Alexander B. Sigalov
University of Massachusetts Medical School
Worcester, Massachusetts, USA

About this Book

Multichain Immune Recognition Receptors (MIRRs) represent a family of surface receptors expressed on different cells of the hematopoetic system and function to transduce signals leading to a variety of biologic responses. These receptors share common structural features, including extracellular ligand-binding domains and intracellular signaling domains carried on separate subunits. Another important feature linking members of the MIRR family is the presence of one or more copies of a cytoplasmic structural module termed the immunoreceptor tyrosine-based activation motif (ITAM). ITAMs consist of conserved sequences of amino acids that contain two appropriately spaced tyrosines (YxxL/Ix6�8YxxL/I; where x denotes non-conserved residues). Following receptor engagement, phosphorylation of ITAM tyrosine residues represents one of the earliest events in the signaling cascade. Although the MIRR-mediated ligand-recognition and the MIRR-triggered signaling cascades are believed to be among the best-studied in biology in recent years, at present the spatial organization of the MIRRs, its reorganization in response to ligand binding as well as the molecular mechanisms underlying the initiation of MIRR signaling remain to be elucidated.

The central idea of this book is to show that the structural similarity of the MIRRs determines the general principles underlying MIRR-mediated transmembrane signaling mechanisms and furthermore, provides the basis for existing and future therapeutic strategies targeting MIRRs. This book intends to assemble reviews on the progress in defining and controlling the spatiotemporal organization of key events in immune cell activation. Improved understanding of MIRR-mediated signaling has a number of potential practical applications, from the rational design of drugs and vaccines to the engineering of cells for biotechnological purposes. In Section 1, spatial organization and physiological function of the MIRR family members such as T cell receptor (TCR), B cell receptor (BCR), Fc receptors, natural killer (NK) cell receptors, and platelet glycoprotein VI (GPVI) will be reviewed. Section 2 will focus on current models of MIRR-triggering and highlight modern technologies to visualize cell-cell interaction contacts such as immunological synapse and to measure protein-protein interactions in space in real time. Potential therapeutic strategies targeting the MIRR-mediated transmembrane signal transduction will be shortly reviewed in Section 3. This book will summarize our current knowledge in this field and illustrate how control of the MIRR-triggered signaling could become a potential target of medical intervention, thus bridging basic and clinical immunology. Describing the molecular basis of MIRR-mediated transmembrane signaling, this volume will address a broad audience ranging from biochemists and immunologists and to molecular biologists and to pharmacologists.

Table of Contents

SECTION I. MIRRS: STRUCTURE AND PHYSIOLOGICAL FUNCTION

1. T-Cell Receptor
Jose M. Rojo, Raquel Bello and Pilar Portolés

2. B-Cell Receptor
Randall J. Brezski and John G. Monroe

3. Fc Receptors
Maree S. Powell and P. Mark Hogarth

4. Natural Killer Cell Receptors
Roberto Biassoni

5. Platelet Glycoprotein VI
Stephanie M. Jung and Masaaki Moroi

SECTION II. MIRR SIGNALING: POSSIBLE MECHANISMS AND THE TECHNIQUES
TO STUDY AND VISUALIZE

6. Clustering Models
Wolfgang W.A. Schamel and Michael Reth

7. Segregation Models
Elaine P. Dopfer, Mahima Swamy, Gabrielle M. Siegers, Eszter Molnar, Jianying Yang
and Wolfgang W.A. Schamel

8. Kinetic Proofreading Model
Byron Goldstein, Daniel Coombs, James R. Faeder and William S. Hlavacek

9. Serial Triggering Model
Jacob Rachmilewitz

10. Conformational Model
Ruth M. Risueño, Angel R. Ortiz and Balbino Alarcón

11. Permissive Geometry Model
Susana Minguet and Wolfgang W.A. Schamel

12. Signaling Chain Homooligomerization (School) Model
Alexander B. Sigalov

13. Visualization of Cell-Cell Interaction Contacts-Synapses and Kinapses
Michael L. Dustin

14. Visualization of Protein Interactions in Living Cells
Tomasz Zal

SECTION III. MIRR SIGNALING AND THERAPY OF IMMUNE DISORDERS

15. Immunogenicity in Peptide-Immunotherapy: From Self/Nonself
to Similar/Dissimilar Sequences
Darja Kanduc

16. Therapeutic Application of Transmembrane T and Natural Killer Cell
Receptor Peptides
Nicholas Manolios, Marina Ali, Michael Amon and Veronika Bender

17. Fc Receptor Targeting in the Treatment of Allergy, Autoimmune Diseases
and Cancer
Akira Nakamura, Tomohiro Kubo and Toshiyuki Takai

18. Therapeutic Blockade of T-Cell Antigen Receptor Signal Transduction
and Costimulation in Autoimmune Disease
Joseph R. Podojil, Danielle M. Turley and Stephen D. Miller

19. MHC and MHC-Like Molecules: Structural Perspectives on the Design
of Molecular Vaccines
Vasso Apostolopoulos, Eliada Lazoura and Minmin Yu

20. SCHOOL Model and New Targeting Strategies
Alexander B. Sigalov

21. Immune Receptor Signaling, Aging and Autoimmunity
Anis Larbi, Tamas Fülöp and Graham Pawelec

22. Viral Pathogenesis, Modulation of Immune Receptor Signaling and Treatment
Walter M. Kim and Alexander B. Sigalov