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Primary Immunodeficiency Disorders - 1st Edition - ISBN: 9780124071797, 9780124115545

Primary Immunodeficiency Disorders

1st Edition

A Historic and Scientific Perspective

Editors: Amos Etzioni Hans Ochs
Hardcover ISBN: 9780124071797
eBook ISBN: 9780124115545
Imprint: Academic Press
Published Date: 1st August 2014
Page Count: 376
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Primary Immunodeficiency Disorders: A Historic and Scientific Perspective provides a complete historical context that is crucial for students and researchers concerned with primary immunodeficiency. When researchers have a poor understanding of the way we arrived where we are in research, they can miss important points about a disease, or miss out on how to approach new diseases. This historical knowledge of research can assist greatly by showing how it was done in the past, demonstrating the successes and failures, so that it can be done better in the future.

This book provides an understanding of the process going from clinical problem to lab and back to the clinic, based on historical experiences. Its chapters proceed from the discovery of the T and B cell lineages through the first BMT for immunodeficiency disorder; lab investigation and gene therapy for PID; the discovery of the gene for AT and its function; understanding cytokine defects; and many other stops along the way.

Key Features

  • Facilitates communication among physicians and other investigators concerned with immunological and inflammatory diseases
  • Summarizes for the first time all the known facts from 60 years of primary immunodeficiency research, and teaches how an important field in medicine was established
  • Provides stimulating discussions on developing new medical therapies
    Highlights the importance of studying humans to understand mechanisms of disease that affect humans


students, scientists and practitioners in immunology, immunodeficiency, professionals in medicine. Also interesting to anyone interested in medicine, historians of science

Table of Contents

  • Contributors
  • Foreword
  • Introduction
  • Chapter 1: Immunity: From Serendipitous Observations to Science-Based Specialty
    • Abstract
    • Serendipitous observations
    • A cell derives from a cell, a microorganism from a microbe
    • Serum therapy, active immunization and the concept of antibodies
    • Epicrisis
  • Chapter 2: Discovery of the T- and B-Cell Compartments
    • Abstract
    • Introduction
    • Discovery of the importance of the thymus in immune system development
    • En route to Bob Good’s research group in minnesota
    • The atmosphere in Bob Good’s laboratory
    • Connecting studies in chicks and immunodeficiency diseases
    • The key experiments in irradiated birds
    • The initial T- and B-cell model and its clinical implications
    • Basic questions posed by the separate T- and B-lineage model
    • The long search for the mammalian bursa-equivalent
    • The identification of B-lineage progenitors
    • An ancient blueprint for the T- and B-cell lineages
    • Acknowledgments
  • Chapter 3: Evolution of the Definition of Primary Immunodeficiencies
    • Abstract
    • Introduction
    • The birth of classical PIDs, illustrated by the discovery of X-linked agammaglobulinemia
    • The concept of PIDs with narrow phenotype, illustrated by X-linked lymphoproliferative disease
    • The development of PIDs with narrow phenotype, illustrated by Mendelian susceptibility to mycobacterial disease
    • PIDs with narrow phenotypes underlying common infections, illustrated by herpes simplex virus encephalitis of childhood
    • Conclusions and perspectives
    • Acknowledgments
  • Chapter 4: From Immunodeficiency to Autoimmunity
    • Abstract
    • A historical journey into recognition of immunodeficiency and autoimmunity
    • Autoimmunity: an often neglected feature of immune deficiency
    • Omenn syndrome: inflammation and autoimmunity in immune deficiency
    • Expanding the spectrum of autoimmunity in RAG deficiency
    • The lesson learned: when combined immunodeficiency and autoimmunity go hand-in-hand
  • Chapter 5: Immunological Tests – from the Microscope to Whole Genome Analysis
    • Abstract
    • Introduction
    • History of the evaluation of humoral immunity
    • History of the evaluation of cellular (T-cell) immunity
    • History of the evaluation of the IL12/23-interferon-γ circuit
    • History of the evaluation of NK-cell defects
    • History of the evaluation of Toll-like receptor defects
    • History of the evaluation of neutrophil immunity
    • History of the evaluation of the complement system
    • Conclusion
    • Acknowledgment
  • Chapter 6: Primary Immunodeficiency in the Developing Countries
    • Abstract
    • Introduction
    • History of primary immunodeficiency in Africa
    • History of primary immunodeficiency in the Middle East
    • History of primary immunodeficiency in Latin America
  • Chapter 7: Jeffrey Asked Us to “Do Something”! Our Journey
    • Abstract
  • Dates of description and gene discovery of major PIDDs
  • Chapter 8: Finally Found: The Ataxia-Telangiectasia Gene and its Function
    • Abstract
    • Defining the clinical characteristics of A-T, a slow evolution driven by serendipity and methodology
    • Understanding the immune deficiency in A-T
    • Discovery of the genetic defect in A-T
    • ATM mutations worldwide
    • Concluding remarks
    • Acknowledgments
  • Chapter 9: Wiskott–Aldrich Syndrome: from a Fatal Hematologic Disorder to a Curable Immunodeficiency
    • Abstract
    • Introduction
    • The discovery of WAS as a novel clinical entity
    • WAS is recognized as a combined immune deficiency
    • WAS, autoimmunity and malignancy
    • The discovery of the molecular basis of WAS/XLT
    • WIP deficiency – an autosomal recessive disorder with a WAS phenotype
    • Concluding remarks
  • Chapter 10: Neutropenia – More Genetic Defects Than Ever Expected
    • Abstract
    • Historical milestones (Fig. 10.1)
    • Pathological mechanisms
    • Clinical presentation
    • Treatment
    • Leukemia secondary to CN
    • Conclusion
    • Acknowledgments
  • Chapter 11: B-Cell Defects: From X-linked Recessive to Autosomal Recessive Agammaglobulinemia
    • Abstract
    • Introduction
    • Bruton’s original case report
    • Elucidation of the pathophysiology
    • Identification of the molecular genetic defect
    • The evolving clinical picture of agammaglobulinemia
    • Diagnosis
    • Treatment
    • Prognosis
    • Autosomal recessive agammaglobulinemia
  • Chapter 12: The Discovery of the Familial Hemophagocytosis Syndromes
    • Abstract
    • Introduction
    • Description: the early years
    • FHL and other inherited HLH conditions: the seventies
    • Assessment of immunologic functions: turn of the century
    • The genetics of HLH: an ongoing process
    • Pathogenesis: from macrophages to T- and NK cells
    • Therapy: from immunosupression and chemotherapy to stem cell transplantation
    • Conclusion
    • Acknowledgments
  • Chapter 13: Chronic Granulomatous Disease – from a Fatal Disease to a Curable One
    • Abstract
    • Introduction
    • Original descriptions
    • The defect
    • The parts
    • Emerging clinical reports
    • Cell fusions and cell-free assays
    • The genes
    • The function
    • Epidemiology
    • Residual superoxide
    • Interferon gamma
    • Survival
    • Bacterial infections
    • Fungal infections
    • Inflammation
    • Lyonization
    • Bone marrow transplantation
    • Gene therapy
    • Other roles for NADPH oxidase
    • Conclusion
    • Acknowledgment
  • Chapter 14: Severe Combined Immunodeficiency – from Discovery to Newborn Screening
    • Abstract
    • History of SCID and its treatment
    • Why screen for SCID?
    • Newborn screening
    • The T-cell receptor excision circle (TREC) screening test for SCID
    • Results to date of TREC newborn screening for SCID
    • TREC newborn screening – excellent, but not perfect for identifying primary immunodeficiencies
    • Acknowledgments
  • Chapter 15: Severe Combined Immunodeficiency as Diseases of Defective Cytokine Signaling
    • Abstract
    • Introduction
    • IL-2 and IL-2 receptors
    • The conundrum and the speculation that IL-2Rγ was shared by multiple cytokines, leading to the designation of this group of cytokines as the γc family of cytokines
    • Critical role for heterodimerization of IL-2Rβ and γc in IL-2 signaling: the association of JAK1 with IL-2Rβ and JAK3 with γc
    • IL-2 also activates PI 3-kinase and MAP-kinase coupled pathways
    • The discovery of JAK3-deficient human SCID as another form of SCID resulting from defective cytokine signaling and the development of JAK3 inhibitors as potent immunosuppressants
    • Discovery of IL-7Rα-deficient SCID: establishing that defective IL-7Rα-dependent signaling explains the defective T-cell development in XSCID and JAK3-deficient SCID
    • Defective IL-15-dependent signaling explains the NK-cell developmental defect in patients with XSCID and JAK3 deficiency
    • The discovery of IL-21 and finding that the B-cell defect in XSCID results AT LEAST IN PART from defective signaling by IL-21
    • The efficacy of bone marrow transplantation for cellular reconstitution and B-cell function in XSCID, JAK3-deficient SCID and IL-7Rα-deficient SCID
    • Does STAT deficiency result in SCID?
    • IL-21R-deficient patients
    • Conclusions
    • Acknowledgments
  • Chapter 16: The Hyper IgM Syndromes – a Long List of Genes and Years of Discovery
    • Abstract
    • Introduction
    • CSR-D caused by a defect in T:B cooperation
    • X-linked CSR-D due to CD40L deficiency
    • Autosomal recessive CSR-D due to CD40 deficiency
    • X-linked CSR-D due to defective nuclear factor kappa B (NF-κB) activation
    • Autosomal recessive CSR-D due to ICOS-deficiency
    • CSR-Ds with normal in vitro B-cell responses to CSR activation
    • CSR-Ds caused by an intrinsic B-cell defect
    • Autosomal recessive activation-induced cytidine deaminase deficiency
    • Uracil-N glycosylase (UNG) deficiency
    • Ig CSR-deficiencies with unknown molecular defect(s)
    • Autosomal recessive mismatch repair deficiency and CSR-D
    • CSR-D in Ataxia Telangiectasia
    • Other Ig CSR-deficiencies associated with a DNA repair defect
    • Conclusion and perspectives
  • Chapter 17: Unraveling the Complement System and its Mechanism of Action
    • Abstract
    • Introduction
    • Early discovery: heat labile alexin and heat stable antibody
    • Hemolytic complement
    • The isolation of complement components
    • The alternative complement pathway
    • Complement fragments and regulatory proteins
    • Mannose-binding proteins
    • Discovery that complement receptors remove immune complexes
    • The history of complement-component deficiencies
    • Animal models of complement deficiency
    • Lessons learned: the nature of scientific advance
  • Chapter 18: DiGeorge Syndrome: A Serendipitous Discovery
    • Abstract
    • Ancient history
    • The thymus as an organ of cellular immunity
    • Additional phenotypic features
    • The genetic basis OF DiGeorge syndrome
    • Clinical and laboratory features of DiGeorge syndrome
    • Treatment of the immune deficiency
    • Secondary humoral defects in chromosome 22q11.2 deletion syndrome
    • Summary
  • Chapter 19: The Many Faces of the Hyper-IgE Syndrome
    • Abstract
    • Introduction
    • Characterization of the disease – phenotypes, inheritance pattern and first linkage analysis: 1966–2004
    • Discovery of the first two genetic defects – TYK2 and STAT3: 2006 and 2007
    • Findings of reduced numbers of Th17 cells and diminished Th17 responses in HIES patients: 2008
    • Discovery of a genetic defect for AR-HIES – DOCK8: 2009
    • HSCT emerges as a successful therapy for HIES: 1998–2012
    • Concluding remarks and a glimpse into the future
    • Acknowledgments
  • Chapter 20: ADA Deficiency – The First Described Genetic Defect Causing PID
    • Abstract
    • Introduction
    • Hilaire J. Meuwissen
    • Rochelle Hirschhorn
    • Michael S. Hershfield
  • Chapter 21: The Leukocyte Adhesion Deficiency Story
    • Abstract
    • Introduction
    • LAD I
    • LAD II
    • LAD III
  • Chapter 22: How Common Variable Immune Deficiency has Changed Over Six Decades
    • Abstract
    • Introduction
    • Clinical conditions
    • Treatment
    • Pathogenesis
    • Genes and CVID
    • Conclusion
  • Chapter 23: From Subcutaneous to Intravenous Immunoglobulin and Back
    • Abstract
    • Introduction
    • Development of human immunoglobulin
    • Adverse reactions to IVIG and SCIG
    • Hyperimmune immunoglobulins
    • Development of therapeutic monoclonal antibodies
    • A look to the future
    • Summary
  • Chapter 24: History of Hematopoietic Stem Cell Transplantation
    • Abstract
    • Introduction
    • The early years
    • Renewed efforts: focus on animal experiments
    • The return to clinical transplantation: 1968–1980
    • Bone marrow transplantation in SCID and Wiskott–Aldrich syndrome
    • Moving ahead: the 1990s and beyond
    • Current and future status of HCT for PIDD
    • Summary
  • Chapter 25: David’s Story
    • Abstract
    • Introduction
    • Birth and early years
    • Research studies on David
    • Immunological studies
    • Haploidentical T-cell depleted bone marrow transplant
    • Post-mortem discoveries
    • David’s immortalized B-cell line: contributions to science
    • Personal reflections
    • A mother’s recollection: Carol Ann Demaret
    • Acknowledgment
  • Chapter 26: How Primary Immunodeficiencies Have Made Gene Therapy a Reality
    • Abstract
    • Introduction
    • Primary immunodeficiencies
    • Target cells
    • Vectors
    • The first clinical trials of gene therapy
    • Technical progress
    • The efficacy of gene therapy for SCID-X1 and ADA deficiency
    • Genotoxicity
    • Improvements in vector safety
    • The latest clinical trials
    • Conclusion
  • Index


No. of pages:
© Academic Press 2015
1st August 2014
Academic Press
Hardcover ISBN:
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About the Editors

Amos Etzioni

Affiliations and Expertise

A. Etzioni, Rambam Medical Center, Department of Pediatrics, Haifa, Israel

Hans Ochs

Affiliations and Expertise

Professor of Pediatrics, Immunology and Rheumatology, Research Affiliate, Center on Human Development and Disability, University of Washington School of Medicine, Seattle, USA


BMA Medical Book Awards 2015: Highly Commended, Basic and Clinical Sciences, British Medical Association

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