Systems-level analysis of innate immunity.

Systems-level analysis of biological processes strives to comprehensively and quantitatively evaluate the interactions between the relevant molecular components over time, thereby enabling development of models that can be employed to ultimately predict behavior. Rapid development in measurement technologies (omics), when combined with the accessible nature of the cellular constituents themselves, is allowing the field of innate immunity to take significant strides toward this lofty goal. In this review, we survey exciting results derived from systems biology analyses of the immune system, ranging from gene regulatory networks to influenza pathogenesis and systems vaccinology.

[1]  Suzanne M. Paley,et al.  Browsing metabolic and regulatory networks with BioCyc. , 2012, Methods in molecular biology.

[2]  Xinxia Peng,et al.  MicroRNA Expression and Virulence in Pandemic Influenza Virus-Infected Mice , 2010, Journal of Virology.

[3]  Virginia Pascual,et al.  An Interferon-Inducible Neutrophil-Driven Blood Transcriptional Signature in Human Tuberculosis , 2010, Nature.

[4]  A. Bowie,et al.  Immune sensing of DNA. , 2013, Immunity.

[5]  J. Blattman,et al.  Retinoic Acid as a Vaccine Adjuvant Enhances CD8+ T Cell Response and Mucosal Protection from Viral Challenge , 2011, Journal of Virology.

[6]  Karin Breuer,et al.  InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curation , 2012, Nucleic Acids Res..

[7]  Peter B. Gilbert,et al.  Genetic impact of vaccination on breakthrough HIV-1 sequences from the Step trial , 2011, Nature Medicine.

[8]  Zachary D. Smith,et al.  Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses , 2009 .

[9]  Trey Ideker,et al.  Cytoscape 2.8: new features for data integration and network visualization , 2010, Bioinform..

[10]  M. McElrath,et al.  Profiling immunity to HIV vaccines with systems biology. , 2012, Current opinion in HIV and AIDS.

[11]  B. Beutler,et al.  The forward genetic dissection of afferent innate immunity. , 2008, Current topics in microbiology and immunology.

[12]  Richard Bonneau,et al.  Integrated inference and analysis of regulatory networks from multi-level measurements. , 2012, Methods in cell biology.

[13]  Yang Liu,et al.  VisANT 4.0: Integrative network platform to connect genes, drugs, diseases and therapies , 2013, Nucleic Acids Res..

[14]  Charles M. Rice,et al.  Corrigendum: A diverse range of gene products are effectors of the type I interferon antiviral response , 2015, Nature.

[15]  Minoru Kanehisa,et al.  Molecular network analysis of diseases and drugs in KEGG. , 2013, Methods in molecular biology.

[16]  Donald K Carter,et al.  HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case–cohort analysis , 2008, The Lancet.

[17]  Theo M Bestebroer,et al.  Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets , 2012, Science.

[18]  K. Walters,et al.  An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response , 2012, Science.

[19]  D. Fuller,et al.  'Omics investigations of HIV and SIV pathogenesis and innate immunity. , 2013, Current topics in microbiology and immunology.

[20]  S. McWeeney,et al.  Systems immunogenetics of vaccines. , 2013, Seminars in immunology.

[21]  A. Aderem,et al.  Bacterial lipopolysaccharides prime macrophages for enhanced release of arachidonic acid metabolites , 1986, The Journal of experimental medicine.

[22]  Livia Perfetto,et al.  MINT, the molecular interaction database: 2012 update , 2011, Nucleic Acids Res..

[23]  Maria Keays,et al.  ArrayExpress update—trends in database growth and links to data analysis tools , 2012, Nucleic Acids Res..

[24]  Alistair G. Rust,et al.  A FOXO3/IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses , 2012, Nature.

[25]  Bastian R. Angermann,et al.  Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses , 2008, The Journal of experimental medicine.

[26]  Mark M. Davis,et al.  Cell type–specific gene expression differences in complex tissues , 2010, Nature Methods.

[27]  Nir Friedman,et al.  A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals. , 2012, Molecular cell.

[28]  Garnet Navarro,et al.  miR-451 Regulates Dendritic Cell Cytokine Responses to Influenza Infection , 2012, The Journal of Immunology.

[29]  T. Lawrence,et al.  Anti-inflammatory lipid mediators and insights into the resolution of inflammation , 2002, Nature Reviews Immunology.

[30]  B. Beutler,et al.  A mutation of Ikbkg causes immune deficiency without impairing degradation of IκBα , 2010, Proceedings of the National Academy of Sciences.

[31]  A. Bowie,et al.  The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling , 2007, Nature Reviews Immunology.

[32]  U. Alon Network motifs: theory and experimental approaches , 2007, Nature Reviews Genetics.

[33]  Rules to 'prime' by , 2009, Nature Immunology.

[34]  Adolfo García-Sastre,et al.  The E3-ligase TRIM family of proteins regulates signaling pathways triggered by innate immune pattern-recognition receptors. , 2013, Immunity.

[35]  Jacob T. Robinson,et al.  Systematic Discovery of TLR Signaling Components Delineates Viral-Sensing Circuits , 2011, Cell.

[36]  Edward A Dennis,et al.  The human plasma lipidome. , 2011, The New England journal of medicine.

[37]  C. Serhan,et al.  Metabolomics‐Lipidomics of Eicosanoids and Docosanoids Generated by Phagocytes , 2011, Current protocols in immunology.

[38]  Michael G. Katze,et al.  Into the Eye of the Cytokine Storm , 2012, Microbiology and Molecular Reviews.

[39]  Gabriele Neumann,et al.  Experimental adaptation of an influenza H5 haemagglutinin (HA) confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets , 2012, Nature.

[40]  O. Ornatsky,et al.  Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. , 2009, Analytical chemistry.

[41]  Amarnath Gupta,et al.  BiologicalNetworks 2.0 - an integrative view of genome biology data , 2010, BMC Bioinformatics.

[42]  Kevin Marsh,et al.  Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. , 2013, The New England journal of medicine.

[43]  Eva K. Lee,et al.  Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans , 2009, Nature Immunology.

[44]  Patrick G. Shaw,et al.  C9orf72 Nucleotide Repeat Structures Initiate Molecular Cascades of Disease , 2014, Nature.

[45]  R. Sugrue,et al.  A systems-based approach to analyse the host response in murine lung macrophages challenged with respiratory syncytial virus , 2013, BMC Genomics.

[46]  D. Greiner,et al.  Humanized mice for immune system investigation: progress, promise and challenges , 2012, Nature Reviews Immunology.

[47]  Daniel E. Zak,et al.  Merck Ad5/HIV induces broad innate immune activation that predicts CD8+ T-cell responses but is attenuated by preexisting Ad5 immunity , 2012, Proceedings of the National Academy of Sciences.

[48]  A. Amalfitano,et al.  Expression of the SLAM Family of Receptors Adapter EAT-2 as a Novel Strategy for Enhancing Beneficial Immune Responses to Vaccine Antigens , 2011, The Journal of Immunology.

[49]  Sandra Romero-Steiner,et al.  Molecular signatures of antibody responses derived from a systems biology study of five human vaccines , 2022 .

[50]  Zhining Wang,et al.  Expression of genes associated with immunoproteasome processing of major histocompatibility complex peptides is indicative of protection with adjuvanted RTS,S malaria vaccine. , 2010, The Journal of infectious diseases.

[51]  Richard Bonneau,et al.  A Validated Regulatory Network for Th17 Cell Specification , 2012, Cell.

[52]  Y. Jacob,et al.  Exploration of Binary Virus–Host Interactions Using an Infectious Protein Complementation Assay* , 2013, Molecular & Cellular Proteomics.

[53]  Chris T. A. Evelo,et al.  WikiPathways: building research communities on biological pathways , 2011, Nucleic Acids Res..

[54]  D. Underhill,et al.  Fungal Recognition by TLR2 and Dectin-1. , 2008, Handbook of experimental pharmacology.

[55]  Mario Roederer,et al.  Single-cell gene-expression profiling reveals qualitatively distinct CD8 T cells elicited by different gene-based vaccines , 2011, Proceedings of the National Academy of Sciences.

[56]  Lisa E. Gralinski,et al.  Integrative Deep Sequencing of the Mouse Lung Transcriptome Reveals Differential Expression of Diverse Classes of Small RNAs in Response to Respiratory Virus Infection , 2011, mBio.

[57]  C. Coban,et al.  Host innate immune receptors and beyond: making sense of microbial infections. , 2008, Cell host & microbe.

[58]  E. Dennis,et al.  An integrated omics analysis of eicosanoid biology 1 , 2009 .

[59]  Kylie M. Quinn,et al.  CD8+ T Cell Responses following Replication-Defective Adenovirus Serotype 5 Immunization Are Dependent on CD11c+ Dendritic Cells but Show Redundancy in Their Requirement of TLR and Nucleotide-Binding Oligomerization Domain-Like Receptor Signaling , 2010, The Journal of Immunology.

[60]  C. Goodnow,et al.  ENU-mutagenesis: insight into immune function and pathology. , 2006, Current opinion in immunology.

[61]  M. Katze,et al.  H5N1 virus causes significant perturbations in host proteome very early in influenza virus-infected primary human monocyte-derived macrophages. , 2012, The Journal of infectious diseases.

[62]  R. Gamelli,et al.  Genomic responses in mouse models poorly mimic human inflammatory diseases , 2013, Proceedings of the National Academy of Sciences.

[63]  Daniel E. Zak,et al.  Overcoming limitations in the systems vaccinology approach: a pathway for accelerated HIV vaccine development. , 2012, Current opinion in HIV and AIDS.

[64]  Sean C. Bendall,et al.  From single cells to deep phenotypes in cancer , 2012, Nature Biotechnology.

[65]  Garnet Navarro,et al.  Differential Host Response, Rather Than Early Viral Replication Efficiency, Correlates with Pathogenicity Caused by Influenza Viruses , 2013, PloS one.

[66]  S. Lockhart,et al.  Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial , 2013, The Lancet.

[67]  Daniel Becker,et al.  Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication , 2010, Nature.

[68]  Kelly Domico,et al.  Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines. , 2013, Immunity.

[69]  Eva K. Lee,et al.  Systems Biology of Seasonal Influenza Vaccination in Humans , 2011, Nature Immunology.

[70]  J. Sundberg,et al.  Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis , 2007, Genes and Immunity.

[71]  Ron Edgar,et al.  Gene Expression Omnibus ( GEO ) : Microarray data storage , submission , retrieval , and analysis , 2008 .

[72]  Joseph N. Brown,et al.  Macaque Proteome Response to Highly Pathogenic Avian Influenza and 1918 Reassortant Influenza Virus Infections , 2010, Journal of Virology.

[73]  Gary D. Bader,et al.  Pathway Commons, a web resource for biological pathway data , 2010, Nucleic Acids Res..

[74]  N. Hacohen,et al.  A Physical and Regulatory Map of Host-Influenza Interactions Reveals Pathways in H1N1 Infection , 2009, Cell.

[75]  B. Williams,et al.  Dynamic Transformations of Genome-wide Epigenetic Marking and Transcriptional Control Establish T Cell Identity , 2012, Cell.

[76]  J. Kublin,et al.  Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study. , 2011, The Lancet. Infectious diseases.

[77]  Alan Aderem,et al.  A microfluidic device for multiplexed protein detection in nano-liter volumes. , 2009, Analytical biochemistry.

[78]  E. Davidson,et al.  Transcriptional regulatory cascades in development: Initial rates, not steady state, determine network kinetics , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Daniel E. Zak,et al.  Systems analysis identifies an essential role for SHANK-associated RH domain-interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses , 2011, Proceedings of the National Academy of Sciences.

[80]  J. Stender,et al.  Epigenomic control of the innate immune response. , 2013, Current opinion in pharmacology.

[81]  R. Sékaly,et al.  Dissecting the HIV-specific immune response: a systems biology approach. , 2012, Current opinion in HIV and AIDS.

[82]  C. Serhan,et al.  Novel anti-inflammatory--pro-resolving mediators and their receptors. , 2011, Current topics in medicinal chemistry.

[83]  Ernesto S. Nakayasu,et al.  Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation , 2012, Molecular systems biology.

[84]  Xinxia Peng,et al.  Lethal Influenza Virus Infection in Macaques Is Associated with Early Dysregulation of Inflammatory Related Genes , 2009, PLoS pathogens.

[85]  S. Plotkin,et al.  Vaccines: correlates of vaccine-induced immunity. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[86]  Julian Parkhill,et al.  Single-cell genomics , 2008, Nature Reviews Microbiology.

[87]  Riet De Smet,et al.  Advantages and limitations of current network inference methods , 2010, Nature Reviews Microbiology.

[88]  Tamara Munzner,et al.  Cerebral: a Cytoscape plugin for layout of and interaction with biological networks using subcellular localization annotation , 2007, Bioinform..

[89]  Eoin Fahy,et al.  LIPID MAPS online tools for lipid research , 2007, Nucleic Acids Res..

[90]  L. Baum Role of Humoral Immunity in Host Defense Against HIV , 2010, Current HIV/AIDS reports.

[91]  K. Walters,et al.  Francisella tularensis subsp. tularensis Induces a Unique Pulmonary Inflammatory Response: Role of Bacterial Gene Expression in Temporal Regulation of Host Defense Responses , 2013, PloS one.

[92]  A. Halayko,et al.  Response of Primary Human Airway Epithelial Cells to Influenza Infection: A Quantitative Proteomic Study , 2012, Journal of proteome research.

[93]  J. Farrar,et al.  Transcriptional response in the peripheral blood of patients infected with Salmonella enterica serovar Typhi , 2009, Proceedings of the National Academy of Sciences.

[94]  D. Price,et al.  Wrestling with the repertoire: The promise and perils of next generation sequencing for antigen receptors , 2012, European journal of immunology.

[95]  Ron Shamir,et al.  Functional genomic delineation of TLR-induced transcriptional networks , 2007, BMC Genomics.

[96]  J Christopher Love,et al.  A high-throughput single-cell analysis of human CD8⁺ T cell functions reveals discordance for cytokine secretion and cytolysis. , 2011, The Journal of clinical investigation.

[97]  Y. Kong,et al.  Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. , 2011, Immunity.

[98]  Eva K. Lee,et al.  Analysis of the consistency of a mixed integer programming-based multi-category constrained discriminant model , 2010, Ann. Oper. Res..

[99]  T. Miyakawa,et al.  Genomic responses in mouse models poorly mimic human inflammatory diseases , 2013 .

[100]  Rona S. Gertner,et al.  Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells , 2013, Nature.

[101]  M. Katze,et al.  Integrated Molecular Signature of Disease: Analysis of Influenza Virus-Infected Macaques through Functional Genomics and Proteomics , 2006, Journal of Virology.

[102]  Philip R. Johnson,et al.  Accelerating Next-Generation Vaccine Development for Global Disease Prevention , 2013, Science.

[103]  Y. Kawaoka,et al.  The Lipid Mediator Protectin D1 Inhibits Influenza Virus Replication and Improves Severe Influenza , 2013, Cell.

[104]  A. Sher,et al.  Cooperation of Toll-like receptor signals in innate immune defence , 2007, Nature Reviews Immunology.

[105]  Eric H Davidson,et al.  A Gene Regulatory Network Subcircuit Drives a Dynamic Pattern of Gene Expression , 2007, Science.

[106]  Daniel S. Chertow,et al.  Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniae Coinfection Is Associated with Loss of Murine Lung Repair Responses , 2011, mBio.

[107]  Bin Li,et al.  Uncovering a Macrophage Transcriptional Program by Integrating Evidence from Motif Scanning and Expression Dynamics , 2008, PLoS Comput. Biol..

[108]  H. Kitano,et al.  Software for systems biology: from tools to integrated platforms , 2011, Nature Reviews Genetics.

[109]  A. Aderem,et al.  Lipidomic Profiling of Influenza Infection Identifies Mediators that Induce and Resolve Inflammation , 2013, Cell.

[110]  Rafael C. Jimenez,et al.  The IntAct molecular interaction database in 2012 , 2011, Nucleic Acids Res..

[111]  S. Akira,et al.  Innate Immune Sensing of Modified Vaccinia Virus Ankara (MVA) Is Mediated by TLR2-TLR6, MDA-5 and the NALP3 Inflammasome , 2009, PLoS pathogens.

[112]  C. Bakal,et al.  Genomic screening with RNAi: results and challenges. , 2010, Annual review of biochemistry.

[113]  J H Moore,et al.  Integrated analysis of genetic and proteomic data identifies biomarkers associated with adverse events following smallpox vaccination , 2009, Genes and Immunity.

[114]  Christie S. Chang,et al.  The BioGRID interaction database: 2013 update , 2012, Nucleic Acids Res..

[115]  A. Aderem,et al.  A 2020 vision for vaccines against HIV, tuberculosis and malaria , 2011, Nature.

[116]  Nir Hacohen,et al.  Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach , 2012, Nature Immunology.

[117]  E. Rosenberg,et al.  Elite control of HIV infection: implications for vaccines , 2006, Retrovirology.

[118]  Virginia Pascual,et al.  A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. , 2008, Immunity.

[119]  A. O’Garra,et al.  Tripartite-motif proteins and innate immune regulation. , 2011, Current opinion in immunology.

[120]  Meghana Kulkarni Digital multiplexed gene expression analysis using the NanoString nCounter system. , 2011, Current protocols in molecular biology.

[121]  M. Roederer,et al.  T-cell quality in memory and protection: implications for vaccine design , 2008, Nature Reviews Immunology.

[122]  Charles N. Serhan,et al.  Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators , 2008, Nature Reviews Immunology.

[123]  Joonsoo Kang,et al.  Immunological Genome Project and systems immunology. , 2013, Trends in immunology.

[124]  B. Palsson,et al.  Insight into human alveolar macrophage and M. tuberculosis interactions via metabolic reconstructions , 2010, Molecular systems biology.

[125]  N. Friedman,et al.  Densely Interconnected Transcriptional Circuits Control Cell States in Human Hematopoiesis , 2011, Cell.

[126]  Rong Fan,et al.  A Clinical Microchip for Evaluation of Single Immune Cells Reveals High Functional Heterogeneity in Phenotypically Similar T Cells Nih Public Access Author Manuscript Design Rationale and Detection Limit of the Scbc Online Methods Microchip Fabrication On-chip Secretion Profiling Supplementary Mater , 2022 .

[127]  H. Zou,et al.  Regularization and variable selection via the elastic net , 2005 .

[128]  J. Schatzle,et al.  Cutting Edge: The Adapters EAT-2A and -2B Are Positive Regulators of CD244- and CD84-Dependent NK Cell Functions in the C57BL/6 Mouse , 2010, The Journal of Immunology.

[129]  Devan V Mehrotra,et al.  Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial , 2008, The Lancet.

[130]  J. Stender,et al.  Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. , 2013, Molecular cell.

[131]  V. Bajic,et al.  Systems biology of innate immunity. , 2006, Cellular immunology.

[132]  Adrian Ozinsky,et al.  Phagocytosis of microbes: complexity in action. , 2002, Annual review of immunology.

[133]  Arndt Benecke,et al.  Systems biology of natural simian immunodeficiency virus infections. , 2012, Current opinion in HIV and AIDS.

[134]  Mario Roederer,et al.  Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine , 2013, Science.

[135]  Jerome H. Kim,et al.  Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. , 2009, The New England journal of medicine.

[136]  S. Kaufmann,et al.  The dual role of biomarkers for understanding basic principles and devising novel intervention strategies in tuberculosis , 2013, Annals of the New York Academy of Sciences.

[137]  Karen Sachs,et al.  Multiplexed mass cytometry profiling of cellular states perturbed by small-molecule regulators , 2012, Nature Biotechnology.

[138]  Bali Pulendran,et al.  Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity , 2006, The Journal of experimental medicine.

[139]  Sean C. Bendall,et al.  Cytometry by time-of-flight shows combinatorial cytokine expression and virus-specific cell niches within a continuum of CD8+ T cell phenotypes. , 2012, Immunity.

[140]  K. Ozato,et al.  TRIM family proteins and their emerging roles in innate immunity , 2008, Nature Reviews Immunology.

[141]  B. Autran,et al.  Elite controllers as a model of functional cure , 2011, Current opinion in HIV and AIDS.

[142]  B. Williams,et al.  Functional classification of interferon‐stimulated genes identified using microarrays , 2001, Journal of leukocyte biology.

[143]  Frederick Klauschen,et al.  A Systems Analysis Identifies a Feedforward Inflammatory Circuit Leading to Lethal Influenza Infection , 2013, Cell.

[144]  Anushya Muruganujan,et al.  PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees , 2012, Nucleic Acids Res..

[145]  Stephen R Quake,et al.  Genomic analysis at the single-cell level. , 2011, Annual review of genetics.

[146]  David E. Swayne,et al.  Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus , 2006, Nature.

[147]  E. Dennis,et al.  Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling , 2012, Proceedings of the National Academy of Sciences.

[148]  R. Medzhitov,et al.  Toll-dependent selection of microbial antigens for presentation by dendritic cells , 2006, Nature.

[149]  T. Aittokallio,et al.  Quantitative Subcellular Proteome and Secretome Profiling of Influenza A Virus-Infected Human Primary Macrophages , 2011, PLoS pathogens.

[150]  M. Tyers,et al.  Osprey: a network visualization system , 2003, Genome Biology.

[151]  Bernhard O. Palsson,et al.  Identification of Potential Pathway Mediation Targets in Toll-like Receptor Signaling , 2009, PLoS Comput. Biol..

[152]  Kathleen A. Kennedy,et al.  Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 , 2006, Nature.

[153]  Lincoln Stein,et al.  Reactome: a database of reactions, pathways and biological processes , 2010, Nucleic Acids Res..

[154]  R. Ahmed,et al.  mTOR regulates memory CD8 T cell differentiation , 2009, Nature.

[155]  Martin Meier-Schellersheim,et al.  Systems biology in immunology: a computational modeling perspective. , 2011, Annual review of immunology.

[156]  Stephen A Ramsey,et al.  A systems biology approach to understanding atherosclerosis , 2010, EMBO molecular medicine.

[157]  Alistair G. Rust,et al.  Role of the transcription factor C/EBPδ in a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals , 2009, Nature Immunology.

[158]  Stephen A. Ramsey,et al.  Genome-wide histone acetylation data improve prediction of mammalian transcription factor binding sites , 2010, Bioinform..

[159]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[160]  R. Germain,et al.  Recent progress using systems biology approaches to better understand molecular mechanisms of immunity. , 2013, Seminars in immunology.