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P R I M A RY I M M U N O D E F I C I E N C Y
DISEASES
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PRIMARY
IMMUNODEFICIENCY
DISE ASES
A MOLECUL A R A ND G E NETI C A PPROACH
THIRD EDITION
EDITED BY
Hans D. Ochs, MD
C. I. Edvard Smith, MD, PhD
Jennifer M. Puck, MD
1
1
Oxford University Press is a department of the University of Oxford.
It furthers the University’s objective of excellence in research, scholarship,
and education by publishing worldwide.
With offices in
Argentina Austria Brazil Chile Czech Republic France Greece
Guatemala Hungary Italy Japan Poland Portugal Singapore
South Korea Switzerland Thailand Turkey Ukraine Vietnam
9 8 7 6 5 4 3 2 1
Printed in the United States of America
on acid-free paper
CONTENTS
v
27. Autosomal Ig CSR Deficiencies Caused by 44. X-Linked Lymphoproliferative Diseases 557
an Intrinsic B-Cell Defect 343 Volker Schuster and Sylvain Latour
Anne Durandy, Sven Kracker, Pauline Gardes, 45. DiGeorge Syndrome: A Chromosome 22q11.2
and Alain Fischer Deletion Syndrome 580
28. Genetic Approach to Common Variable Deborah A. Driscoll and Kathleen E. Sullivan
Immunodeficiency and IgA Deficiency 356
46. Introduction to Disorders Associated with DNA
Lennart Hammarström Repair and Methylation Defects 593
29. Introduction to Syndromes of Immune Dysregulation Mark O’Driscoll and Penny A. Jeggo
and Autoimmunity 366
47. Ataxia-Telangiectasia 602
Hans D. Ochs and Jennifer M. Puck
Leman Yel, Martin F. Lavin, and Yosef Shiloh
30. Autoimmune Lymphoproliferative Syndrome 368
48. Chromosomal Instability Syndromes Other
Thomas A. Fleisher, Frederic Rieux-Laucat, than Ataxia-Telangiectasia 632
and Jennifer M. Puck
Rolf-Dieter Wegner, James J. German, Krystyna H.
31. Autoimmune Polyglandular Syndrome Type 1 387 Chrzanowska, Martin Digweed, and Markus Stumm
Maureen A. Su and Mark S. Anderson 49. Immunodeficiency with Centromere Instability
32. Immune Dysregulation, Polyendocrinopathy, and Facial Anomalies (ICF Syndrome) 662
Enteropathy, and X-Linked Inheritance 395 R. Scott Hansen, Corry M. R. Weemaes, and Silvère
Troy R. Torgerson, Eleonora Gambineri, M. van der Maarel
and Hans D. Ochs 50. Introduction to Granulocyte Disorders 672
33. Recurrent Fever Syndromes 414 Karl Welte, Cornelia Zeidler, and David C. Dale
Lori Broderick, Daniel L. Kastner, 51. Severe Congenital Neutropenia 677
and Hal M. Hoffman
Christoph Klein
34. Introduction to Innate Immunity and Syndromic
Primary Immunodeficiency Disorders 448 52. Chronic Granulomatous Disease 689
Jean-Laurent Casanova Dirk Roos, Steven M. Holland, and Taco W. Kuijpers
35. Inherited Disorders of the Interleukin- 53. Cell Adhesion and Leukocyte Adhesion Defects 723
12–Interleukin-23/Interferon-Gamma Circuit 450 Amos Etzioni and Ronen Alon
Steven M. Holland and Jean-Laurent Casanova 54. Inherited Hemophagocytic Lymphohistiocytosis
36. Inborn Errors of NF-κB Immunity. Genetic, Syndromes 742
Immunological, and Clinical Heterogeneity 467 Geneviève de Saint Basile
Capucine Picard, Jordan S. Orange, Anne Puel, 55. Genetically Determined Deficiencies
Shen-Ying Zhang, and Jean-Laurent Casanova of Complement Components 757
37. Cartilage-Hair Hypoplasia 484 Kathleen E. Sullivan and Jerry A. Winkelstein
Outi Mäkitie 56. Assessment of the Immune System 780
38. Hyper-IgE Recurrent Infection Syndromes 489 Francisco A. Bonilla and Klaus Warnatz
Alexandra F. Freeman, Bodo Grimbacher, Karin R. 57. Genetic Aspects of Primary Immunodeficiencies 807
Engelhardt, Steven Holland, and Jennifer M. Puck
Jennifer M. Puck
39. Hepatic Veno-Occlusive Disease with
58. Immunodeficiency Information Resources 821
Immunodeficiency 501
Crina Samarghitean, Jouni Väliaho,
Tony Roscioli and Melanie Wong
and Mauno Vihinen
40. WHIM Syndrome 509
59. Conventional Therapy of Primary Immunodeficiency
George A. Diaz Diseases 833
41. Pulmonary Alveolar Proteinosis 520 E. Richard Stiehm and Helen M. Chapel
Luigi D. Notarangelo 60. Bone Marrow Transplantation for Primary
42. Role of TMC6 and TMC8 Genes and EVER Immunodeficiency Diseases 854
Proteins in Epidermodysplasia Verruciformis 525 Rebecca H. Buckley, Despina Moshous, and Alain Fischer
Maciej Lazarczyk, Patricia Cassonnet, 61. Gene Therapy 876
and Michel Favre
Fabio Candotti and Alain Fischer
43. Wiskott-Aldrich Syndrome 531
Hans D. Ochs and Luigi D. Notarangelo Index 899
vi • CONTENTS
FOREWORD
The first edition of this masterfully written and edited com- is the human microbiome, especially that found in the intes-
pendium on the subject of primary immunodeficiency dis- tine. It is now clear that the bacterial, viral, and fungal popula-
eases contained descriptions of about 70 entities. The second tions in our bodies are several logs higher than the number of
edition, published 8 years later, described about 120 distinct cells making up our bodies. The intestinal microbiome is made
primary immunodeficiency diseases. The current third edi- up of numerous species, many previously unknown and not
tion, in 2013, details about 250 conditions. This exponen- amenable to culture, but now discoverable by novel genetic
tial increase in the recognition of errors in host defense has methods. These unicellular organisms apparently are critical
occurred in diminishing intervals of time, attesting to the in the development of our normal host defense, and altera-
rapid advances in genetics, molecular biology, and cell biol- tions of their diverse makeup are instrumental in the pathol-
ogy and the equally fast application of basic science in clinical ogy of autoimmunity and at least some examples of defects in
medicine. In examining the recent literature, we have found host defense.
descriptions of five new immunodeficiencies in one week, All in all, it is becoming clear that immunology and host
so the field continues to grow. Similarly, these advances have defenses in general, as is true for perhaps all medical specialties
begun to move into translational medicine with more fre- and subspecialties, are controlled and altered by genetics, and
quent, but still early, reports of successful therapies. that immunodeficiency diseases are but results of the power
It is quite likely that host defense is influenced by hundreds of the infinite variation and fluidity of our genome. It may be
of genes, most of which will be shown to produce disease if that future editions of this important subject perhaps should
altered by mutations, copy number variations, deletions and be expanded to “Abnormalities of Host Defense,” of which
insertions, or epigenetic phenomena, the latter often caused immunodeficiency is an important component.
by environmental influences but still transmissible to future A potentially even more important outcome of the studies
generations. Another pathogenic mechanism is mediated by so well described in this book and those to come is a greater
molecular changes in small RNA species, recently shown to understanding of immunology and host defense in general.
enhance or reduce gene expression. New genetic methods By studying the interaction of the many genes described with
already being applied to the search for causes of Mendelian the application of system biology, understanding the role of
and complex genetic diseases will permit discovery of new modifiers, enhancers, and inhibitors will lead to possible strat-
genes influencing the various mechanisms of defense against egies of therapeutic intervention. The chapters on susceptibil-
pathogens. These methods include genome-wide association ity and resistance to specific infectious diseases provide cogent
studies, followed by second- and third-generation sequenc- examples of the beginning of such possibilities.
ing. Specific mutations will be found in patients with frequent Finally, as already recognized by Drs. Good and Cooper in
infections or autoimmune symptoms by whole-exome and the forewords of the first two editions, and greatly expanded
whole-genome sequencing. Other genetic phenomena, such in this volume, the roles of innate and adaptive immunity, of
as uniparental disomy and reversion of mutations (first proven phagocytes, and of complement in host defense vastly broaden
in adenosine deaminase deficiency), will also clarify puzzling our understanding of this fascinating field.
clinical findings in patients.
A field of importance to further understanding of the Kurt Hirschhorn and Rochelle Hirschhorn
development of our normal immune response and its failures New York, August 2012
v ii
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FOREWORD TO THE FIR ST EDITION
Modern immunology can be considered to have been launched Further investigations throughout the 1960s, 1970s, and
in 1952, when Colonel Ogden Bruton described an 8-year 1980s confirmed that this compartmentalization related to
old boy who, from 2 years of age, experienced recurrent, the fundamental lymphocyte dichotomy of B cells versus
life-threatening infections including episodes of bacterial thymus-dependent T cells. Moreover, patients with different
pneumonia and sep-ticemia. Using the newly-introduced immunodeficiency syndromes helped define the nature and
technique, serum elec-trophoresis, Bruton found the boy to the role in immune responses of other components of the host
be agammaglobulinemic. When challenged with antigens, defense system, such as phagocytes and complement, and to
he failed to produce specific antibodies. Upon treatment by recognize the diseases that occur when these components are
passive immunization with large doses of intramuscularly- absent or not functional.
injected gammaglobulin, his susceptibility to infections was Over the last decade, advances in molecular biology have
dramatically terminated. Detailed investigations of similar allowed for an even greater understanding of the immune
patients, by Charles Janeway in Boston and my group in Min- system, and the multitude of molecular pathways that regu-
neapolis, demonstrated many similarly affected children, and late growth, differentiation, communication, and effector
proved that agammaglobulinemia was often an X-linked, functions within and between cells. In 1993, two groups of
inherited disorder. researchers, led by David Vetrie and Satoshi Tsukada, discov-
In the course of caring for agammaglobulinemic patients, ered that the difficulties of Bruton’s patient and other patients
we realized that they were especially susceptible to encapsu- with XLA were due to many different mutations of an
lated bacterial pathogens, including Streptococcus pneumoniae, X-linked gene that encodes a B-cell specific tyrosine kinase,
Haemophilus influenzae, Streptococcus pyogenes, Pseudomonas Btk. In the few years since that discovery, the molecular
aeruginosa, and to a lesser extent, Staphylococcus aureus. In genetic universe has expanded phenomenally, so that almost
contrast however, they could impressively resist infections every month there is news of the identification of another
caused by fungi, coliforms, tuberculosis, bacillus Calmette- immune disease gene.
Guérin (BCG), and many viruses such as measles, chicken The present volume, edited by Professors H. D. Ochs,
pox, rubella, and vaccinia. Thus, the susceptibility profile of C.I.E. Smith, and J. M. Puck, is the first comprehensive guide
agammaglobulinemic patients bisected the microbial uni- to this new molecular genetic universe. Herein, diseases of
verse. As an experiment of nature, patients with X-linked the immune system are presented and analyzed, both in terms
agammaglobulinemia (XLA) introduced us to additional, of their clinical features and in the context of the impres-
crucially important concepts concerning how plasma cells sive molecular and genetic definitions which can be put for-
and lymph node germinal centers, which are lacking in agam- ward in 1998. Over 90 well-defined primary diseases of the
maglobulinemic patients, must be the source of antibodies human immune system are listed in the introductory chapter
providing resistance to encapsulated bacterial pathogens. We of this book; specific diseases are discussed in later chapters
reasoned that distinct mechanisms of defense that were intact organized by syndrome (Part II). The current understanding
in agammaglobulinemic patients must have been designed to of each disorder is outlined, including discussions of clinical
protect against other types of infections. Lymphocytes in the issues and clinical presentation, infections, genetic mutations,
deep paracortical regions of lymph nodes, which appeared protein function, cell biology, and management. Framing
normal in XLA patients, were found to mediate this second these discussions of individual diseases are two equally mod-
type of immune protection, cellular immunity, which was ern presentations—first, a section of seven chapters outlining
later shown to be dependent on the thymus. This conclusion the essential concepts of immunology and genetics needed to
was partially derived from the study of a different group of understand primary immunodeficiency diseases, and at the
patients, those with DiGeorge syndrome, who had congenital end, a section covering the most current approaches to assess-
absence of the thymus. ment and treatment of patients with these conditions. Each
Thus, it was evident from the beginning that patients with authoritative chapter is written by a world leader in the field,
immunodeficiencies, as experiments of nature, helped us to or in many cases by a pair or group of immunological special-
bisect not only the microbial universe, but also the universe of ists with complementary perspectives, to present the most
lym-phoid cells and the universe of immunological responses. up-to-date and complete information available.
ix
This book is an impressive demonstration of how far we derived from the study of individuals with primary immuno-
have come. Recent studies of primary immunodeficiency dis- deficiency exemplified by Bruton’s original agammaglobulin-
eases have, perhaps more than any other group of diseases, emic patient. Analysis of each of the immune system diseases
revealed the power of modern molecular genetics to define in its own way represents the molecular interpretation of an
diseases in precise molecular terms. This approach has already informative experiment of nature. In the aggregate, these
suggested therapeutic possibilities which have proven success- analyses help us understand more deeply how man can exist
ful; it has also set the stage for testing gene therapies meant free of infection while living in a veritable sea of microorgan-
to cure primary immunodeficiency diseases at the molecular isms. This volume constitutes a milestone, marking where we
level. Just how disruptions of Btk account for all of the mor- now stand and indicating where we are heading, as we con-
phological and immunological abnormalities and disease sus- tinue to interpret lessons in a most constructive fashion from
ceptibilities of patients with XLA has not yet been elucidated, the greatest teachers of modern immunology: patients with
but future work will show how this molecule interacts with primary immunodeficiency diseases.
other gene products in the B lymphocyte. Studying XLA will
continue to reveal fundamental issues in lymphology and Robert A. Good, M.D., Ph.D., D.Sc.
immunobiology. All Children’s Hospital
The knowledge of primary immunodeficiency diseases St. Petersburg, Florida
reflected in this volume continues to grow, based on insights July 1998
x • F O R EWO R D TO T H E F I R S T E D I T I O N
FOREWORD TO THE SECOND EDITION
The primary immunodeficiency diseases, the first of which of both T and B cells. With the ensuing molecular biology
were recognized over 50 years ago, are now generally appre- revolution, the pace of the genetic analysis of the immuno-
ciated as major health problems by affected patients, their deficiency diseases quickened remarkably. As more and more
families, physicians, and even the general public. In 1999, this details have been learned about the life history of T and B lin-
book was the first comprehensive compendium devoted to eage cells, many of the genetically determined defects in these
primary immunodeficiency diseases. While most are relatively differentiation pathways can now be identified quite precisely
rare, some of these conditions, like IgA deficiency and com- in genetic and molecular terms.
mon variable immunodeficiency, occur with a frequency that As is indicated in the contents of this book, we currently
makes these patients likely to be seen by most physicians. have sufficient information about the lymphocyte differen-
The study of patients with these genetically determined tiation pathways to categorize primary immunodeficiency
immune disorders in conjunction with the study of animal diseases into gene mutations that affect (1) DNA transcrip-
models has led to remarkable progress in our understanding tion factors; (2) rearrangement and expression of the T cell
of the interacting components of the complex immune sys- receptor (TCR) and immun-oglobulin genes; (3) signal trans-
tem and how they function in humans. As a consequence, ducing components of the TCR and B cell receptor (BCR)
earlier recognition and better treatment options are provided complexes; (4) essential signaling pathway elements employed
for patients with primary immunodeficiency diseases, as well by TCR and BCR; (5) coreceptor molecules that are essential
as for the even larger number of individuals with secondary for normal function of T and B cells; (6) cytokines and cyto-
immune deficiency conditions. This authoritative book, now kine receptors that promote T and B cell production, prolifer-
in its second edition, contains a comprehensive account of ation, and differentiation; and (7) cell surface molecules that
currently available information. In the short years since the are necessary for normal lymphocyte homing and intercellular
first publication, the number of known immunodeficiency interactions in the peripheral lymphoid tissues, including the
genes has grown from less than 70 to well over 120, reflect- spleen, lymph nodes, intestinal Peyer’s patches, and appendix.
ing the tremendous expansion of knowledge in this field. The It has also become increasingly evident that the normal func-
rich base of information contained in these pages makes it tion of the effector T and B cell populations depends on other
clear that there are few fields in medicine in which laboratory- types of cells as well. An especially important cell partner is
based research and the study of diseases in patients have been the dendritic cell, because it responds to potential pathogens
so mutually complementary as for the primary immunodefi- by presenting antigen to initiate the T cell response and, in
ciency diseases. turn, the B cell response. Although few primary immunode-
The first immunodeficiency diseases to be identified, ficiency diseases have as yet been attributed to developmental
namely X-linked agammaglobulinemia, and the more clini- flaws in this cell type, impaired dendritic cell function is an
cally severe congenital lymphopenic syndromes were diseases important component of the immunodeficiency caused by
that are now known to reflect compromised development in gene mutations that prevent CD40 expression or expression
the effector limbs of the adaptive immune system. Experi- of the CD40 ligand on T cells.
mental delineation of the developmentally distinct lineages The specific adaptive immune responses mediated by T
of lymphocytes, the thymus-dependent population of T cells, and B cells and their collaborators, although essential, are only
and the bone marrow-derived B cells, made possible the recog- a part of the overall host defense strategy. There is an ever-
nition of their respective roles in cell-mediated and humoral growing awareness that innate immunity is equally important
immunity. Accordingly, the primary immunodeficiency dis- and complex. Disorders of the complement system, abnormal
eases were found to belong to distinct classes, those primarily function of phago-cytic cells, and deficiencies of the chemo-
affecting T cell development, like the thymic underdevelop- kines and chemokine receptors that influence lymphocyte-
ment seen in the DiGeorge syndrome, and those featuring phagocytic cell interactions can all result in an impaired ability
impaired B cell development and antibody production, as to eliminate pathogens. Natural killer cells with their diverse
seen in Bruton X-linked agammaglobulinemia. Severe com- array of activating and inhibitory receptors are also beginning
bined immunodeficiency (SCID), recognized first by Glan- to be recognized as one of the dysfunctional cell types in some
zmann and Riniker, featured instead a developmental failure immunodeficiency disorders.
xi
Infections are the major complications of the immunode- Immunoglobulin replacement, employed first by Bruton to
ficiency diseases, and, as recognized by the late Robert Good, treat a boy with congenital agammaglobulinemia, has been
a true giant in the establishment of the field and author of the refined through the development of safe and efficient prepara-
original forword to the first edition of this book, the types of tions of intravenous immunoglobulin. Better ways to perform
infections differ according to the specific gaps in host defense. bone marrow transplantation have made this life-saving mode
Primary antibody deficiency states predispose to serious bac- of cellular engineering safer and available to more patients
terial infections, as do certain complement component and with severe combined immunodeficiency disease. Enzyme
neutrophil deficiencies. Viral and fungal infections are par- replacement can benefit SCID patients with adenosine deam-
ticularly notable in patients with T cell dysfunction. Differ- inase deficiency. Finally, gene therapy has proven effective
ent infectious disease patterns are seen with other host defense for the cure of two types of SCID, albeit presently with an
defects. For example, mycobacterial and salmonella infections attendant risk of lymphoproliferative disease. For all too many
are common in patients who have mutations in the genes for patients with primary immunodeficiency diseases, however, a
IL-12 or the receptors for IL-12 and interferon-γ, because cure is still not yet possible and will come only with improved
these signaling molecules are especially important for normal knowledge that must be gained through continued study. In
macrophage activation to kill intracellular pathogens. Charac- the meantime, early diagnosis remains the key for a quality life
terization of the different patterns of infections has been sig- for many patients with an immunodeficiency disease. Toward
nificantly enhanced by the development of databanks devoted this end, this newly updated book provides a remarkably com-
to patients with the relatively rare primary immunodeficiency prehensive and clinically useful source of information about
diseases. this challenging group of disorders.
Treatment has advanced in parallel with improved diag-
nosis of immunodeficiency diseases, understanding of their Max D. Cooper, M.D.
cellular and molecular basis, and better definition of their The University of Alabama at Birmingham
clinical consequences. Prophylactic antibiotics can be help- and the Howard Hughes Medical Institute
ful in reducing the frequency of certain types of infections. Birmingham, AL
x ii • F O R EWO R D TO T H E S E C O N D E D I T I O N
CONTRIBU TOR S
x iii
George A. Diaz, MD, PhD Alain Fischer, MD
Department of Genetics and Genomic Sciences INSERM U768
Department of Pediatrics Faculté de Médecine
Mount Sinai School of Medicine Université de Paris
New York, NY Department of Immunology and Hematology
Center for Primary Immunodeficiencies (CEDI)
Martin Digweed, PhD
Hôpital Necker-Enfants Malades
Institute of Medical and Human Genetics
Paris, France
Charité—Universitätsmedizin
Berlin, Germany Thomas A. Fleisher, MD
Department of Laboratory Medicine, CC
Lionel Donato, MD
National Institutes of Health
University of Strasbourg
Bethesda, MD
Hautepierre University Hospital
Department of Pediatric Pneumology Michael M. Frank, MD
Strasbourg, France Department of Pediatrics
Duke University School of Medicine
Deborah A. Driscoll, MD
Durham, NC
Department of Obstetrics and Gynecology
Perelman School of Medicine Alexandra F. Freeman, MD
University of Pennsylvania National Institute of Allergy and Infectious
Philadelphia, PA Diseases
National Institutes of Health
Anne Durandy, MD, PhD
Bethesda, MD
INSERM U768
Faculté de Médecine Wilhelm Friedrich, MD
Université de Paris Department of Pediatrics
Department of Immunology and Hematology University Ulm
Hôpital Necker-Enfants Malades Ulm, Germany
Paris, France Anna Fusco, PhD
Melissa E. Elder, MD, PhD Department of Pediatrics, Unit of Immunology
Division of Immunology, Rheumatology, and Infectious “Federico II” University
Diseases Naples, Italy
Department of Pediatrics Eleonora Gambineri, MD
University of Florida Department of Pediatrics
Gainesville, FL Anna Meyer Children’s Hospital
Karin R. Engelhardt, PhD University of Florence
Centre of Chronic Immunodeficiency Florence, Italy
Universitätsklinkum Freiburg Pauline Gardes, PhD
Freiburg, Germany INSERM U768
Teresa Español, MD Faculté de Médecine
Immunology Unit Université de Paris
Hospitals Vall d’Hebron Department of Immunology and Hematology
Barcelona, Spain Center for Primary Immunodeficiencies (CEDI)
Hôpital Necker-Enfants Malades
Amos Etzioni, MD
Paris, France
Meyer Children’s Hospital
Rappaport Faculty of Medicine James J. German, MD
Technion Department of Pediatrics
Haifa, Israel Weill Medical College of Cornell University
New York, NY
Michel Favre, PhD
Unité de Génétique Silvia Giliani, PhD
Papillomavirus et Cancer Humain, F-75015 Department of Pediatrics
Institut Pasteur University of Brescia
Paris, France Brescia, Italy
Stefan Feske, MD, PhD Bodo Grimbacher, MD
Associate Professor of Pathology Centre of Chronic Immunodeficiency
Department of Pathology Langone Medical Center Universitätslinikum Freiburg
New York University New York, NY Freiburg, Germany
x iv • C O N T R I B U TO R S
Eyal Grunebaum, MD Sven Kracker, PhD
The Hospital for Sick Children INSERM U768
and Faculté de Médecine
Department of Developmental and Stem Cell Biology Université de Paris
University of Toronto Hôpital Necker-Enfants Malades
Toronto, Canada Paris, France
R. Scott Hansen, PhD Taco W. Kuijpers, MD, PhD
Division of Medical Genetics Pediatric Hematology, Immunology and Infectious
Department of Medicine Diseases
University of Washington Emma Children’s Hospital
Seattle, WA Academic Medical Center
Daniel Hanau, MD, DSc University of Amsterdam
UMR S725, INSERM Amsterdam, The Netherlands
EFS-Alsace, Strasbourg Sylvain Latour, PhD
University Louis Pasteur INSERM U768
Strasbourg, France Laboratoire du Developpement Normal et Pathologique du
Lennart Hammarström, MD, PhD Système Immunitaire
Karolinska Institutet Hôpital Necker-Enfants Malades
Department of Laboratory Medicine Université de ParisParis, France
Stockholm, Sweden
Martin F. Lavin, PhD
Rochelle Hirschhorn, MD Queensland Institute of Medical Research
New York University Langone Medical Center The Bancroft CenterBrisbane, Queensland, Australia
New York, NY
Maciej Lazarczyk, MD, PhD
Manfred Hoenig, MD Unité de Génétique
Department of Pediatrics Papillomavirus et Cancer Humain
University Ulm Institut Pasteur
Ulm, Germany Paris, France
Hal M. Hoffman, MD and
Departments of Pediatrics and Medicine INSERM U563, CPTP; Université Toulouse III
University of California, San Diego Paul Sabatier, F-31300
San Diego, CA Toulouse, France
C O N T R I B U TO R S • xv
Luigi D. Notarangelo, MD Alessandro Plebani, MD
Division of Immunology and The Manton Center for Department of Pediatrics
Orphan Disease Research University of Brescia
Boston Children’s Hospital and Harvard Medical School Brescia, Italy
Boston, MA
Jennifer M Puck, MD
Robert L. Nussbaum, MD Department of Pediatrics
Department of Medicine and
Institute for Human Genetics Benioff Children’s Hospital
University of California, San Francisco University of California San Francisco
San Francisco, CA San Francisco, CA
xvi • C O N T R I B U TO R S
Dirk Roos, PhD E. Richard Stiehm, MD
Dept. of Blood Cell Research Department of Pediatrics
Sanquin Research David Geffen School of Medicine at UCLA
Amsterdam, The Netherlands Los Angeles, CA
Tony Roscioli, PhD Markus Stumm, PhD
Sydney Children’s Hospital Institute of Medical and Human Genetics
School of Women’s and Children’s HealthUniversity of Charité—Universitätsmedizin
New South Wales Berlin, Germany
Sydney, Australia
Maureen A. Su, MD, PhD
Marko Salmi, MD, PhD Department of Pediatrics
University of Turku University of North Carolina
and Chapel Hill, NC
The National Institute of Health and Welfare
Turku, Finland Kathleen E. Sullivan, MD, PhD
Department of Pediatrics
Crina Samarghitean, MD, PhD The Children’s Hospital of Philadelphia
Institute of Biomedical Technology Perelman School of Medicine, University of Pennsylvania
University of Tampere Philadelphia, PA
Tampere, Finland
Naomi Taylor, MD, PhD
Volker Schuster, MD Institut de Génétique Moléculaire de Montpellier
Department of Pediatrics Montpellier, France
Hospital for Children and Adolescents
University of Leipzig Troy R. Torgerson, MD, PhD
Leipzig, Germany Department of Pediatrics
University of Washington School of Medicine
Klaus Schwarz, MD Seattle Children’s Research Institute
Institute of ClinicalTransfusion Medicine and Seattle, WA
Immunogenetics
University Ulm Stuart E. Turvey, DPhil
Ulm, Germany Division of Infectious and Immunological Diseases
BC Children’s Hospital and Child & Family Research
Yosef Shiloh, PhD Institute
Department of Human Molecular Genetics and University of British Columbia
Biochemistry Vancouver, British Columbia, Canada
Sackler School of Medicine
Tel Aviv University Roxane Tussiwand, PhD
Ramat Aviv, Israel Center for Biomedicine
Division of Developmental and Molecular Immunology
Lawrence R. Shiow, MD, PhD University of Basel
Department of Pediatrics Basel, Switzerland
and
Benioff Children’s Hospital Jouni Väliaho, MSc
University of California, San Francisco Institute of Biomedical Technology
San Francisco, CA University of Tampere
Tampere, Finland
C.I. Edvard Smith, MD, PhD
Clinical Research Center Mirjam van der Burg, PhD
Department of Laboratory Medicine Department of Immunology
Karolinska Institutet at Novum-Huddinge Erasmus MC
Stockholm, Sweden University Medical Center Rotterdam
Rotterdam, The Netherlands
Gerald J. Spangrude, PhD
Department of Medicine, Division of Silvère M. van der Maarel, PhD
Hematology Department of Human Genetics
University of Utah Leiden University Medical Center
Salt Lake City, UT Leiden, The Netherlands
C O N T R I B U TO R S • x v ii
Mauno Vihinen, PhD Kinderklinik, Medizinische Hochschule Hannover
Institute of Biomedical Technology Hannover, Germany
University of Tampere
Jerry A. Winkelstein, MD
Tampere, Finland
Department of Pediatrics
and
Johns Hopkins University School of Medicine
Department of Experimental Medical Science
Baltimore, MD
Lund University
Lund, Sweden Melanie Wong, PhD
Anna Villa, MD The Children’s Hospital Westmead
Istituto di Ricerca Genetica e Biomedica Sydney University
Consiglio Nazionale delle Ricerche Westmead, NSW, Australia
Milan, Italy Leman Yel, MD
Klaus Warnatz Global Medical Director
Centre of Chronic Immunodeficiency Baxter Healthcare Corporation, Bioscience
Universitätsklinkum Freiburg Westlake Village, CA
University Freiburg-Medical Center Rae S. M.Yeung, MD, PhD
Freiburg, Germany The Hospital for Sick Children
Corry M. R. Weemaes, MD University of Toronto
Department of Pediatrics Toronto, Ontario, Canada
Radboud University Nijmegen Medical Centre Cornelia Zeidler, MD
Nijmegen, The Netherlands Department of Molecular Hematopoiesis
Rolf-Dieter Wegner, MD Kinderklinik, Medizinische Hochschule Hannover
Institute of Medical and Human Genetics Hannover, Germany
Charité—Universitätsmedizin Shen-Ying Zhang, MD, PhD
Berlin, Germany St. Giles Laboratory of Human Genetics of Infectious
Arthur Weiss, MD, PhD Diseases
Department of Microbiology & Immunology The Rockefeller University
Howard Hughes Medical Institute New York, NY
University of California San Francisco
Juan Carlos Zúñiga-Pflücker, PhD
San Francisco, CA
Department of Immunology, University of Toronto
Karl Welte, MD Sunnybrook Research Institute
Department of Molecular Hematopoiesis Toronto, Ontario, Canada
xviii • C O N T R I B U TO R S
1.
GENETICALLY DETERMINED IMMUNODEFICIENCY
DISEASES: A PER SPECTIVE
C. I. Edvard Smith, Hans D. Ochs, and Jennifer M. Puck
W
e are in an era of explosive growth in our under- The “classical” PIDs are single gene disorders with either
standing of the molecular and genetic basis of autosomal recessive or X-linked recessive inheritance, such
immune defects. In the early 1990s, only a hand- as severe combined immunodeficiency (SCID), Wiskott-
ful of genes had been associated with primary immunodefi- Aldrich syndrome (WAS), or X-linked agammaglobulinemia
ciency disorders (PIDs). By 2000, when the first edition of (XLA). In contrast, dominant inheritance is typically seen
this book was published, some 60 genes causing PID had been when a mutation affects a protein that normally functions
identified. The most recent summary of PID genes (Table 1.1) in a multimeric complex. For example, in autoimmune lym-
and their products (Fig. 1.1), with over three times this num- phoproliferative syndrome (ALPS) caused by heterozygous
ber, is already incomplete due to the rapid pace of discovery of mutations in the genes encoding Fas or Fas-ligand, both the
additional genes that are defective in an ever-broadening spec- receptor and its ligand are assembled into homotrimers. For
trum of clinical immune disorders. Advances in basic research a trimer to be functional, all monomeric components need
in immunology, combined with the increasing ease of deter- to be unmutated; dominant interference with the function of
mining DNA sequence variants, have greatly facilitated the protein produced by a normal allele results from having one
tasks of finding DNA mutations in PID patients and prov- or two mutated monomers in the assembled complex. If nor-
ing their functional significance. The ability to define genetic mal and mutated protein monomers are produced in equal
diseases of the immune system in molecular terms has made amounts, only one out of eight trimeric signaling units will be
possible improved diagnosis, appreciation of the clinical spec- free from any mutated chains and able to function properly
trum, genetic counseling and testing, and, most exciting, new (Chapter 29). Because only a single mutation event is needed
therapeutic strategies including gene therapy. Moreover, the and a survival advantage is conferred on cells with defective
discovery of each previously unknown disease gene feeds back Fas-mediated apoptosis, de novo somatic mutations of a single
into the pool of scientific knowledge, increasing our under- FAS gene allele have been found capable of causing acquired
standing of molecular immune networks. dominant ALPS (Holzelova et al., 2004). Another example
In contrast to many other heritable diseases, PIDs are not is the hyper-IgE syndrome, where missense mutations impair
obvious at birth but become evident only when the affected STAT3 dimer formation, reducing the intracellular JAK-STAT
individual is exposed to microbes and develops severe infec- signaling by 75 percent (Chapter 37). Dominant inheritance
tions or responds to self-antigens with autoaggression. is also seen in some forms of severe congenital neutropenia, in
Although individually rare, these disorders are treatable and which a mutated, misfolded protein activates the “unfolded
therefore important to detect promptly. The spectrum of dis- protein response,” a series of cellular stress responses that are
eases is very broad and covers both increased susceptibility to activated by the accumulation of malformed proteins and can
infections and impaired regulation of immune function lead- ultimately trigger cellular removal by apoptosis (Chapter 50).
ing to autoimmunity. The inheritance of PIDs can be recessive As we have pointed out in previous editions of this book,
or dominant; some produce symptoms early in life, while oth- susceptibility versus resistance to infections can depend on
ers are manifested later; and acquired forms of PID associated inheritance of variant forms of immune system components.
with somatic mutations are increasingly recognized. HIV typically uses the CCR5 co-receptor to enter human
1
Exploring the Variety of Random
Documents with Different Content
Black eyes are truer still, I ween,
Than any other:
Dark were the eyes of Eden’s Queen,
And Mary Mother.
THE CRUCIFIXION.
OLD FRENCH SONNET.
While Jesus suffered for the human race
Upon the tree, death came and found him there.
Transfixed with shame, at first he did not dare
To look upon his sovereign’s awful face.
TO ⸺.
POESY.
Before the human hand a stylus held,
Ere papyrus’ or parchment’s mute appeal,
Sweet songs were sung whose echoes charm us still;
From dying lips undying music welled.
Wedded to strains from chosen souls that swelled,
Were rescued from oblivion’s clammy seal,
Fantastic legend, laws of commonweal,
Heroic deeds in days of hoary eld.
THE ROSE.
The flushing wave bloomed into wondrous flower,
And rosy light burst forth unknown till then,
When Aphrodite dawned on gods and men.
Thy birth, O Rose, was in that mystic hour.
Transcendent Rose, pride of the Paphian bower,
And sweet consoler of the thorny glen,
What virgin charms thy blush illumines when
Upon the virgin heart Love seals his power.
LA DIVA.
A sea of faces ripple round her where,
As on a sunny isle, the Diva glows
Behind the footlights like a full-blown rose;
A hush expectant fills the brooding air.
TO A HAPPY LOVER.
Flaunt not before the world thy happy love,
Like the poor fatuous one whose pleasure lies
Not in Love’s glance, but in the envious eyes
Of other fools; deep in the myrtle grove
Seek some untrodden way, shadowed above;
There, if Love will, his unknown harmonies,
His inmost heart and core, his tears and sighs,
And unimagined mysteries thou mayest prove.
METEMPSYCHOSIS.
I.
I was a huntsman in my youth, and knew
Each bird and beast that haunts the forest tall,
Or wings the air, hard by the water-fall.
Over the plain and up the mountain blue
My twanging bow was heard, my arrows flew.
My bowstring now is rent, my arrows all
Like spears that from the withered pine-cones fall,
Have from my shrunken quiver vanished too.
Yet sometimes o’er me steals the olden mood,
And wandering in the forest deep and dark,
I greet each old familiar tree and mark,
Each spot whereon the lovely quarry stood,
While faintly through my withered veins once more
Leaps the triumphant thrill I knew of yore.
II.
I.
DESPAIR—THE ABYSS.
II.
QUESTIONING.
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