Molecular Mechanisms of Immunological Self-Recognition

by Frederick Alt (Editor), Henry J. Vogel (Editor)

Overview

Molecular Mechanisms of Immunological Self-Recognition covers the understanding of immunological self-recognition. The introductory chapter of the book summarizes the dawn of the insight into immunological tolerance, and provides an overview of research on the underlying mechanisms. The book addresses the developments in the molecular mechanisms of B and T cell tolerance and describes the failure of tolerance in autoimmunity. The text concludes by furnishing orienting perspectives and highlighting new information presented. The novel findings characterized as impressive advances pertain to the areas of B cell development and the generation of molecular diversity; V gene usage, especially from transgenes, in positive and negative thymic selection; the handling of positive and negative signals by T and B cells; anergy in postthymic T cells; the design of peptide-based therapy for autoimmune diseases; and the design of therapy with the aid of monoclonal antibodies. Immunologists will find the text useful.

Product Details

ISBN-13:	9781483215938
Publisher:	Elsevier Science
Publication date:	06/28/2014
Sold by:	Barnes & Noble
Format:	eBook
Pages:	274
File size:	8 MB

About the Author

Frederick Alt received his Ph.D. in Biology from Stanford University in 1977 where he worked with Robert Schimke and discovered gene amplification and genomic instability in mammalian cancer cells. Alt moved to MIT for postdoctoral work with David Baltimore, where he helped elucidate basic principles of recombination in the immune system. His work with Baltimore included the discovery that production of membrane versus secreted immunoglobulin is achieved via differential RNA processing and the discovery that allelic exclusion of Immunoglobulin (Ig) gene rearrangements is controlled by feedback from protein products. With Baltimore, Alt also elucidated major aspects of the V(D)J recombination mechanism, including involvement of site-specific DNA double strand breaks (DSBs) that are end joined, and the discovery of ”N” regions, which represent a major source of antigen receptor diversity.

Dr. Alt moved to Columbia University in 1982 as Assistant Professor of Biochemistry. He became Professor of Biochemistry and Molecular Biophysics in 1985 and HHMI Investigator in 1987. At Columbia, he established the role of Ig chains in regulating B cell development and discovered that antigen receptor genes are assembled by a common V(D)J recombinase. He then elucidated a role for non-coding gene transcription and "chromatin accessibility" as means to target the lineage, stage, and allele specific activity of the V(D)J recombinase. He extended that work to show that IgH class switch recombination (CSR) is B cells to particular IgH classes is directed by activation of non-coding transcription units that contain the CSR target sequences. At Columbia, he also discovered N-myc, based on its amplification in human neuroblastomas and he characterized the Myc cellular oncogene family.

In 1991, Dr. Alt moved to Boston Children' Hospital (BCH) and Harvard Medical School as a Professor of Genetics and HHMI Investigator. He also became a Senior Investigator at the Immune Disease Institute (IDI). He was appointed Charles A. Janeway Professor of Pediatrics in 1993, Scientific Director of IDI in 2005, and Director of the Program in Cellular and Molecular Medicine (PCMM) at Children's Hospital in 2008. He also became President of IDI in 2010 and continues to serve as director since the merger of IDI with BCH where it remains the PCMM. At CHB and IDI, Dr. Alt's group confirmed his earlier proposal with Baltimore that N regions are added by terminal dexoynucleotidyl transferase, demonstrating that TdT is a V(D)J recombinase component. They also discovered that the joining activity of the V(D)J recombinase is carried out by a multi-component general cellular non-homologous DNA end joining (NHEJ) pathway. Subsequently, Dr. Alt was involved in the discovery of a number of the NHEJ factors and he then went on to discover the key role of NHEJ proteins in maintenance of genomic stability. Dr. Alt continues to elucidate many new aspects of the mechanism and control of V(D)J recombination and IgH CSR and also continues to elucidate mechanisms that generate and suppress genomic instability, most recently through development of high through-put methods to study DSBs and chromosomal translocations.

In 1994, Dr. Alt was elected to the U.S. National Academy of Sciences, the American Academy of Arts and Sciences, and the American Academy of Microbiology; in 1999 he was elected to the European Molecular Biology Organization; in 2010 he was elected a Fellow of the American Association for Advancement of Sciences; and in 2011 he was elected to the Institute of Medicine. In 2004, Alt received the Clowes Memorial Award from AACR; in 2005 he received the Rabbi Shai Shacknai Prize from Hebrew University, the Pasarow Foundation Prize for Extraordinary Achievement in Cancer Research, the Leukemia&Lymphoma Society de Villiers International Achievement Award, and the Irvington Institute Award. In 2007, Alt received the NCI Alfred K. Knudson Award for pioneering contributions that have revolutionized Cancer Genetics, the AAI-Huang Meritorious Career Award, and the Novartis Basic Immunology Prize for his discoveries on B cell development and antigen responses. In 2009, he received the Cancer Research Institute William B. Coley Award for Distinguished Research in Basic Immunology for fundamental contributions to understanding of B-cell development and B cell lymphomagenesis. For his overall contributions, he most recently received the 2012 Arthur Kornberg and Paul Berg Award for Lifetime Achievement in Biomedical Sciences from Stanford University Medical School. Dr. Alt serves on numerous editorial boards and is Editor in Chief of Advances in Immunology. He also has served on various national and international advisory boards and is currently Chair, of the SAC of the Cold Spring Harbor Laboratory. Dr. Alt has mentored over 100 students and research fellows, many of whom have become leaders in immunology, genetics, or cancer biology and he received the 2003 American Association of Immunologists Excellence in Mentoring Award. The Cancer Research Institute of New York annually presents the Frederick W. Alt Award for New Discoveries in Immunology.

Table of Contents

Preface


Part I Introduction


1 Immunological Tolerance Revisited in the Molecular Era


The Dawn of Immunologic Tolerance


One Cell-One Antibody, and Implications


In Vitro Lymphocyte Cloning Techniques Validate Repertoire Purging as a Tolerance Mechanism; Clonal Abortion versus Clonal Anergy


Clonal Abortion and Clonal Anergy Come of Age in the Molecular Era


The Genesis of High-Affinity Antibodies


Soluble Antigen Can Cause Adult Tolerance, Including a Failure of Appearance of High-Affinity B Cells


Summary and Conclusions


References


Part II B Cell Tolerance


2 Mechanisms and Meaning of B Lymphocyte Tolerance


Introduction


The Deletion-Anergy Decision


Consequences of Deletion versus Anergy


References


3 Tolerant Autoreactive B Lymphocytes in the Follicular Mantle Zone Compartment: Substrates for Receptor Editing and Reform


Introduction


Localization of Transgene-Expressing B Cells within Peripheral Lymphoid Organs


Timing of Tolerance Induction during Bone Marrow B Cell Differentiation


Recovery from Receptor Modulation and Tolerance


Deletion or Anergy?


Does the Follicular Mantle Zone Serve as a "Reform School" for Wayward B Cells?


References


Part III Lymphocyte Signaling


4 T Cell Anergy


Introduction


Cellular Characteristics


Biochemical Events Resulting from TCR Occupancy


Reversal of Anergy


Conclusion


References


5 The T Cell Antigen Receptor: Biochemical Aspects of Signal Transduction


Introduction


Substrate Analysis in Murine and Human T Cells; Possible Tyrosine Kinase Regulation of Phospholipase C


Analysis of Tyrosine Phosphatases


The Serine Kinase Pathway


FYN Is a T Cell Receptor-Associated Tyrosine Kinase


References


6 Structure and Signaling Function of B Cell Antigen Receptors of Different Classes


Introduction


Results


References


Part IV T Cell Tolerance


7 Self-Nonself Discrimination by T Lymphocytes


Introduction


Negative and Positive Selection of a Transgenic Receptor Specific for the Male-Specific Peptide Presented by Class I H-2Db MHC Molecules


Lack of Allelic Exclusion of the a TCR Chain in αß TCR Transgenic Mice


Mutations in the Peptide-Binding Groove of MHC Molecules Affect Antigenicity and Negative as Well as Positive Selection


Positive Selection: Expansion of Mature Thymocytes or Maturation of Immature Thymocytes?


Postthymic Expansion of Mature T Cells


Postthymic Tolerance


Discussion


References


8 Transgenic Mouse Model of Lymphocyte Development


Introduction


T Cell Receptor Transgenic Mouse as a Model System to Study T Lymphocyte Development


Clonal Deletion of Self-Reactive T Cells


Positive Selection Model of the Origin of MHC-Restricted T Cells


Molecular Requirements for Positive Selection


Future Issues in T Cell Development Using TCR Transgenic Mice


References


9 Recognition Requirements for the Positive Selection of the T Cell Repertoire: A Role of Self-Peptides and Major Histocompatibility Complex Pockets


Introduction


Results and Discussion


Summary


References


10 Mechanisms of Peripheral Tolerance


Introduction


Results


Distinct Mechanisms of Peripheral Tolerance


Conclusions


References


11 An Analysis of T Cell Receptor-Ligand Interaction Using a Transgenic Antigen Model for T Cell Tolerance and T Cell Receptor Mutagenesis


Introduction


T Cell Receptor Mutagenesis


A Paired Antigen/TCR Transgenic System


References


12 T Cell Repertoire and Tolerance


Introduction


Superantigens


Tolerance to Self-Superantigens Shapes the T Cell Repertoire


Vβ Interaction with the Self-Superantigen Mls-la


Vβ Interaction with the Foreign Superantigens


References


13 Sequential Occurrence of Positive and Negative Selection during T Lymphocyte Maturation


Introduction


Results and Discussion


References


14 Tolerance Induction in the Peripheral Immune System


Introduction


Materials and Methods


Results


Discussion


References


Part V Autoimmunity


15 Activation-Induced Cell Death of Effector T Cells: A Third Mechanism of Immune Tolerance


Introduction


Experimental Results


Interpretations


References


16 T Cells Involved in Inductive Events in the Pathogenesis of Autoimmune Diabetes Mellitus


Text


References


17 Genetic Control of Diabetes and Insulitis in the Nonobese Diabetic Mouse: Analysis of the NOD.H-2b and B10.H-2nod^ Strains


Introduction


Materials and Methods


Results and Discussion


Concluding Remarks


References


18 Islet Tolerance in Humans and Transgenic Mice


Text


References


19 Fluorescence-Activated Cell Sorter Analysis of Peptide-Major Histocompatibility Complex


Introduction


FACS Binding Assay


Results


Discussion


References


20 Tolerance to Self: A Delicate Balance


Introduction


Monoidiotypy


TCR-Specific Antibody Modulation of Disease


TCR Peptide Modulation


Discussion


References


21 Prevention, Suppression, and Treatment of Experimental Autoimmune Encephalomyelitis with a Synthetic T Cell Receptor V Region Peptide


Introduction


Animal Studies


Human Studies


Summary


References


Part VI Perspectives


22 Tolerance of Self: Present and Future


The 1975 Baseline


F Liver Antigen


Negative Signaling


Anergy, and the Need for a Defined Anergic Phenotype


Thymus Lobe Cultures


Autoimmunity and Epitope Linkage


Toward Gene Therapy in Autoimmunity


References


Index