Toll And Toll-like Receptors:: An Immunologic Perspective by Tina Rich

Toll And Toll-like Receptors:: An Immunologic Perspective

byTina Rich

Hardcover | January 7, 2005

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Until recently innate immunity was viewed as the poorer relative of the sophisticated adaptive immune response. We now know, however, that these 'higher' immune responses are actually underpinned by an elegantly hewn system of innate immune surveillance. Discovered first by developmental biologists, again by immunologists, and even by sociologists, Toll receptors have revolutionized our understanding of innate immunology. Although a small part of a complex system, Toll receptor biology compels us to revisit existing models of self - non-self recognition.

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Title:Toll And Toll-like Receptors:: An Immunologic PerspectiveFormat:HardcoverDimensions:228 pages, 9.49 × 6.5 × 0 inPublished:January 7, 2005Publisher:Springer USLanguage:English

The following ISBNs are associated with this title:

ISBN - 10:0306482371

ISBN - 13:9780306482373

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Table of Contents

IntroductionToll Receptors and the Renaissance of Innate Immunity ....................... 1Beginnings ............................................................................................ 2The Innate and Adaptive Immune Systems ........................................... 2Saturation Screening of the Drosophila Genome .................................... 3The Toll Receptor in Development ....................................................... 4The Implication of Toll in Fly Immunity .............................................. 5A Problem with Vaccination.................................................................. 6The Question of Escape Mutants .......................................................... 7The Evolution of Toll Receptors ........................................................... 8To the Clinic ....................................................................................... 141. The Function of Toll-Like Receptors ................................................... 18Developmental Functions .................................................................... 19The Role in Defense ............................................................................ 22Divisions of Immunity ........................................................................ 27Expression and Function of TLRs in Cellsof Autonomous Immunity ............................................................... 30Expression and Function of TLRs in Cells of Central Immunity ......... 33The Roles of TLRs in APC-T Cell Interactions ................................ 39TLRs and Theories about the Function of the Immune System ........... 44TLRs in Health and Disease ................................................................ 512. Structures and Motifs Involved in Toll Signaling ................................. 56Components of the Extracellular Pathway:The Extracellular Leucine-Rich Repeat Domain of TLRs ................ 56Structural Diversity of TLR Ligands .................................................... 61Mechanism of Ligand Binding and Signal Transduction ..................... 70Pathogen Recognition by TLRs ........................................................... 70Mechanism of Signal Transduction ..................................................... 74Components of the Intracellular Pathway ............................................ 753. "Supramolecular" Activation Custers in Innate Immunity ................... 94Lipopolysaccharide Recognition .......................................................... 95Structure of LPS .................................................................................. 95The Search for the LPS "Signal Transducer" ....................................... 96Microdomains ................................................................................... 1014. Interleukin-1 Receptor/Toll-Like Receptor Signaling ......................... 110The "Hardware" of IL-1R/TLR Signaling ......................................... 110The NF-êB Family of Transcription Factors ..................................... 115IL-1R Signaling ................................................................................. 115Mechanisms of TLR Signaling .......................................................... 118Termination of IL-1R/TLR Signaling ............................................... 120The Toll Pathway in Drosophila Melanogaster .................................... 122TLR-Mediated Apoptosis .................................................................. 1245. Virus Induced Signaling to Initiate the Interferon MediatedAnti Viral Host Response ................................................................... 131Initiation of the Host Immune Response ........................................... 132Toll-Like Receptors ........................................................................... 132Double Stranded RNA as the Principle Viral PAMP ......................... 135Interferon Regulatory Factors (IRFs) ................................................. 135IRF-3 and IRF-7 ............................................................................... 136IRF-9 ................................................................................................ 136IRF-3 Activation ............................................................................... 136The IFN Loop ................................................................................... 138Interactions at IFN Promoters ........................................................... 139Viral Evasion Strategies ..................................................................... 1406. The Induction of Dendritic Cell Activation and Maturationby Toll-Like Receptor Signaling ......................................................... 147Comparisons Between TLRs and Toll ............................................... 148Microbial Recognition by TLRs ........................................................ 149Signal Transduction of TLRs ............................................................ 152Regulation of Adaptive Immunity by DCs ........................................ 154Crosstalk between Toll-Like and Other Receptors ............................. 156Perspectives ....................................................................................... 1567. Pathogen Avoidance Using Toll Signaling in C. elegans ..................... 162The Single C. elegans TLR TOL-1 Is Essential for Development ....... 163tol-1 Mutants Are Not Hyper Susceptible to Fungalor Bacterial Infection ..................................................................... 163TOL-1 Dependant Avoidance Behavior ............................................ 163Sensing a Bacterial Signal .................................................................. 164Communication Between Infected Worms ........................................ 1648. Forward Genetic Analysis of TLR Pathways:A Shared System for the Detection of Endotoxinand Viral Infection ............................................................................. 168Innate Immunity and the Endotoxin Mystery ................................... 168The Paralogous Status of the LPS Receptor Suggests thatEach of the TLRs May Serve As a Discrete Microbial Sensor ......... 170The Details of Signaling, and the Role of Adapter Proteins ............... 172The MyD88-Dependent and Independent Signaling Pathways ......... 174The Forward Genetic Approach, and the Identification of Lps2,Proximal Mediator of MyD88-Independent Signaling .................. 174The Nature of Signaling from the LPS Receptor:Two and Only Two Primary Rami ................................................ 175The Existence of Lps2-Dependent and Lps2-IndependentCell Populations ............................................................................ 175Two Populations of Macrophages Distinguished on the Basisof Responses to Poly I:C ................................................................ 175Limits of the Forward Genetic Approach, and What May BeExpected of Innate Immune Signaling in the Future ..................... 1779. Agonists of Toll-Like Receptor 9: Modulation of Host ImmuneResponses with Synthetic Oligodeoxynucleotides ............................... 181CpG DNA Structure ......................................................................... 184Role of Flanking Sequences ............................................................... 185The Role of Nucleotides Adjacent to the CpG Dinucleotidein DNA ......................................................................................... 190Immunomers..................................................................................... 190Immunomer Design Enhances the Metabolic Stabilityof CpG DNA ................................................................................ 191The Significance of d(CpG) Dinucleotides and the Roleof Functional Groups of Cytosine and Guaninein Immune Stimulation ................................................................. 193Recognition of a Bicyclic Heterobase at the C-Positionand the Negation of Species Specificity ......................................... 196Secondary Structure in CpG DNA Affects ImmunostimulatoryActivity .......................................................................................... 197Species Specific Recognition of CpG DNA ....................................... 198Therapeutic Applications of CpG DNA ............................................ 199CpG DNAs in Clinical Trials ............................................................ 204The Safety of CpG DNA .................................................................. 204Index ..................................................................................................213