Rahme, Laurence G. ; Remick, Daniel G. ; Schoenfeld, David A. ; Shapiro, Michael B. ; Schwacha, Martin ; Silver, Geoffrey M. ; Smith, Richard D. ; Storey, John ; Toner, Mehmet ; Warren, H. Shaw ; West, Michael A. / Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 42. pp. 15564-15569.
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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-2Rα). 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.",
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T1 - Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways

AU - Laudanski, Krzysztof

AU - Miller-Graziano, Carol

AU - Xiao, Wenzhong

AU - Mindrinos, Michael N.

AU - Richards, Daniel R.

AU - De, Asit

AU - Moldawer, Lyle L.

AU - Maier, Ronald V.

AU - Bankey, Paul

AU - Baker, Henry V.

AU - Brownstein, Bernard H.

AU - Cobb, J. Perren

AU - Galvano, Steve E.

AU - Davis, Ronald W.

AU - Tompkins, Ronald G.

AU - Billiar, Timothy R.

AU - Camp, David

AU - Finnerty, Celeste

AU - Casella, George

AU - Chaudry, Irshad H.

AU - Choudhry, Mashkoor

AU - Elson, Constance

AU - Freeman, Bradley

AU - Gamelli, Richard L.

AU - Gibran, Nicole S.

AU - Harbrecht, Brian G.

AU - Hayden, Douglas L.

AU - Herndon, David

AU - Horton, Jureta W.

AU - Hubbard, William

AU - Hunt, John Lee

AU - Johnson, Jeffrey

AU - Klein, Matthew B.

AU - Lederer, James A.

AU - Logvinenko, Tanya

AU - Lowry, Stephen F.

AU - Mannick, John A.

AU - Mason, Philip H.

AU - McDonald-Smith, Grace P.

AU - McKinley, Bruce A.

AU - Minei, Joseph P.

AU - Moore, Ernest E.

AU - Moore, Frederick A.

AU - Nathens, Avery B.

AU - O'Keefe, Grant E.

AU - Rahme, Laurence G.

AU - Remick, Daniel G.

AU - Schoenfeld, David A.

AU - Shapiro, Michael B.

AU - Schwacha, Martin

AU - Silver, Geoffrey M.

AU - Smith, Richard D.

AU - Storey, John

AU - Toner, Mehmet

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N2 - 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-2Rα). 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.

AB - 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-2Rα). 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.

KW - Anergy

KW - Apoptosis

KW - Costimulatory receptors

KW - Immunosuppression

KW - Network analysis

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