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Primary Immunodeficiency Diseases A Molecular
Cellular Approach 2nd ed 2nd Edition Hans D. Ochs
(Author) Digital Instant Download
Author(s): Hans D. Ochs (Author), C. I. Edward Smith (Author), Jennifer M.
Puck (Author)
ISBN(s): 9781429420457, 1429420456
Edition: 2
File Details: PDF, 10.38 MB
Year: 2006
Language: english
Primary Immunodeficiency
Diseases:
A Molecular and Genetic
Approach,
Second Edition

Hans D. Ochs, MD
C. I. Edvard Smith, MD, PhD
Jennifer M. Puck, MD,
Editors

OXFORD UNIVERSITY PRESS

Primary Immunodeficiency Diseases
This page intentionally left blank
Primary Immunodeficiency Diseases
A MOLECULAR AND GENETIC APPROACH

Second Edition

Edited by

Hans D. Ochs, MD
C. I. Edvard Smith, MD, PhD
Jennifer M. Puck, MD

1
2007
 1
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Library of Congress Cataloging-in-Publication Data

Primary immunodeficiency diseases : a molecular and genetic approach / edited by
Hans D. Ochs, C. I. Edvard Smith, Jennifer M. Puck.—2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-19-514774-2
ISBN-10: 0-19-514774-X
1. Immunological deficiency syndromes—Genetic aspects.
I. Ochs, Hans D., 1936– . II. Smith, C. I. Edvard, 1951– . III. Puck, Jennifer, 1949– .
[DNLM: 1. Immunologic Deficiency Syndromes—genetics. WD 308 P9523 2006]
RC606.G46 2006
616.97'9042—dc22 2005027951

1 3 5 7 9 8 6 4 2
Printed in the United States of America
on acid-free paper
 To our teachers, colleagues, and students
To our patients
and to our families
Who inspired, questioned, supported, and encouraged

Robert Good, who wrote the foreword for the first edition of this book, and Fred
Rosen, a co-author of the chapter on Wiskott Aldrich Syndrome in both the first
and second editions, have recently died. Dr. Good and Dr. Rosen were giants in
the field of primary immunodeficiencies and their unique heritage dates back to
the very beginnings of the recognition and classification of these disorders. We
are fortunate to have had such wonderful colleagues and grateful to them for their
outstanding contributions to the field and to this book.
This page intentionally left blank
 Foreword

The primary immunodeficiency diseases, the first of which were pathways can now be identified quite precisely in genetic and
recognized over 50 years ago, are now generally appreciated as molecular terms.
major health problems by affected patients, their families, physi- As is indicated in the contents of this book, we currently have
cians, and even the general public. In 1999, this book was the sufficient information about the lymphocyte differentiation path-
first comprehensive compendium devoted to primary immunode- ways to categorize primary immunodeficiency diseases into gene
ficiency diseases. While most are relatively rare, some of these mutations that affect (1) DNA transcription factors; (2) rearrange-
conditions, like IgA deficiency and common variable immunode- ment and expression of the T cell receptor (TCR) and immun-
ficiency, occur with a frequency that makes these patients likely oglobulin genes; (3) signal transducing components of the TCR
to be seen by most physicians. and B cell receptor (BCR) complexes; (4) essential signaling
The study of patients with these genetically determined im- pathway elements employed by TCR and BCR; (5) coreceptor
mune disorders in conjunction with the study of animal models molecules that are essential for normal function of T and B cells;
has led to remarkable progress in our understanding of the inter- (6) cytokines and cytokine receptors that promote T and B cell
acting components of the complex immune system and how they production, proliferation, and differentiation; and (7) cell surface
function in humans. As a consequence, earlier recognition and molecules that are necessary for normal lymphocyte homing and
better treatment options are provided for patients with primary intercellular interactions in the peripheral lymphoid tissues, in-
immunodeficiency diseases, as well as for the even larger num- cluding the spleen, lymph nodes, intestinal Peyer’s patches, and
ber of individuals with secondary immune deficiency conditions. appendix. It has also become increasingly evident that the nor-
This authoritative book, now in its second edition, contains a mal function of the effector T and B cell populations depends on
comprehensive account of currently available information. In the other types of cells as well. An especially important cell partner
short years since the first publication, the number of known im- is the dendritic cell, because it responds to potential pathogens
munodeficiency genes has grown from less than 70 to well over by presenting antigen to initiate the T cell response and, in turn,
120, reflecting the tremendous expansion of knowledge in this the B cell response. Although few primary immunodeficiency
field. The rich base of information contained in these pages makes diseases have as yet been attributed to developmental flaws in
it clear that there are few fields in medicine in which laboratory- this cell type, impaired dendritic cell function is an important
based research and the study of diseases in patients have been so component of the immunodeficiency caused by gene mutations
mutually complementary as for the primary immunodeficiency that prevent CD40 expression or expression of the CD40 ligand
diseases. on T cells.
The first immunodeficiency diseases to be identified, namely The specific adaptive immune responses mediated by T and B
X-linked agammaglobulinemia, and the more clinically severe cells and their collaborators, although essential, are only a part of
congenital lymphopenic syndromes were diseases that are now the overall host defense strategy. There is an ever-growing aware-
known to reflect compromised development in the effector limbs ness that innate immunity is equally important and complex.
of the adaptive immune system. Experimental delineation of the Disorders of the complement system, abnormal function of phago-
developmentally distinct lineages of lymphocytes, the thymus- cytic cells, and deficiencies of the chemokines and chemokine
dependent population of T cells, and the bone marrow–derived B receptors that influence lymphocyte–phagocytic cell interactions
cells, made possible the recognition of their respective roles in can all result in an impaired ability to eliminate pathogens. Nat-
cell-mediated and humoral immunity. Accordingly, the primary ural killer cells with their diverse array of activating and inhibitory
immunodeficiency diseases were found to belong to distinct receptors are also beginning to be recognized as one of the dys-
classes, those primarily affecting T cell development, like the functional cell types in some immunodeficiency disorders.
thymic underdevelopment seen in the DiGeorge syndrome, and Infections are the major complications of the immunodefi-
those featuring impaired B cell development and antibody pro- ciency diseases, and, as recognized by the late Robert Good, a
duction, as seen in Bruton X-linked agammaglobulinemia. Se- true giant in the establishment of the field and author of the origi-
vere combined immunodeficiency (SCID), recognized first by nal forword to the first edition of this book, the types of infections
Glanzmann and Riniker, featured instead a developmental failure differ according to the specific gaps in host defense. Primary anti-
of both T and B cells. With the ensuing molecular biology revo- body deficiency states predispose to serious bacterial infections,
lution, the pace of the genetic analysis of the immunodeficiency as do certain complement component and neutrophil deficiencies.
diseases quickened remarkably. As more and more details have Viral and fungal infections are particularly notable in patients
been learned about the life history of T and B lineage cells, many with T cell dysfunction. Different infectious disease patterns are
of the genetically determined defects in these differentiation seen with other host defense defects. For example, mycobacterial
viii Foreword

and salmonella infections are common in patients who have mu- available to more patients with severe combined immunodefi-
tations in the genes for IL-12 or the receptors for IL-12 and ciency disease. Enzyme replacement can benefit SCID patients
interferon-γ, because these signaling molecules are especially with adenosine deaminase deficiency. Finally, gene therapy has
important for normal macrophage activation to kill intracellular proven effective for the cure of two types of SCID, albeit
pathogens. Characterization of the different patterns of infec- presently with an attendant risk of lymphoproliferative disease.
tions has been significantly enhanced by the development of For all too many patients with primary immunodeficiency dis-
databanks devoted to patients with the relatively rare primary im- eases, however, a cure is still not yet possible and will come only
munodeficiency diseases. with improved knowledge that must be gained through continued
Treatment has advanced in parallel with improved diagnosis study. In the meantime, early diagnosis remains the key for a
of immunodeficiency diseases, understanding of their cellular quality life for many patients with an immunodeficiency disease.
and molecular basis, and better definition of their clinical conse- Toward this end, this newly updated book provides a remarkably
quences. Prophylactic antibiotics can be helpful in reducing the comprehensive and clinically useful source of information about
frequency of certain types of infections. Immunoglobulin replace- this challenging group of disorders.
ment, employed first by Bruton to treat a boy with congenital
agammaglobulinemia, has been refined through the development Max D. Cooper, M.D.
of safe and efficient preparations of intravenous immunoglob- The University of Alabama at Birmingham
ulin. Better ways to perform bone marrow transplantation have and the Howard Hughes Medical Institute
made this life-saving mode of cellular engineering safer and Birmingham, AL
 Foreword to the First Edition

Modern immunology can be considered to have been launched in other components of the host defense system, such as phagocytes
1952, when Colonel Ogden Bruton described an 8-year old boy and complement, and to recognize the diseases that occur when
who, from 2 years of age, experienced recurrent, life-threatening these components are absent or not functional.
infections including episodes of bacterial pneumonia and sep- Over the last decade, advances in molecular biology have al-
ticemia. Using the newly-introduced technique, serum elec- lowed for an even greater understanding of the immune system,
trophoresis, Bruton found the boy to be agammaglobulinemic. and the multitude of molecular pathways that regulate growth,
When challenged with antigens, he failed to produce specific an- differentiation, communication, and effector functions within
tibodies. Upon treatment by passive immunization with large and between cells. In 1993, two groups of researchers, led by
doses of intramuscularly-injected gammaglobulin, his suscepti- David Vetrie and Satoshi Tsukada, discovered that the difficulties
bility to infections was dramatically terminated. Detailed investi- of Bruton’s patient and other patients with XLA were due to
gations of similar patients, by Charles Janeway in Boston and many different mutations of an X-linked gene that encodes a
my group in Minneapolis, demonstrated many similarly affected B-cell specific tyrosine kinase, Btk. In the few years since that
children, and proved that agammaglobulinemia was often an discovery, the molecular genetic universe has expanded phenom-
X-linked, inherited disorder. enally, so that almost every month there is news of the identifica-
In the course of caring for agammaglobulinemic patients, tion of another immune disease gene.
we realized that they were especially susceptible to encapsulated The present volume, edited by Professors H. D. Ochs, C.I.E.
bacterial pathogens, including Streptococcus pneumoniae, Smith, and J. M. Puck, is the first comprehensive guide to this
Haemophilus influenzae, Streptococcus pyogenes, Pseudomonas new molecular genetic universe. Herein, diseases of the immune
aeruginosa, and to a lesser extent, Staphylococcus aureus. In system are presented and analyzed, both in terms of their clinical
contrast however, they could impressively resist infections features and in the context of the impressive molecular and gene-
caused by fungi, coliforms, tuberculosis, bacillus Calmette- tic definitions which can be put forward in 1998. Over 90 well-
Guérin (BCG), and many viruses such as measles, chicken pox, defined primary diseases of the human immune system are listed
rubella, and vaccinia. Thus, the susceptibility profile of agamma- in the introductory chapter of this book; specific diseases are dis-
globulinemic patients bisected the microbial universe. As an ex- cussed in later chapters organized by syndrome (Part II). The
periment of nature, patients with X-linked agammaglobulinemia current understanding of each disorder is outlined, including dis-
(XLA) introduced us to additional, crucially important concepts cussions of clinical issues and clinical presentation, infections,
concerning how plasma cells and lymph node germinal centers, genetic mutations, protein function, cell biology, and manage-
which are lacking in agammaglobulinemic patients, must be the ment. Framing these discussions of individual diseases are two
source of antibodies providing resistance to encapsulated bacter- equally modern presentations—first, a section of seven chapters
ial pathogens. We reasoned that distinct mechanisms of defense outlining the essential concepts of immunology and genetics
that were intact in agammaglobulinemic patients must have been needed to understand primary immunodeficiency diseases, and at
designed to protect against other types of infections. Lympho- the end, a section covering the most current approaches to as-
cytes in the deep paracortical regions of lymph nodes, which ap- sessment and treatment of patients with these conditions. Each
peared normal in XLA patients, were found to mediate this authoritative chapter is written by a world leader in the field, or
second type of immune protection, cellular immunity, which was in many cases by a pair or group of immunological specialists
later shown to be dependent on the thymus. This conclusion was with complementary perspectives, to present the most up-to-date
partially derived from the study of a different group of patients, and complete information available.
those with DiGeorge syndrome, who had congenital absence of This book is an impressive demonstration of how far we have
the thymus. come. Recent studies of primary immunodeficiency diseases
Thus, it was evident from the beginning that patients with im- have, perhaps more than any other group of diseases, revealed
munodeficiencies, as experiments of nature, helped us to bisect the power of modern molecular genetics to define diseases in
not only the microbial universe, but also the universe of lym- precise molecular terms. This approach has already suggested
phoid cells and the universe of immunological responses. Further therapeutic possibilities which have proven successful; it has
investigations throughout the 1960s, 1970s, and 1980s confirmed also set the stage for testing gene therapies meant to cure pri-
that this compartmentalization related to the fundamental lym- mary immunodeficiency diseases at the molecular level. Just
phocyte dichotomy of B cells versus thymus-dependent T cells. how disruptions of Btk account for all of the morphological and
Moreover, patients with different immunodeficiency syndromes immunological abnormalities and disease susceptibilities of pa-
helped define the nature and the role in immune responses of tients with XLA has not yet been elucidated, but future work will
x Foreword to the First Edition

show how this molecule interacts with other gene products in the living in a veritable sea of microorganisms. This volume consti-
B lymphocyte. Studying XLA will continue to reveal fundamen- tutes a milestone, marking where we now stand and indicating
tal issues in lymphology and immunobiology. where we are heading, as we continue to interpret lessons in
The knowledge of primary immunodeficiency diseases re- a most constructive fashion from the greatest teachers of mod-
flected in this volume continues to grow, based on insights de- ern immunology: patients with primary immunodeficiency dis-
rived from the study of individuals with primary immunodeficiency eases.
exemplified by Bruton’s original agammaglobulinemic patient.
Analysis of each of the immune system diseases in its own way Robert A. Good, M.D., Ph.D., D.Sc.
represents the molecular interpretation of an informative experi- All Children’s Hospital
ment of nature. In the aggregate, these analyses help us under- St. Petersburg, Florida
stand more deeply how man can exist free of infection while July 1998
 Contents

Contributors xiii 11. V(D)J Recombination Defects 153

Jean-Pierre de Villartay, Klaus Schwarz, and Anna Villa
Part I Overview
12. Immunodeficiency Due to Defects of Purine
1. Genetically Determined Immunodeficiency Diseases: Metabolism 169
A Perspective 3 Rochelle Hirschhorn and Fabio Candotti
C. I. Edvard Smith, Hans D. Ochs, and Jennifer M. Puck
13. Severe Combined Immunodeficiency Due to
2. Genetic Principles and Technologies in the Study Mutations in the CD45 Gene 197
of Immune Disorders 16 Talal A. Chatila and Markku Heikinheimo
Jennifer M. Puck and Robert L. Nussbaum
14. Severe Combined Immunodeficiency Due to Defects in T Cell
3. Mammalian Hematopoietic Development Receptor–Associated Protein Kinases 203
and Function 27 Melissa E. Elder
Gerald J. Spangrude
15. Human Interleukin-2 Receptor α Deficiency 212
4. T Cell Development 39 Chaim M. Roifman
Rae S. M. Yeung, Pamela S. Ohashi, Mary E. Saunders,
and Tak W. Mak 16. CD3 and CD8 Deficiencies 216
José R. Regueiro and Teresa Espanol
5. Molecular Mechanisms Guiding B Cell Development 61
17. Molecular Basis of Major Histocompatibility Complex
Antonius G. Rolink, Jan Andersson, Ulf Grawunder,
Class II Deficiency 227
and Fritz Melchers
Walter Reith, Barbara Lisowska-Grospierre, and
Alain Fischer
6. Signal Transduction by T and B Lymphocyte
Antigen Receptors 71
18. Peptide Transporter Defects in Human Leukocyte Antigen
Neetu Gupta, Anthony L. DeFranco, and Arthur Weiss
Class I Deficiency 242
Henri de la Salle, Lionel Donato, and Daniel Hanau
7. Lymphoid Organ Development, Cell Trafficking,
and Lymphocyte Responses 93
19. CD40, CD40 Ligand, and the Hyper-IgM Syndrome 251
Sirpa Jalkanen and Marko Salmi
Raif S. Geha, Alessandro Plebani, and Luigi D. Notarangelo

8. Phagocytic System 103 20. Autosomal Hyper-IgM Syndromes Caused

Kuender D. Yang, Paul G. Quie, and Harry R. Hill by an Intrinsic B Cell Defect 269
Anne Durandy, Patrick Revy, and Alain Fischer
Part II Syndromes
21. X-linked Agammaglobulinemia: A Disease
9. X-Linked Severe Combined Immunodeficiency 123 of Btk Tyrosine Kinase 279
Jennifer M. Puck C. I. Edvard Smith, Anne B. Satterthwaite, and
Owen N. Witte
10. Autosomal Recessive Severe Combined Immunodeficiency
Due to Defects in Cytokine Signaling Pathways 137 22. Autosomal Recessive Agammaglobulinemia 304
Fabio Candotti and Luigi Notarangelo Mary Ellen Conley
xii Contents

23. Genetic Approach to Common Variable Immunodeficiency 36. Immunodeficiencies with Associated Manifestations of Skin,
and IgA Deficiency 313 Hair, Teeth, and Skeleton 513
Lennart Hammarström and C. I. Edvard Smith Mario Abinun, Ilkka Kaitila, and
Jean-Laurent Casanova
24. Autoimmune Lymphoproliferative Syndrome 326
Jennifer M. Puck, Frederic Rieux-Laucat, Françoise Le Deist, 37. Chronic Granulomatous Disease 525
and Stephen E. Straus Dirk Roos, Taco W. Kuijpers, and John T. Curnutte

25. Autoimmune Polyendocrinopathy, Candidiasis, 38. Cell Adhesion and Leukocyte Adhesion Defects 550
Ectodermal Dystrophy 342 Amos Etzioni and John M. Harlan
Leena Peltonen-Palotie, Maria Halonen, and Jaakko
Perheentupa
39. Cyclic and Congenital Neutropenia Due to Defects
in Neutrophil Elastase 565
26. Immune Dysregulation, Polyendocrinopathy, Enteropathy, and
David C. Dale and Andrew G. Aprikyan
X-Linked Inheritance 355
Troy R. Torgerson, Eleonora Gambineri, Steven F. Ziegler,
40. Chediak-Higashi Syndrome 570
and Hans D. Ochs
Richard A. Spritz
27. Periodic Fever Syndromes 367
Daniel L. Kastner, Susannah Brydges, and Keith M. Hull 41. Inherited Hemophagocytic Syndromes 578
Geneviève de Saint Basile
28. Inherited Disorders of the Interleukin-12/23–Interferon
Gamma Axis 390 42. Genetically Determined Deficiencies of the
Melanie J. Newport, Steven M. Holland, Michael Levin, and Complement System 589
Jean-Laurent Casanova Kathleen E. Sullivan and Jerry A. Winkelstein

29. Ataxia-Telangiectasia 402 Part III Assessment and Treatment

Martin F. Lavin and Yosef Shiloh
43. Assessment of the Immune System 611
30. Chromosomal Instability Syndromes Other Than Helen M. Chapel, Siraj Misbah, and A. David B. Webster
Ataxia-Telangiectasia 427
Rolf-Dieter Wegner, James J. German, Krystyna H. 44. Genetic Aspects of Primary Immunodeficiencies 633
Chrzanowska, Martin Digweed, and Markus Stumm Jennifer M. Puck

31. Wiskott-Aldrich Syndrome 454

45. Immunodeficiency Information Services 644
Hans D. Ochs and Fred S. Rosen
Jouni Väliaho, Crina Samarghitean, Hilkka Piirilä, Marianne
Pusa, and Mauno Vihinen
32. X-Linked Lymphoproliferative Disease Due to Defects
of SH2D1A 470
46. Conventional Therapy of Primary
Volker Schuster and Cox Terhorst
Immunodeficiency Diseases 655
E. Richard Stiehm and Helen M. Chapel
33. DiGeorge Syndrome: A Chromosome 22q11.2
Deletion Syndrome 485
Deborah A. Driscoll and Kathleen E. Sullivan 47. Bone Marrow Transplantation for Primary
Immunodeficiency Diseases 669
34. Hyper-IgE Recurrent Infection Syndromes 496 Rebecca H. Buckley and Alain Fischer
Bodo Grimbacher, Jennifer M. Puck, and Steven M. Holland
48. Gene Therapy 688
35. Immunodeficiency with Centromere Instability Fabio Candotti and Alain Fischer
and Facial Anomalies 505
R. Scott Hansen, Corry Weemaes, and Cisca Wijmenga Index 707
 Contributors

Mario Abinun, MD, MSc Krystyna H. Chrzanowska, MD, PhD

Department of Pediatrics Department of Medical Genetics
Newcastle General Hospital The Children’s Memorial Health Institute
Newcastle upon Tyne, United Kingdom Warsaw, Poland

Jan Andersson, MD Mary Ellen Conley, MD

Department of Clinical-Biological Sciences (DKBW) Department of Immunology
Developmental and Molecular Immunology St. Jude Children’s Research Hospital
Center for Biomedicine Memphis, TN
University of Basel
Basel, Switzerland John T. Curnutte, MD, PhD
DNAX Research, Inc.
Andrew G. Aprikyan, PhD Palo Alto, CA
Department of Medicine
University of Washington David C. Dale, MD
Seattle, WA University of Washington
Seattle, WA
Susannah Brydges, PhD
National Institute of Arthritis and Musculoskeletal Anthony L. DeFranco, MD
and Skin Diseases Department of Microbiology & Immunology
National Institutes of Health University of California San Francisco
Bethesda, MD San Francisco, CA

Rebecca H. Buckley, MD Henri de la Salle, PhD

Department of Pediatrics EFS-Alsace, Strasbourg
Duke University Medical Center Université Louis-Pasteur
Durham, NC Strasbourg, France

Fabio Candotti, MD Genevieve de Saint Basile, MD, PhD

Genetics and Molecular Biology Branch INSERM U 429
National Human Genome Research Institute Hôpital Necker–Enfants Malades
National Institutes of Health Paris, France
Bethesda, MD
Jean-Pierre de Villartay, PhD
Jean-Laurent Casanova, MD, PhD INSERM U429
University of Paris René Descartes-INSERM U 550 Hôpital Necker Enfants-Malades
Hôpital Necker–Enfants Malades Paris, France
Paris, France
Martin Digweed
Helen M. Chapel, MD Institut für Humangenetik
Department of Clinical Immunology Humboldt-Universität
John Radcliffe Hospital Charite-Campus Virchow
Oxford, United Kingdom Berlin, Germany
Talal A. Chatila, MD Lionel Donato, MD
Department of Pediatrics Centre Hospilalier Régional Universitaire de Strasbourg
David Geffen School of Medicine Hopital de Hautepierre
University of California at Los Angeles Pediadric Pneumology
Los Angeles, CA Strasbourg, France

xiii
xiv Contributors

Deborah A. Driscoll, MD Lennart Hammarström, MD, PhD

Department of Obstetrics and Gynecology Department of Clinical Immunology
University of Pennsylvania Karolinska University Hospital in Huddinge
Philadelphia, PA Stockholm, Sweden
Anne Durandy, MD, PhD Daniel Hanau, MD, DSc
INSERM U 429 INSERM U 725
Hopital Necker–Enfantes Malades EFS-Alsace, Strasbourg
Paris, France Université Louis-Pasteur
Strasbourg, France
Melissa E. Elder, MD, PhD
Department of Pediatrics R. Scott Hansen, PhD
University of Florida Department of Medicine
Gainesville, FL Medical Genetics
Teresa Español, MD University of Washington
Inmunología Seattle, WA
Hospital Vall d’Hebron
John M. Harlan, MD
Barcelona, Spain
Department of Medicine
Amos Etzioni, MD University of Washington
Meyer Children’s Hospital Seattle, WA
Rappaport School of Medicine, Technion
Haifa, Israel Markku Heikinheimo, MD
Children’s Hospital
Alain Fischer, MD Biomedicum Helsinki
Imserm U429 University of Helsinki
Hôpital Necker–Enfants Malades Helsinki, Finland
Paris, France
Harry R. Hill, MD
Eleonora Gambineri, MD Departments of Pathology, Pediatrics, and Medicine
Department of Pediatrics University of Utah
“Anna Meyer” Children’s Hospital Salt Lake City, UT
University of Florence
Florence, Italy Rochelle Hirschhorn, MD
Section of Medical Genetics
Raif S. Geha, MD Departments of Medicine, Cell Biology and Pediatrics
Division of Immunology New York University School of Medicine
Children’s Hospital New York City, NY
Harvard Medical School
Boston, MA Steven M. Holland, MD
Chief, Laboratory of Clinical Infectious Diseases
James J. German, MD
National Institute of Allergy and infectious Diseases
Department of Pediatrics
National Institutes of Health
Weill Medical College of Cornell University
Bethesda, MD
New York, NY
Ulf Grawunder, MD Keith M. Hull, MD, PhD
Department of Clinical-Biological Sciences (DKBW) National Institute of Arthritis and Musculoskeletal
Developmental and Molecular Immunology and Skin Diseases
Center for Biomedicine National Institutes of Health
University of Basel Bethesda, MD
Basel, Switzerland
Sirpa Jalkanen, MD, PhD
Bodo Grimbacher, MD MediCity Research Lab
Department of Medicine University of Turku
Medizinische Universitätsklinik Turku, Finland
Freiburg, Germany
Ilkka Kaitila, MD, PhD
Neetu Gupta, MD Clinical Genetics Research
Department of Microbiology & Immunology Haartman Institute
University of California San Francisco University of Helsinki
San Francisco, CA Helsinki, Finland
Maria Halonen, MD Daniel L. Kastner, MD, PhD
Department of Molecular Medicine Genetics and Genomics Section
National Public Health Institute National Institute of Arthritis and Musculoskeletal and Skin Diseases
Biomedicum Helsinki National Institutes of Health
Helsinki, Finland Bethesda, MD
 Contributors xv

Taco W. Kuijpers, MD, PhD Pamela S. Ohashi, PhD

Emma Children’s Hospital Campbell Family Institute for Breast Cancer Research
Academic Medical Center Ontario Cancer Institute
University of Amsterdam University Health Network
Amsterdam, The Netherlands Departments of Medical Biophysics and Immunology
University of Toronto
Martin F. Lavin Toronto, Ontario, Canada
Queensland Institute of Medical Research
The Bancroft Centre Leena Peltonen-Palotie, MD, PhD
Brisbane, Australia Department of Medical Genetics, University of Helsinki
Department of Molecular Medicine, National
Françoise Le Deist, MD Public Health Institute
Departments of Pediatrics and Microbiology Biomedicum
University of Montreal Helsinki, Finland
Hopital Sainte Justine
Montreal, Canada Jaakko Perheentupa, MD
Department of Pediatrics
Michael Levin, MD University of Helsinki
Brighton and Sussex Medical School Helsinki, Finland
University of Sussex
Brighton, United Kingdom Hilkka Piirílä, MSc
Institute of Medical Technology
Barbara Lisowska-Grospierre, PhD University of Tampere
INSERM U 429 Tampere, Finland
Université René Descartes
Hopital Necker–Enfants Malades Alessandro Plebani, MD
Paris, France Department of Pediatrics
“Angelo Nocivelli” Institute for Molecular Medicine
Tak W. Mak, MD University of Brescia
Campbell Family Institute for Breast Brescia, Italy
Cancer Research
Jennifer M. Puck, MD
Princess Margaret Hospital
Department of Pediatrics and Institute for Human Genetics
Toronto, Canada
University of California, San Francisco
Fritz Melchers, PhD San Francisco, CA
Max Planck Institute for Infection Biology
Marianne Pusa, MSc
Berlin, Germany;
Institute of Medical Technology
University of Basel
University of Tampere
Biozentrum
Tampere, Finland
Basel, Switzerland
Paul G. Quie, MD
Siraj Misbah, MSc International Medical Education
Department of Clinical Immunology and Research Program
John Radcliffe Hospitals University of Minnesota Medical School
Oxford, United Kingdom Minneapolis, Minnesota
Melanie J. Newport, PhD Jose R. Regueiro, MD
Brighton and Sussex Medical School Inmunologia
University of Sussex Facultad de Medicina
Brighton, United Kingdom Universidad Complutense
Madrid, Spain
Luigi D. Notarangelo, MD
Department of Pediatrics Walter Reith, MD
“Angelo Nocivelli” Institute for Molecular Medicine Department of Pathology and Immunology
University of Brescia University of Geneva Medical School
Brescia, Italy Centre Medical Universitaire
Geneva, Switzerland
Robert L. Nussbaum, MD
Department of Medicine and Patrick Revy, MD
Institute for Human Genetics INSERM U 429
University of California, San Francisco Hôpital Necker–Enfants Malades
San Francisco, CA Paris, France
Hans D. Ochs, MD Frédéric Rieux-Laucat, PhD
Department of Pediatrics INSERM U 429
University of Washington Hôpital Necker–Enfants Malades
Seattle, WA Paris, France
xvi Contributors

Chaim M. Roifman, MD Gerald J. Spangrude, PhD

Division of Immunology and Allergy Department of Hematology
The Hospital for Sick Children University of Utah
Toronto, Canada Salt Lake City, UT
Antonius Rolink, MD, PhD Richard A. Spritz, MD
Developmental and Molecular Immunology Human Medical Genetics
Center for Biomedicine University of Colorado Health Sciences
University of Basel Center-Fitzsimons
Basel, Switzerland Aurora, CO
Dirk Roos, PhD E. Richard Stiehm, MD
Department of Blood Cell Research Department of Pediatrics
Sanquin Research and Landsteiner Laboratory Mattal Children’s Hospital at UCLA
Academic Medical Center Los Angeles, CA
University of Amsterdam
Amsterdam, The Netherlands Stephen E. Straus, MD
Laboratory of Clinical Infectious Disease
Fred S. Rosen National Institute of Allergy and Infectious Diseases
Department of Pediatries and Center for Blood Research National Institutes of Health
Harvard Medical School Bethesda, MD
Boston, MA
Markus Stumm, PhD
Marko Salmi, MD, PhD Institut für Humangenetik
MediCity Research Laboratory Otto-von-Guericke-Universität
National Public Health Institute Magdeburg, Germany
University of Turku
Turku, Finland Kathleen E. Sullivan, MD, PhD
Department of Pediatrics
Crina Samarghitean, MD University of Pennsylvania
Institute of Medical Technology School of Medicine
University of Tampere Philadelphia, PA
Tampere, Finland
Cox Terhorst, PhD
Anne B. Satterthwaite, PhD Division of Immunology
Department of Internal Medicine Beth Israel Deaconess Medical Center
University of Texas Southwestern Medical Center Harvard Medical School
at Dallas Boston, MA
Dallas, TX
Troy R. Torgerson, MD, PhD
Mary E. Saunders, PhD Department of Pediatrics
Campbell Family Institute for Breast Cancer Research University of Washington
Toronto, Ontario, Canada Seattle, WA
Volker Schuster, MD Jouni Väliaho, MSc
Department of Pediatrics Institute of Medical Technology
University of Leipzig University of Tampere
Leipzig, Germany Tampere, Finland
Klaus Schwarz, MD Mauno Vihinen, PhD
Institute for Clinical Transfusion Medicine and Institute of Medical Technology
Immunogenetics University of Tampere
Department of Transfusion Medicine Tampere, Finland
University of Ulm
Ulm, Germany Anna Villa, MD, PhD
CNR-ITB
Yosef Shiloh, PhD Segrate, Italy
Department of Human Genetics and Molecular
Medicine A. David B. Webster, MD
Sackler School of Medicine Department of Clinical Immunology
Tel Aviv University Royal Free Hospital School of Medicine
Ramat Aviv, Israel London, United Kingdom

C. I. Edvard Smith, MD, PhD Corry Weemaes, PhD

Clinical Research Center Department of Pediatrics
Karolinska Institutet at Novum-Huddinge University Hospital Nijmegen
Stockholm, Sweden Nijmegen, Netherlands
 Contributors xvii

Rolf-Dieter Wegner, MD Owen N. Witte, MD

Institut für Humangenetik Howard Hughes Medical Institute
Humboldt-Universität University of California Los Angeles
Charite–Campus Virchow Los Angeles, CA
Berlin, Germany
Kuender D. Yang, MD, PhD
Arthur Weiss, MD, PhD Chang Gung Children’s Hospital at
Howard Hughes Medical Institute Kaohsiung
University of California San Francisco Chang Gung University
San Francisco, CA Taiwan, Republic of China
Cisca Wijmenga, PhD
Complex Genetics Section Rae S. M. Yeung, MD, PhD
DBG-Department of Medical Genetics The Hospital for Sick Children
University Medical Center Utrecht University of Toronto
Utrecht, Netherlands Toronto, Ontario, Canada

Jerry A. Winkelstein, MD Steven F. Ziegler, PhD

Department of Pediatrics Department of Immunology
Johns Hopkins University School of Medicine Benaroya Research Institute
Baltimore, MD Virginia Mason Medical Center
Seattle, WA
This page intentionally left blank
 I
Overview
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 1

Genetically Determined Immunodeficiency

Diseases: A Perspective
C. I. EDVARD SMITH, HANS D. OCHS, and JENNIFER M. PUCK

We are in an era of explosive growth in our understanding of the an unanticipated fast pace of progress in dissecting the complex
molecular and genetic basis of immune defects. In the early immunologic networks responsible for protecting individuals
1990s, only a handful of genes were known to be associated with from a hostile environment.
these diseases, but now many are recognized and the process of Since the publication of the first edition, the rate of new dis-
discovering additional immunodeficiency genes is proceeding coveries in the field has not slowed down. Instead, a flurry of
rapidly. Advances in basic research in immunology, combined new disease entities has been defined and new treatment regi-
with the availability of the DNA sequence of nearly the entire mens have been introduced, the most notable being successful
human and mouse genomes plus refined technologies for localiz- treatment by gene therapy for two genotypes of severe combined
ing disease traits, have led to the discovery of the precise molec- immunodeficiency (Chapter 48).
ular basis for 140 or more disorders of human host defenses. A Of great interest is the new identification of human diseases
recent example of novel approaches is the discovery of CD3δ de- caused by mutations affecting components of the innate immune
ficiency through use of microarray technology (Dadi et al., 2003; system. Previously, defects in the complement system pathways
Chapter 16). The ability to redefine genetic diseases of the im- (Chapter 42) and the interferon γ (IFN-γ) signaling pathway
mune system in molecular terms has made possible improved di- (Chapter 28) were recognized, and mouse models of innate im-
agnosis, appreciation of the spectrum of clinical presentations mune mediators such as the Toll receptors were reported. How-
that can be traced to a given disease gene, genetic counseling and ever, the true function of innate immune pathways in humans
testing, and, most exciting, new therapeutic strategies including could not be fully appreciated until naturally occurring loss-of-
gene therapy. Moreover, the discovery of each previously un- function mutations were identified and characterized in human
known disease gene feeds back into the pool of scientific knowl- patients. The recent report of patients with bacterial infections
edge of immunology, illuminating and strengthening our evolving who lack the protein IRAK4, mediating signaling downstream
models of immune pathways. from the Toll receptor, provides a new opening for learning the
This volume contains accounts of gene identification, muta- significance of the innate immune system in protecting humans
tion detection, and clinical and research applications for a wide from infections and cancer (Picard et al., 2003).
array of distinct genetic immune disorders. A summary of known Important developments during the past 15 years have in-
inherited immunodeficiencies is provided in Table 1.1. The creased our understanding of disease processes. A majority of the
methods used to identify and understand these disorders consti- novel primary immunodeficiency disease genes were identified
tute a survey of modern molecular genetics and human immunol- by mapping a familial abnormality to a chromosomal region, fol-
ogy. The first edition of this book in 1999 marked an historic lowed by the analysis of candidate genes. In some cases the func-
turning point in the field of immunodeficiencies, demonstrating tion of the identified gene product had already been studied in
that many of primary disorders of the immune system could be detail prior to identification of human disease-causing mutations,
understood at the molecular level. Seven years later, we are sure but frequently new insights, some quite surprising, have arisen
that new discoveries will continue to make this collection incom- from relating an immune system gene to a clinical phenotype.
plete even as it is published, but we can also proudly document For example, even though the function of CD45 phosphatase was
3
Table 1.1. Primary Immunodeficiency Diseases
Defective Protein, Reference or
Designation and Gene Name* Pathogenesis Inheritance Locus Book Chapter

A. Combined B and T Cell Immunodeficiencies

1. Severe combined immunodeficiency (SCID) without T and B cells (T −B−)
a. SCID with leukocyte Stem cell defect affecting maturation of AR Unknown de Waal and
deficiency. Reticular dysgenesis. leukocytes, including all lymphocytes Seynhaeve, 1959
b. SCID with radiosensitivity. DNA cross-link repair 1C protein/Artemis AR 10p13 11
Artemis deficiency.
DCLRE1C
c. SCID with RAG1 deficiency Recombinase-activating protein 1. AR 11p13 11
RAG1 Deficient rearrangement of B and T cell
receptor genes (RAG1 and RAG2 are
adjacent genes)
d. SCID with RAG2 deficiency Recombinase-activating protein 2. Deficient AR 11p13 11
RAG2 rearrangement of B and T cell receptor genes
2. SCID with nonfunctional T and B cells
a. Omenn syndrome with RAG1 Recombinase-activation protein 1, partially AR 11p13 11
deficiency deficient rearrangement of B and T cell
RAG1 receptor genes
b. Omenn syndrome with RAG2 Recombinase-activation protein 2 partially AR 11p13 11
deficiency deficient rearrangement of B and T cell
RAG2 receptor genes
c. Omenn syndrome with Artemis DNA cross-link repair 1C protein Artemis AR 10p13 11
deficiency
DCLRE1C
d. Omenn syndrome with IL-7Rα Interleukin-7 receptor α chain AR 5p13 11
deficiency
IL-7R
e. DNA ligase deficiency IV Ligase IV, ATP-dependent AR 13q33–34 11,30
LIG4
f. SCID with microcephaly due to DNA repair factor (XRCC4-like factor, AR 2q35 11,30
deficiency of non-homologous Cernunnos) involved in non-homologous
end-joining factor 1 end-joining
NHEJ1
3. SCID without T cells (T−B+)
a. X-linked SCID (γc-chain deficiency) Common γ (γc) chain protein, a component of XL Xq13.1–13.3 9
IL2RG receptors for cytokines IL-2, -4, -7, -9, -15,
and -21.
b. SCID with Jak3 (Janus kinase 3) Janus-activating kinase 3 (Jak3), a cytoplasmic AR 19p13.1 10
deficiency tyrosine kinase interacting with γc to transmit
JAK3 signals from IL-2, -4, -7, -9, -15, and -21
c. SCID with IL-7Rα deficiency Interleukin-7 receptor α chain AR 5p13 11
IL7R
d. SCID with CD45 deficiency Protein tyrosine phosphatase receptor type C AR 1q31–q32 13
PTPRC
e. SCID with CD3 δ-chain deficiency CD3δ component of CD3 antigen receptor AR 11q23 16
CD3D complex
f. Human Nude/SCID Forkhead box N1 protein, winged-helix-nude AR 17q11–q12 Frank et al., 1999
FOXN1 (Whn). Transcription factor required for
thymus and hair follicle development
4. Deficiencies of purine metabolism
a. SCID with ADA (adenosine deaminase) ADA is required for purine metabolism; AR 20q13.2–q13.11 12
deficiency elevated purine metabolites (primarily dATP)
ADA toxic to T and B cells
b. SCID with PNP (purine nucleoside PNP is required for purine metabolism; elevated AR 14q13.1 12
phosphorylase) deficiency purine metabolites (primarily dGTP) toxic to
NP T and B cells
5. MHC class II (major histocompatiblity complex class II) deficiency secondary to deficiencies of transcription factors for MHCII expression
a. CIITA (MHCII transactivator) deficiency MHCII transactivating protein, a non-DNA AR 16p13 17
MHC2TA binding component of the MHCII promoter-
binding complex; complementation group A
b. RFXANK deficiency Regulatory factor X-associated AR 19p12 17
RFXANK ankyrin-containing protein, an MHCII
promoter-binding protein; complementation
group B
(continued)

4
Table 1.1. (continued)
Defective Protein, Reference or
Designation and Gene Name* Pathogenesis Inheritance Locus Book Chapter

c. RFX-5 deficiency MHCII promoter X box regulatory factor 5, an AR 1q21 17

RFX5 MHCII promoter-binding protein;
complementation group C
d. RFXAP deficiency Regulatory factor X-associated protein, an AR 13q 17
RFXAP MHCII promoter-binding protein;
complementation group D
6. MHC class I deficiency
a. TAP1 deficiency Transporter protein associated with antigen AR 6q21.3 18
TAP1 presentation 1
b. TAP2 deficiency Transporter protein associated with antigen AR 6q21.3 18
TAP2 presentation 2
c. Tapasin deficiency TAP binding protein (tapasin) AR 6p21.3 18
TAPBP
7. Class-switch recombination defect (hyper-IgM syndromes) affecting both B and T cells; see also B.6.
a. CD40L deficiency CD40 ligand (CD154). Tumor necrosis factor XL Xq26 19
TNFSF5 superfamily member 5
b. CD40 deficiency CD40. Tumor necrosis factor receptor AR 20q12–q.13.2 19
TNFRSF5 superfamily member 5
8. Non-SCID CD3 deficiency due to absence of proteins forming the CD3 complex required for T cell receptor signaling See A.2.e for SCID with CD3δ
deficiency
a. CD3ε deficiency CD3ε polypeptide AR 11q23 16
CD3E
b. CD3γ deficiency CD3γ polypeptide AR 11q23 16
CD3G
c. CD3Z-deficiency CD3ζ polypeptide (TiT3 complex) AR 1q22–q25 Rieux-Laucat
et al., 2006
9. CD8 deficiency CD8 antigen, α polypeptide (p32) AR 2p12 16
CD8A
10. ZAP-70 deficiency Cytoplasmic tyrosine kinase ZAP-70 (T-cell AR 2q12 14
ZAP-70 receptor ζ-chain associated protein kinase,
70kDa). Signaling from the T-cell receptor
during T-lineage development
11. IL-2 R α-chain deficiency IL-2 receptor α-chain is required for regulation AR 10p14–p15 15
IL2RA and control of autoreactive T cells
12. p56 Lck deficiency Lymphocyte-specific protein tyrosine kinase. AR 1p34.3 14
LCK Required for T cell maturation in the thymus
B. Deficiencies Predominantly Affecting Antibody Production
1. Agammaglobulinemia
a. XLA (X-linked agammaglobulinemia) Btk (Bruton agammaglobulinemia tyrosine XL Xq21.3 21
BTK kinase) required for intracellular
signaling in B cell development
b. X-linked hypogammaglobulinemia with Btk not affected; unknown XL X 21
growth hormone deficiency
c. µ heavy-chain deficiency µ heavy-chain. Required for development of AR 14q32.3 22
IGHM B cells from B lineage progenitors
d. λ5 surrogate light-chain deficiency λ5 surrogate light-chain. Part of receptor AR 22q11.22 22
IGLL1 complex on pre-B cells required for B
lineage differentiation
e. Igα deficiency Ig-associated α chain signaling component of AR 19q13.2 22
CD79A pre-B and B cell receptor complex required
for B lineage differentiation and B cell
signaling
f. BLNK deficiency B-cell linker/SLP-65/BASH. B cell signaling AR 10q23.2–q23.33 22
BLNK protein
g. LRRC8 deficiency Leucine rich repeat containing 8 AD 9q34.2 Sawada et al.,
transmembrane protein 2003
2. Selective deficiency of Ig isotypes/subclasses due to isolated or combined deficiencies
a. IgA deficiency Failure of IgA B cell differentiation Complex — 23
b. α1 subclass deficiency IgA1 is the major IgA subclass AR 14q32.33 23
IGHA1
c. α2 subclass deficiency IgA2 is mainly found in the gastrointestinal AR 14q32.33 23
IGHA2 tract
(continued)

5
Table 1.1. (continued)
Defective Protein, Reference or
Designation and Gene Name* Pathogenesis Inheritance Locus Book Chapter

d. γ1 subclass deficiency IgG1 constitutes 65% of serum IgG AR 14q32.33 23

IGHG1
e. γ2 subclass deficiency IgG2 constitutes 25% of serum IgG AR 14q32.33 23
IGHG2
f. γ3 subclass deficiency (partial) IgG3 constitutes 8% of serum IgG. Partial IgG3 AR 14q32.33 Yount et al., 1967
IGHG3 deficiency is associated with the ‘g’ allotype
and caused by reduced isotype switching
g. γ4 subclass deficiency IgG4 constitutes 4% of serum IgG AR 14q32.33 23
IGHG4
h. IgG subclass deficiency with or without Defect in differentiation of a B lymphocyte Unknown — 23
IgA deficiency subset or in expression of IgG
i. ε isotype deficiency IgE is encoded by a single gene AR 14q32.33 23
IGHE
3. Light-chain deficiency
a. κ light-chain deficiency κ light chain binds to a heavy chain to form AR 2p11 Stavnezer-
IGKC immunoglobulins Nordgren et al.,
1985
4. Common variable immunodeficiency (for WHIM see F8)
a. Common variable immunodeficiency of Serum IgG low, IgA low or absent, IgM Complex — 23
unknown origin variable. Variable impairment
of T cell function
b. ICOS (inducible costimulator) ICOS is expressed by activated T cells and AR 2q33 23
deficiency interacts with ICOSL (B7RP-1). Deficiency
ICOS results in late-onset B cell loss
c. CD19 deficiency CD19 antigen expressed by B cells AR 16p11.2 23
CD19
d. TACI deficiency Tumor necrosis factor receptor super family AD, AR 17p11.2 23
TNFRSF13B member 13B
e. BAFF receptor deficiency Tumor necrosis factor receptor super family AR 22q13.1–q13.3 23
TNFRSF13C member 13C
5. Other antibody deficiencies
a. Antibody deficiency with normal Defective antigen-specific antibody production Unknown — 43
immunoglobulin levels
b. Transient hypogammaglobulinemia Delayed maturation of T cell helper function Unknown — Gitlin and
Janeway,
of infancy 1956; Tiller and
Buckley, 1978;
Kilic et al.,
2000
6. Defects of class-switch recombination and somatic hypermutation (hyper-IgM syndromes) affecting B cells; see also A.7.
a. AID deficiency Activation-induced cytidine deaminase AR 12p13 20
AICDA
b. UNG deficiency Uracil-DNA glycosylase AR 12 20
UNG
c. Selective deficiency in Ig class-switch Defect downstream of AID, normal somatic Unknown — 20
recombination hypermutation
C. Defects in Lymphocyte Apoptosis
1. Autoimmune lymphoproliferative syndrome (ALPS); see also D.2.
a. ALPS type Ia (defective CD95) Apoptosis mediator CD95 (Fas/APO-1) AD, AR 10q23–q24.1 24
TNFRSF6 required for lymphocyte homeostasis Induces
apoptosis via engagement of FasL
b. ALPS type Ib (defective CD178) Fas Ligand (FasL). Inducing apoptosis via AD 1q23 24
TNFSF6 engagement of Fas
c. ALPS type IIa (caspase 10 deficiency) Caspase 10; apoptosis-related cysteine protease AR 2q33–q34 24
CASP10
d. ALPS type IIb (caspase 8 deficiency) Caspase 8; apoptosis-related cysteine protease AR 2q33–q34 24
CASP8 CASP8 and CASP10 are adjacent genes
D. Other Well-Defined Immunodeficiency Syndromes
1. Wiskott-Aldrich syndrome, X-linked Wiskott-Aldrich syndrome protein (WASP), XL Xp11.22 31
thrombocytopenia and X-linked especially important in platelets and T cells
neutropenia (continued)
WASP

6
Table 1.1. (continued)
Defective Protein, Reference or
Designation and Gene Name* Pathogenesis Inheritance Locus Book Chapter

2. Autoimmune disorders; see also C.1.

a. APECED (autoimmune Autoimmune regulator-1 (AIRE-1) or APECED AR 21q22.3 25
polyendocrinopathy with candidiasis and protein. Transcription factor expressed in the
ectodermal dystrophy) thymus
AIRE
b. IPEX (immune deficiency/dysregulation, Forkhead box P3 transcription factor. Expressed XL Xp11.23 26
polyendocrinopathy, enteropathy, by CD4+ CD25+ regulatory T cells (T reg)
X-linked)
FOXP3
3. X-linked lymphoproliferative syndrome SH2 domain protein 1A (also called XL Xq25–q26 32
(Duncan disease) SLAM-associated protein, SAP). Involved in
SH2D1A intra-cellular signaling of T and NK cells;
protects against severe outcome of EBV
infection
4. DiGeorge/velo-cardio-facial syndrome. Multiple congenital anomalies most often due AD 22q11.2 33
(22q11.2 deletion syndrome) to deletion of DGCR (DiGeorge
DGCR chromosomal region). Developmental defect
of thymus. May be associated with congenital
heart disease, hypoparathyroidism, and other
congenital abnormalities
5. CHH (cartilage-hair hypoplasia) RNA component of mitochondrial RNA- AR 9p13 36
RMRP processing endoribonuclease
6. Hyper-IgE recurrent infection syndrome Unknown AD, AR, Some cases 34
(Job syndrome) Sporadic Chromosome 4
7. Chronic mucocutaneous candidiasis Unknown AR, AD 2p (AD) Chilgren et al.,
1967; Atkinson
et al., 2001
E. Defects of Phagocyte Function
1. Chronic granulomatous disease caused by defective intracellular oxidative burst required for bacterial and fungal killing.
a. X-linked CGD Cytochrome phagocyte oxidase (phox) XL Xp21.1 37
CYBB gp91phox. Cytochrome b-245 β-polypeptide
b. p22phox deficiency Cytochrome oxidase p22phox AR 16q24 37
CYBA
c. p47phox deficiency Cytochrome oxidase p47phox AR 7q11.23 37
NFC1
d. p67phox deficiency Cytochrome oxidase p67phox AR 1q25 37
NFC2
2. Leukocyte adhesion defects (LAD)
a. LAD1 CD18 cell surface protein. Cell surface AR 21q22.3 38
ITGB2 adhesion complex (CD11a,b,c/CD18)
requires integrin β2 (CD18) to be stably
expressed
b. LAD2 N-acetylated α-linked acidic dipeptidase2. AR 11q14.3–q21 38
NAALLAD2 Fucose transporter required for proper
carbohydrate addition; patient cells lack
sialyl-Lewis X
c. LAD3 Defect in G protein-coupled receptor AR Unknown 38
(GPCR)-mediated stimulation of integrins at
the endothelial contact. May affect Rap-1
regulation
d. LAD with RAC2 deficiency RAS-related, RHO family small GTP-binding AR 22q12.13–q13.2 38
RAC2 protein RAC2. Predominant in neutrophils,
involved in O2− production, actin
cytoskeleton
3. Chediak-Higashi syndrome Lysomal trafficking regulator. Required for AR 1q42–q43 40
LYST formation of lysosomes and cytoplasmic
granules
4. Griscelli syndrome
a. Griscelli syndrome type 1 Myosin-VA (5A). Involved in organelle AR 15q21 41
MYO5A transport
(continued)

7
Table 1.1. (continued)
Defective Protein, Reference or
Designation and Gene Name* Pathogenesis Inheritance Locus Book Chapter

b. Griscelli syndrome type 2 Rab27A, GTP-binding protein. Regulates AR 15q21 41

RAB27A cytotoxic granule exocytosis associated with
the accelerated phase of Griscelli syndrome.
Myosin-VA (5A) and Rab27A are closely
linked on chromosome 15q21
5. Glucose 6-phosphate dehydrogenase Granulocyte intracellular killing defect XL Xq28 37
deficiency associated with complete absence of G6PD
G6PD in phagocytes
6. Myeloperoxidase (MPO) deficiency MPO is required to convert H2O2 to hypohalous AR 17q23.1 Lehrer and Cline,
MPO acid. Intracellular killing of fungi is impaired. 1969; Nauseef
et al., 1994
7. Glycogen storage disease type 1b Solute carrier family 37 (glycerol-6-phosphate AR 11q23.3 Hiraiwa et al., 1999
SLC37A4 transporter), member 4. Neutropenia,
impaired neutrophil migration due to
defective glucose 6-phosphate translocase
8. Neutropenia
a. Cyclic neutropenia and Neutrophil elastase 2. Includes Kostmann AR (AD) 19p13.3 39
severe congenital
neutropenias syndrome
ELA2
b. Congenital X-linked neutropenia WASP Wiskott-Aldrich Syndrome Protein XL Xp11.22 31
(WASP)—see D.1
9. Dyskeratosis congenita Dyskeratosis congenita 1, dyskerin. Affected XL Xq28 Heiss et al., 1998
DKC1 males have epithelial abnormalities, cancer
predisposition, bone marrow failure
10. Shwachman Bodian Diamond syndrome Highly conserved protein of unknown function. AR 7q11 Boocock et al.,
SBDS Pancreatic insufficiency and bone marrow 2003
dysfunction, including neutropenia
11. Familial hemophagocytic lymphohistiocytosis (FHL)
a. FHL1 Unknown AR 9q22 41
b. FHL2 Perforin deficiency Perforin 1 (pore forming protein) AR 10q22 41
PRF1
c. FHL3 Vesicle priming protein unc-13 homolog D AR 17q25.3 41
UNC13D (C. elegans)
F. Defects of the Innate Immune System: Receptors and Signaling Components
1. Interferon-γ receptor deficiency. Cell surface receptors for IFNγ protect against salmonella and mycobacterial disease.
a. IFNγ receptor 1 deficiency IFNγ-receptor 1 (or α-chain) is required for AR 6q23–24 28
IFNGR1 binding as well as signaling by associating
with Jak1.
b. IFNγ receptor 2 deficiency IFNγ-receptor 2 (or β-chain) is required for AR 21q22.1–q22.2 28
IFNGR2 signaling by associating with Jak2.
2. IL-12 p40 deficiency Interleukin-12 40 KD subunit. IL-12 is required AR 5q31.1–q33.1 28
ILI2B for the production of IFN γ by T and NK cells
3. IL-12Rβ1 deficiency Receptor β chain for interleukin-12 AR 19p13.1 28
ILI2RB
4. STAT1 deficiency Signal transducer and activator of transcription AD, AR 2q12–q13.2 28
STAT1 1, 91 KDa.
5. STAT5b deficiency Signal transducer and activator of transcription AR 17q21 Kofoed et al., 2003
STAT5B 56, 80 KDa. Immunodeficiency and growth
hormone insensitivity
6. IRAK-4 deficiency Interleukin-1 receptor-associated kinase 4 AR 12q12 Picard et al., 2003
IRAK4 Chapter 8
7. X-linked anhidrotic ectodermal dysplasia Inhibitor of κ light polypeptide gene enhancer XL Xq28 36
with immunodeficiency in B cells, kinase γ. NF-κB essential
IKKBG modulator (NEMO)
8. Anhidrotic ectodermal dysplasia with T Nuclear factor of κ light polypeptide gene AD 14q13 36
cell deficiency enhancer in B cells, inhibitor α
NFKB1A
9. Warts, hypogammaglobulinemia, Chemokine C-X-C motif receptor 4 (CXCR4) AD 2q21 23
recurrent bacterial infections, and
‘myelokathexis’ (WHIM)
CXCR4
(continued)

8
Table 1.1. (continued)
Defective Protein, Reference or
Designation and Gene Name* Pathogenesis Inheritance Locus Book Chapter

G. DNA Breakage-Associated and DNA Epigenetic Modification Syndromes (for Artemis, ligase IV, and NHEJ1 deficiency—see section A2)
1. DNA breakage-associated syndromes
a. Ataxia-telangiectasia (A-T) mutated Cell cycle check point ATM protein kinase AR 11q22.3 29
ATM
b. Nibrin Nijmegen breakage syndrome 1 protein nibrin. AR 8q21 30
NBS1 Participates in DNA repair together with
RAD50 and MRE11
c. Bloom syndrome DNA repair protein BLM AR 15q26.1 30
BLM
d. A-T like disease (A-TLD) DNA damage-response protein AR 11q21 30
MRE11A
e. DNA ligase deficiency I Ligase I, DNA, ATP-dependent. AR 19 30
LIG1
2. Immunodeficiency, centromere instability DNA (cytosine-5)-methyltransferase 3b. AR 20q11.2 35
and facial abnormalities syndrome (ICF)
DNMT3B
H. Defects of the Classical Complement Cascade Proteins
1. C1q deficiency
a. C1QA C1 α-polypeptide AR 1p36.3–p.34.1 42
b. C1QB C1 β-polypeptide AR 1p36.3–p.34.1 42
c. C1QG C1 γ-polypeptide AR 1p36.3–p.34.1 42
2. C1r and C1s deficiency
a. C1R C1r subcomponent. Often combined with C1s AR 12p13 42
defect
b. C1S C1s subcomponent. Often combined with C1r AR 12p13 42
defect
3. C2 deficiency C2 gene is encoded within the MHC cluster AR 6p21.3 42
C2
4. C3 deficiency Major factor for both classical and alternative AR 19p.13.3 42
C3 complement pathways
5. C4 deficiency
a. C4A C4A subunit AR 6p21.3 42
b. C4B C4B subunit. C4A and C4B are adjacent genes AR 6p21.3 42
within the MHC cluster.
6. C5 deficiency C5 peptide. Initiates formation of the membrane AR 9q33–9q34.1 42
C5 attack complex (MAC)
7. C6 deficiency C6 peptide. Part of MAC AR 5p13 42
C6
8. C7 deficiency C7 peptide. Part of MAC AR 5p13 42
C7
9. C8 deficiency
a. C8A C8α-polypeptide AR 1p32 42
b. C8B C8β-polypeptide AR 1p32 42
c. C8G C8γ-polypeptide, binds covalently to the AR 9q 42
C8α-chain; C8 is part of MAC.
10. C9 deficiency C9 peptide. Part of MAC. C6, C7, and C9 genes AR 5p13 42
C9 are clustered on chromosome 5p13.
I. Defects of the Alternative Complement Pathway
1. Factor B deficiency Factor B serine protease. Interacts with factor D. AR 6p21.3 42
BF The gene is encoded within the MHC cluster.
2. Factor D deficiency Factor D interacts with factor B. AR 19p13.3 42
DF
3. Factor H1 deficiency Factor H deficiency leads to uncontrolled AR 1q32 42; Edwards
HF1 activation of the alternative C′ pathway. A et al., 2005;
polymorphism (Y402H) is responsible for Haines et al., 2005;
∼ 50% of age-related macular degeneration. Klein et al., 2005
4. Properdin factor C deficiency Contributes to activation of C3 via the XL Xp11.3–p11.23 42
PFC alternative pathway.
J. Complement Regulatory Proteins
1. C1 inhibitor deficiency C1 inhibitor, a serine protease inhibitor. AD 11q11–q13.1 42
C1NH Haploinsufficiency results in hereditary
angioedema (continued)
9
10 Overview

Table 1.1. (continued)

Defective Protein, Reference or
Designation and Gene Name* Pathogenesis Inheritance Locus Book Chapter

2. C4-binding protein deficiency Presumed defect in C4 binding; dissociates and

degrades C4 (classical C- pathway)
a. C4BPA C4 binding protein α AR 1q32 42
b. C4BPB C4 binding protein β AR 1q32 42
3. Decay-accelerating factor (CD55) deficiency Glycosyl phosphatidylinositol (GPI)-anchored AR 1q32 42
DAF antigen. Impairs C′ killing by controlling
both pathways
4. Factor I deficiency C3-inactivator AR 4q25 42
IF
5. CD59 (antigen P18-20) or protectin 20 kDa GPI-anchored antigen. Inhibits lysis by AR 11p13 42
deficiency classical C′ pathway
CD59
6. Mannose-binding lectin deficiency
a. Mannose-binding lectin deficiency Mannose-binding lectin activates a distinct, AR and AD 10q11.2 42
MBL2 antibody-independent complement pathway
b. Mannan-binding lectin-associated serine Mannan-binding serine protease 2. Activates AR 1p36.3–p36.2 42
protease 2 deficiency complement pathway by cleaving
MASP2 mannose-binding lectin
K. Periodic Fever Syndromes
1. Familial Mediterranean fever (FMF) Pyrin (marenostrin) AR 16p13.3 27
MEFV
2. Hyperimmunoglobulinemia D with Mevalonate kinase AR 12q24 27
periodic fever syndrome, hyper-IgD
syndrome
MVK
3. Tumor necrosis factor receptor-associated TNF receptor 1 cytokine receptor (CD120a) AD 12p13.2 27
periodic syndrome (TRAPS)
TNFRSF1A
4. Cold autoinflammatory syndrome 1
a. Familial cold urticaria (FCU) and Cryopyrin /NALP3/PYPAF1 AD 1q44 27
Muckle-Wells syndrome (MWS)
CIAS1
b. Chronic infantile neurological, Cyropyrin /NALP3/PYPAF1 AD 1q44 27
cutaneous and articular syndrome
CINCA syndrome
CIAS1
5. Granulomatous sinovitis with uveitis and Caspase recruitment domain (CARD) family, AD 16q12 27
cranial neuropathies (Blau syndrome) member 15. Intracellular sensor of bacterial
CARD15 peptidoglycan
6. Crohn’s disease Caspase recruitment domain (CARD) family, Polygenic 16q12 27
CARD15 member 15. Intracellular sensor of bacterial
peptidoglycan. Mutated in a subset of
Crohn’s disease

AD, autosomal dominant; AR, autosomal recessive; EBV, Epstein-Barr virus; NK, natural killer; XL, X-linked.
*Gene names, in italics, according to the Human Genome Organization, http://www.gene.ucl.ac.uk/nomenclature/; Wain et al., 2002, and online Mendelian Inheritance in
Man, http://www.nebi.nlm.nih.gov/omim/.

studied extensively over several years and known to be essential their incidence in control populations, in patients with certain
for lymphocyte activation, no one had predicted that CD45 defi- immunodeficiency syndromes. In this book we have included
ciency would result in human severe combined immunodeficiency diseases caused by genes encoding functionally important com-
(SCID) (Chapter 13). In an even more unexpected development, ponents of lymphocytes, phagocytes, and proteins in the innate
the identification of a defective RNA component of an endori- immune system. This means that we have broadened the tra-
bonuclease as the cause of cartilage-hair hypoplasia was certainly ditional meaning of the word immunodeficiency, which was in-
not anticipated (Chapter 36). troduced to describe the lack of a component protecting an
individual from infections. The majority of leukocyte abnormali-
ties indeed cause susceptibility to infections. In some diseases
Infections, Autoimmunity, and Cancer:
the defective component is only expressed in leukocytes, and the
Features of Genetic Immunodeficiencies
defect, therefore, is inherent to this lineage. In other abnormali-
The hallmark of primary immunodeficiencies is an increased sus- ties, such as ataxia telangiectasia (Chapter 29), Bloom syndrome
ceptibility to infections. However, both malignancies and auto- (Chapter 30), and DiGeorge anomaly (Chapter 33), the gene is
immune disorders are known to occur at high rates, compared to expressed outside the hematopoietic lineage and nonimmune
 Genetically Determined Immunodeficiency Diseases 11

features may even prevail. Among patients with most comple- “immune surveillance” on the theory that the immune cells, partic-
ment defects and periodic fevers, abnormal susceptibility to in- ularly natural killer (NK) cells, are programmed to eliminate
fection is less pronounced. transformed cells. Another mechanism contributing to tumor de-
Autoimmunity is often a complex phenomenon involving velopment is impaired eradication of microorganisms with an
dysregulation or imbalance in immune pathways and networks. oncogenic potential such as Epstein Barr virus (EBV); EBV lym-
However, discovery of apoptosis defects associated with autoim- phoproliferative disease is seen in several immunodeficiencies,
munity, such as the mutations in the apoptosis mediator CD95 particularly X-linked lymphoproliferative disease (Chapter 32).
(Fas) in patients with autoimmune lymphoproliferative syndrome In some inherited immunodeficiencies with an increased inci-
(ALPS), illustrates that mutations in a single gene can have an dence of tumors, however, such as Artemis deficiency and Bloom
important effect (Chapter 24). This syndrome is often due to a syndrome, the mutated gene encodes an enzyme affecting DNA
dominant interfering mutation of CD95 that impairs physiologic breakage and rejoining (Chapters 11, 29, and 30).
apoptosis with the subsequent potential for accumulating self-
reactive lymphocytes, which in turn mediate autoimmune re-
Genetic Immunodeficiencies in the Spectrum
sponses. More generally, the observation was made many years
of Host Defense Disorders
ago that the incidence of autoimmune disorders is increased in
certain primary immunodeficiency diseases, such as common The immune system is part of the multifaceted general defense
variable immunodeficiency and immunoglobulin A (IgA) defi- system evolved to protect higher organisms from harmful inva-
ciency (Chapter 23) and Wiskott-Aldrich syndrome (Chapter 31). sion of microorganisms. The first lines of defense against infec-
Allergy is recognized as having a genetic component, but at tions are anatomical, mechanical, and chemical barriers. When
present is not associated with a single-gene primary immuno- the skin or mucosa is breached—for instance, by a burn or ab-
deficiency. However, high levels of IgE are associated with hypo- normality involving the skin or respiratory tract (severe eczema,
morphic mutations (i.e., with residual protein activity) in the cystic fibrosis, or disorders of ciliary function in respiratory
genes, which cause Omenn syndrome (Chapter 11) and in pa- epithelium)—susceptibility to infections is readily apparent. Sim-
tients with the Wiskott-Aldrich syndrome or immune dysregula- ilarly, the normally low pH of the stomach or vagina and the ac-
tion, polyendocrinopathy, enteropathy with X-linked inheritance tion of secreted enzymes and antibacterial defensins discourage
(IPEX). In certain hyper-IgE syndromes, which can be inherited as bacterial invasion. Because small numbers of potentially patho-
an autosomal dominant or recessive trait, very high levels of IgE genic organisms routinely get past these barrier defenses, the
are found, but the molecular cause is not yet known (Chapter 34). reticuloendothelial system, principally the spleen, serves to filter
Enhanced tumor susceptibility is not a hallmark of all primary and neutralize invaders in the bloodstream. Thus splenic defi-
immunodeficiencies, but in certain disorders such as Wiskott- ciency, most commonly due to sickling hemoglobinopathies, is a
Aldrich syndrome (WAS) the frequency of malignancy, particu- major cause of immune compromise. Phagocytes and lympho-
larly lymphoma, is known to be high (Chapter 31). Malignancies cytes and their humoral products constitute a highly specialized
in immunocompromised individuals may be secondary to chronic and coordinated network responsible for selective recognition
infections, which may induce overstimulation of the immune and elimination of microorganisms that have passed through the
system and thus increase the risk of transforming mutations as- body’s outer barriers.
sociated with cell division. Tumor development in patients with The most common causes of immunodeficiency worldwide
primary immunodeficiencies has also been attributed to defective are acquired. These are most often malnutrition and immunosup-

Figure 1.1. Simplified schematic diagram

of mediators of leukocyte activation and in-
teractions between T and B cells,
macrophages, and neutrophils. Secreted,
membrane-associated, and cytoplasmic pro-
teins are labeled in boldface if primary im-
munodeficiency disorders are known to
result when they are absent or defective. IL-
Rc, common chain of IL-2, 4, 7, 9, and 15
receptors;
IFN-R, interferon receptor; TCR, T cell
receptor; SLeX, S-Lewis X receptor. For
other abbreviations, see Table 1.1.
12 Overview

pression secondary to bacterial, fungal, parasitic, and particu- usual infections, the common denominator of most genetically
larly viral infections, not only with human immunodeficiency determined primary immunodeficiency disorders. The types of
virus (HIV) but also with other viruses, such as measles and pathogenic organisms, the course of the infections, and the effec-
EBV. In developed countries, iatrogenic immunosuppression is tiveness of available therapies were, over time, recognized to be
also found in settings of cancer therapy, organ transplantation, correlated with the nature of the immune defect. These clinical
and chronic steroid administration. observations remain the most important tools for suspecting and
In contrast, diseases for which the primary cause is a heritable diagnosing patients with immunodeficiency (see Chapter 43).
defect in an immune system gene are infrequent; the common es- For example, recurrent sinopulmonary infections might suggest
timate is around 1 per 10,000 births, but the true incidence is not an antibody disorder, while bacterial, viral, and fungal infections,
known. Such rare events might be considered to have limited which fail to respond to conventional treatment, suggest T cell or
significance on the global scale. However, an understanding of combined defects.
rare, heritable immunodeficiencies at the molecular level helps As our appreciation of the different host defense mechanisms
physicians diagnose and treat individuals with acquired immune has progressed, new immunologic tests have evolved that have
deficits. There is also a long list of additional inherited syn- improved the diagnostic capability of physicians caring for pa-
dromes that appear related to immune deficiency (Ming et al., tients with an abnormal predisposition to infection. From the dis-
1996). The recent appreciation of the interplay between different covery of agammaglobulinemia and its consequences by Bruton
combinations of inherited and environmental factors promises to (1952) to the enumeration and phenotyping of B cells, T cells,
help investigators uncover the molecular etiology of more com- and T-cell subsets and the functional testing of lymphocytes and
mon disorders with complex inheritance, such as the majority of phagocytes in vitro, we have come a long way in understanding
common variable immunodeficiency and IgA deficiency al- normal immune processes and recognizing specific abnormalities
though also here single gene defects without any known environ- in immunodeficient patients. Classification combining immuno-
mental influence have been identified (Chapter 2). On the other logical tests and empirical observations has in turn led to improved
hand, a certain genetic makeup may protect an individual from therapeutic approaches, such as immunoglobulin replacement for
infections; for example, persons lacking the chemokine receptor patients with agammaglobulinemia.
CCR5 on the surface of their T cells are relatively protected from Grouping of human immunodeficiencies into a series of syn-
HIV infection, as this virus uses CCR5 as a coreceptor (Deng et dromes by clinical presentation and laboratory findings has made
al., 1996; Dragic et al., 1996; Biti et al., 1997). it possible to recognize how dysfunction of each of the distinct
Although this book’s main focus is on the recognizable, branches of the immune system, and in some cases genetically
single-gene primary immunodeficiency syndromes and their mo- distinct disease entities, can produce a particular pattern of infec-
lecular defects, the advances in understanding of these diseases tions and clinical presentations. Such a disease classification sys-
have furthered our knowledge of the normal development and tem has been composed and periodically updated by the World
function of each component of the immune system. New insights Health Organization Scientific Group on Primary Immunodefi-
from primary immunodeficiency demonstrate that efficient pro- ciency Diseases (WHO Scientific Group, 1995, 1997; Chapel
tection against microorganisms depends not only on the perfor- et al., 2003). As new syndromes have been discovered and their
mance of each individual component but, equally important, on a associated genes identified, the nomenclature describing primary
flawless interdigitation of the innate immune system, neutrophils, immunodeficiency disorders has been modified and expanded
and activated T and B lymphocytes. (Wain et al., 2002, 2004).
Figure 1.1 shows a simplified diagram of many major compo- Molecular disease classification is now being integrated with
nents of the immune system and of gene products that are critical ever-more sophisticated and specific in vitro testing of immune
for the development and regulation of immune responses. Each cell functions. This new level of definition serves to refine further
of the molecules highlighted in bold letters has been associated the clinical and laboratory classifications already established,
with a primary heritable immunodeficiency. Under normal circum- making possible longitudinal clinical follow-up and tailoring of
stances, the costimulation of B cells by antigens, antigen-activated treatments for each genotype. In Table 1.1 a summary of currently
T cells, and lymphokines results in the production of antibodies recognized primary disorders of the immune system is given and
of evolving isotypes from IgM to IgG and with increasingly each disorder associated with a known disease gene has the gene
high affinity. These antibodies form antigen–antibody complexes name listed along with the disease name. The logical extension of
to opsonize microorganisms, neutralize viruses, and activate the this type of classification is to gather information from large num-
complement cascade. Some of the complement subunits liberated bers of patients with each specific gene disorder into databases
during complement activation are potent chemotactic agents that that include clinical presentation, molecular data including spe-
attract neutrophils and macrophages. To emigrate from the vascu- cific gene mutations, treatments, outcome, and long-term follow-
lar spaces, phagocytic cells need adhesion molecules and a cy- up. Some attempts in this direction have already been made (Smith
toskeletal system that permits movement. To trap antigen for and Vihinen, 1996; Levy et al., 1997; Winkelstein et al., 2003); the
presentation to T cells, macrophages with Fc and complement re- rarity of each individual disorder dictates that databases of pooled
ceptors and also follicular dendritic cells and B cells are strategi- patient information are necessary to provide unprecedented ability
cally distributed throughout the tissues. Before the T- and to analyze the immunodeficiency diseases.
B-cell–specific responses to invasion can be mobilized, the innate
immune system provides significant basic protection.
Spectrum of Clinical
Immunodeficiency Syndromes
Evolution of the Classification of
How many mutated genes causing primary immunodeficiency dis-
Genetic Immunodeficiencies
eases are there? Mutations interfering with expression may be
The first descriptions of immunodeficiency diseases grew out of irrelevant if the gene product is redundant or nonessential; muta-
clinical observations of patients with recurrent, severe, or un- tions may escape detection by producing profound abnormalities
 Genetically Determined Immunodeficiency Diseases 13

Figure 1.2. Pedigree of a family

with X-linked agammaglobuline-
mia (XLA), illustrating medical
progress in diagnosing and treat-
ing affected males. Males,
squares; males diagnosed with
XLA, filled squares. Females,
circles; mutation carriers, circles
with filled center. Slash, de-
ceased. Individuals who may
have had the XLA mutation are
indicated with a question mark.
Year of birth (b) and age of death
are indicated for selected individ-
uals. Individuals III-1, III-4, and
IV-3 died of pneumonia. IV-4
died of pulmonary insufficiency,
having suffered many bouts of
pneumonia from early childhood
until diagnosis at age 7.

incompatible with viability; or mutations may cause a heritable of affected members. Figure 1.2 represents a kindred now rec-
disease with a characteristic phenotype. The total number of genes ognized to be carrying X-linked agammaglobulinemia (XLA)
in humans is estimated to be around 22,000. Estimates based on (Chapter 21). Inspection of the pedigree reveals that individual
subtraction experiments suggest that the number of genes prima- III-3, born in 1918, is an obligate carrier of this condition. It is
rily involved in leukocyte development and function may be more interesting that she had two brothers who died early in life; al-
than 1000. Allowing for some redundancy, somewhat fewer than though definitive information is lacking, they may have been
1000 single-gene primary immunodeficiencies might be possible, affected with XLA. Her oldest son, IV-3, suffered from recur-
around seven times the number now recognized in Table 1.1. rent upper and lower respiratory tract infections and died of
The more common single-gene immunodeficiency diseases pneumonia in 1948 at the age of 4 years. Her two younger sons,
have been studied extensively, but their true frequencies in dif- IV-4 and IV-6, were able to receive the newly available antibi-
ferent populations are still only roughly estimated. The most otic penicillin. They survived multiple episodes of pneumonia
frequently seen monogenic primary immunodeficiencies are and were diagnosed with XLA in the mid-1950s, shortly after
X-linked, requiring only a single mutational event to be manifest. Bruton’s discovery of agammaglobulinemia (Bruton, 1952). By
More than 2000 patients with one of five X-linked immunodefi- the time intramuscular immunoglobulin treatment was insti-
ciencies have recently been collectively registered and reported tuted, both boys had developed chronic lung disease and
(see Chapter 45). There are far more immunodeficiency disor- bronchiectasis. IV-4 was one of the first patients treated with
ders that are inherited as autosomal recessive traits. However, be- high doses of intravenous immunoglobulin (IVIG) for echovirus
cause they require loss of function of both copies of a gene on infection with dermatomyositis, fasciitis, and meningitis
homologous chromosomes, the incidence of these diseases is far (Mease et al., 1981). He died of chronic respiratory failure at
lower. If one considers that an estimated number of genetically the age of 50.
determined human diseases is around 5000 and over 2300 have The younger generations of this family have a much more
been mapped on the human genome (Online Mendelian Inheri- hopeful prognosis. When individual V-3 developed his first pneu-
tance in Man, 2005), it is clear that many potential primary im- monia at the age of 2, he was referred to a university center,
munodeficiency disorders have so far not been identified as where the diagnosis of XLA was confirmed and treatment with
distinct entities. If they have actually occurred, they may have immunoglobulin was initiated. He has remained healthy with
presented as sporadic cases and not been recognized as gene- regular immunoglobulin replacement and presently has a full-
tically determined immune deficiencies. time job and no chronic disease. XLA was diagnosed in the
Furthermore, mutations located in different regions of the youngest member of this kindred, VI-3, at the time of birth by
same gene may cause diseases with different manifestations or documentation of absent B cells in cord blood. He was immedi-
phenotypes, referred to as allelic heterogeneity (see Chapter 2). ately started on immunoglobulin treatment and remains com-
This is exemplified by mutations of the WAS gene, some of pletely healthy.
which tend to present as full-blown WAS, whereas others are Gene therapy has been pursued in primary immunodeficien-
more regularly associated with X-linked thrombocytopenia and cies since the early trials of gene replacement for adenosine
still others with isolated neutropenia (see Chapter 31). deaminase (ADA) deficiency in 1990 (Chapter 48). However,
only in 2000 was therapeutic benefit achieved, when patients
with X-linked SCID became the first humans to have their dis-
Progress in Diagnosis and Treatment
ease reversed by gene therapy as their sole treatment (Cavazzana-
Progress in immunology, genetics, and molecular biology has Calvo et al., 2000). Recent reports of highly effective gene therapy
changed the way we diagnose and treat affected patients. This is protocols for both X-linked SCID, due to common γ-chain defi-
illustrated by the histories of families with multiple generations ciency, and ADA SCID (Aiuti et al., 2003) demonstrate the
14 Overview

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 2

Genetic Principles and Technologies

in the Study of Immune Disorders
JENNIFER M. PUCK and ROBERT L. NUSSBAUM

Medical genetics is the subspecialty of medicine concerned with It is customary in human genetics to refer to the location of a
the investigation, diagnosis, treatment, counseling, and manage- particular gene on a chromosome as the locus for that gene. The
ment of patients and families with inherited disease. Research DNA sequence in and around a gene (such as in introns, flanking
in medical genetics focuses on identifying the genes involved in regions, or even within coding regions) may be variable among
human hereditary diseases and the changes in DNA sequence that the individuals in the population. The term allele is used to de-
cause or predispose to these diseases; elucidating disease patho- scribe different DNA sequence variants, and the particular pair
genesis, including both genetic and environmental factors; under- of alleles an individual possesses for a given gene is called the
standing the inheritance patterns of diseases in families; developing genotype. Alleles can be rare, deleterious mutations that cause
new treatments or cures for hereditary disorders; and helping pa- disease, or fairly frequent normal variants of no known clinical
tients and families make reproductive decisions and cope with significance. If greater than 2% of the population has a DNA se-
the impact of genetic disorders on the health of family members. quence that differs from the DNA sequence in other individuals,
Although a complete discussion of medical genetics is beyond the variation is called a polymorphism. A group of polymorphic
the scope of this book and can be reviewed in several texts (Vogel alleles at a set of loci close together in a row on a single chromo-
and Motulsky, 1996; Scriver et al., 2001; Nussbaum et al., 2006), some is called a haplotype. Because the loci are close to each
it is essential to present here an overview of the terminology, other, recombination between homologous chromosomes will
concepts, and methods of modern molecular genetics. This intro- occur only rarely in the region containing these loci and there-
duction will outline the approaches that have led to the identifi- fore the entire block of alleles contained in a particular haplotype
cation of the genes involved in over 140 specific disorders of the tend to be inherited together.
immune system. These findings should make possible further
revolutionary changes, not only in the discovery of additional
Mechanisms of Inheritance
disease genes, but also in understanding the pathogenesis of de-
fects in host defenses. Using this understanding, we may create
Mendelian vs. Complex Inheritance
effective new therapies.
The normal complement of 46 chromosomes in a human Mendelian inheritance is a term used to describe the hereditary
cell consists of 23 pairs of homologous chromosomes (Fig. 2.1). patterns seen in diseases caused by DNA mutations in single
Twenty-two of the 23 pairs are autosomes and are the same in genes inherited from parents by their offspring. Thus, Mendelian
men and women; the remaining pair, the sex chromosomes, con- disorders include most of the rare primary immunodeficiency
sist of two X chromosomes in females and one X and one Y diseases described in this book. An increasing awareness of a
(carrying the male-determining genes) in males. The two homolo- genetic contribution to other diseases has led to the designation
gous chromosomes that make up any of the 22 pairs (23 pairs in non-Mendelian or complex inheritance to refer to instances in
females) are identical in size, centromere placement, and arrange- which an individual’s genetic makeup has a more variable and
ment of genes. more complex role in disease causation. Examples of complex

16
 Medical Genetics in the Study of Immune Disorders 17

Figure 2.1. Normal human metaphase

chromosomes from a male, aligned to
show the 22 pairs of autosomes, plus one
X and one Y. The banding pattern is re-
vealed by Giemsa staining. Giemsa-light
regions are particularly rich in genes.
(Kindly provided by Amalia Dutra.)

diseases include multifactorial diseases in which one or more

gene mutations must interact with each other and/or environmen-
tal factors in order for a disease to be manifest.

Autosomal Recessive Inheritance

In autosomal recessive inheritance (Fig. 2.2), disease usually
results when a person inherits two defective copies of the same
autosomal gene; the affected individual can be either a homozy-
gote, if two identically defective copies of the same gene are
inherited, or a compound heterozygote if there are two different
deleterious mutations in the gene. The parents are unaffected het-
erozygotes who carry one normal copy and one abnormal copy
of the gene. By definition, in recessive disease, heterozygous car-
riers of recessive disorders are not affected because the normal
copy of the gene compensates for the defective copy. The typical
familial inheritance pattern in autosomal recessive illness is for
disease to occur in one or more full brothers and sisters, with
both genders affected equally and both parents unaffected. Re-
cessive disorders are seen with increased frequency in children
of consanguineous marriages, in which the parents are related to
each other (Fig. 2.2), and in genetically isolated populations, be-
cause both parents have a greater chance of carrying the same Figure 2.2. Autosomal recessive inheritance. Circles, females; squares,
defective gene inherited from a single common ancestor. The males; filled symbol, affected; symbol with dot, silent carrier. Roman
numerals designate generations, with each individual within a generation
genotypes of affected individuals in such instances are expected
identified by an integer. This pedigree demonstrates a consanguineous
to show homozygous mutations. A lack of family history is not an mating, double horizontal line, between cousins III-1 and III-2 (a typical,
argument against autosomal recessive inheritance because, with but not required characteristic of autosomal recessive disease pedigrees).
small sibship sizes typical of many contemporary families, a single An arrow marks the proband, the first person in the family to come to
affected child born to unaffected parents is the rule rather than medical attention. For updated conventions for pedigree drawing, see
the exception. Bennett et al. (1995).
18 Overview

Recessive illness usually results from loss of function of a gene syndrome (see Chapter 33). This model for dominant inheritance
whose product is normally present in excess so that even a half- is called haploinsufficiency. In contrast, more than two copies of
normal amount of the gene product is adequate to prevent disease. a gene may also cause disease inherited in an autosomal domi-
For example, homozygotes with deletion of the first exon of the nant manner, as is seen with duplication of the PMP22 gene in
gene encoding adenosine deaminase (ADA) have a profound defi- Charcot-Marie-Tooth IA peripheral neuropathy (Boerkel et al.,
ciency of the enzyme, resulting in early onset of severe combined 2002) or triplication of the α-synuclein gene in familial Parkin-
immunodeficiency (SCID) (see Chapter 12). In contrast, heterozy- son disease (Singleton et al., 2003).
gotes, with one deleted and one functional copy of the gene, have In a second pathogenetic mechanism, a gain of novel func-
an amount of enzyme activity intermediate between that found in tion, a dominant mutation may cause a new or altered protein to
normals and that in patients with ADA-deficient SCID; but even a be made that is endowed with a novel or toxic activity not found
small fraction of the normal activity is sufficient to protect them in the normal gene product. An example is the acute myeloid
from expressing any immunological defect. leukemia M4Eo subtype associated with a somatic (not germline,
and thus not inherited from one generation to the next) inversion
of chromosome 16 (Liu et al., 1993). This chromosomal rearrange-
Autosomal Dominant Inheritance
ment causes the apposition of the 5′ portion of the transcription
In autosomal dominant inheritance (Fig. 2.3), an individual needs factor gene CBFB with the 3′ end of the gene encoding myosin
only one copy of a gene alteration for the disease to occur. The heavy chain, a structural protein of muscle. The result is a chimeric
parent from whom the genetic alteration was inherited may him- protein that interacts in an abnormal way with other transcription
self or herself be affected, or may be a silent, or nonpenetrant, elements to interfere with the normal transcription program of
carrier. Alternatively, neither parent may harbor the alteration myeloid progenitor cells.
seen in the child if the child’s mutation arose spontaneously in A third type of mutation frequently causing dominant inheri-
one of the two gametes, egg or sperm, from which the child was tance is dominant negative mutation, such as that seen in most
formed. The typical inheritance pattern in autosomal dominant patients with an autoimmune lymphoproliferative syndrome (see
illness is to see multiple affected individuals, both genders af- Chapter 24). Patients with heterozygous mutations in the gene
fected equally, with transmission of the disease from one genera- encoding the apoptosis mediator CD95 or Fas have defective pro-
tion to the next. A lack of family history is not a strong argument grammed cell death through the homotrimeric Fas receptor com-
against autosomal dominant inheritance, however, because a non- plex. In vitro studies of the mutated gene products show not only
penetrant carrier parent or a new mutation will make the affected failure of the mutant protein to transmit a death signal itself but
individual appear as a sporadic occurrence of the disease in the also interference by these altered Fas proteins with death signal
family. transmission by coexpressed normal Fas (Fisher et al., 1995). The
If a dominantly inherited condition requires the presence of mutated Fas proteins may produce steric interference when in-
an alteration on only one chromosome, it would seem contradic- corporated into the normal trimeric Fas receptor complex.
tory that some heterozygotes for the defective gene can show no Finally, a mechanism operating in some dominantly inherited
evidence of the disease (lack of penetrance), as illustrated for in- cancer syndromes is that of a two-hit process (Knudson, 1971).
dividual II-4 in Figure 2.3. However, such lack of penetrance is a The first hit is an inherited mutation that inactivates one allele of
well-described phenomenon in autosomal dominant disorders. a tumor-suppressor gene, rendering an individual heterozygous
Incomplete penetrance is seen if the onset of the disorder is age- for the mutated gene. One defective allele for this type of inheri-
dependent or if an additional factor or factors, such as a second tance is not in itself sufficient to cause disease. However, an indi-
spontaneous somatic mutation or an environmental agent or in- vidual who carries only one normal copy of a tumor-suppressor
fluence, must be superimposed on the underlying genetic defect gene is at markedly increased risk for developing cancer. All that
in order for the disease to become clinically evident. is required is that a single somatic cell undergo a second muta-
Mutations can cause dominantly inherited diseases through tion inactivating the remaining normal allele for that one cell to
a number of different mechanisms. In the most straightforward undergo pathologic, unregulated growth and produce a clonal can-
situation, abnormal amounts of the gene product may be inade- cer. Second hits are frequently genomic deletions in a single cell
quate or allow accumulation toxic metabolites. For example, defi- as it divides, resulting in loss of heterozygosity at the disease lo-
ciency of one copy of a gene or multiple genes contained within cus in the tumor cells.
microdeletions of chromosome 22 is responsible for DiGeorge
X-Linked Inheritance
Mutations in X-linked genes have strikingly different conse-
quences in males and females and cause diseases with a distinc-
tive X-linked pattern of inheritance (Fig. 2.4). This is because of
the different number of X chromosomes in males and females
and the unique biological properties of the mammalian X chro-
mosome. In a male carrying a defective X-linked gene, clinically
apparent abnormality always occurs because his only copy of the
gene is disrupted. Male hemizygosity for the X chromosome ex-
plains the large number of X-linked immunodeficiencies (Fig. 2.5)
Figure 2.3. Autosomal dominant inheritance. Note male-to-male trans- and the high proportion of males diagnosed with inherited im-
mission from subject II-2 to III-4, strongly suggesting dominant inheri- munodeficiency. In females with X-linked gene defects, the situ-
tance. II-4 is a nonpenetrant carrier. Circles, females; squares, males; filled ation is more complex. In order to provide dosage compensation
symbol, affected; symbol with circle, at risk but currently unaffected car- and to equalize gene expression for X-linked genes in males and
rier; arrow, proband. females, one of the two X chromosomes in a female’s somatic
 Medical Genetics in the Study of Immune Disorders 19

Figure 2.4. X-linked inheritance. Circles, females;

squares, males; filled symbol, affected; symbol with dot,
silent carrier. Male-to-male transmission is not present.

cells is chosen at random, early in embryonic life, to undergo a have inactivated the X chromosome carrying the normal gene
near total and irreversible inactivation (Lyon, 1966). Thus, in predominate in a tissue, female heterozygotes may be sympto-
contrast to the situation with a heterozygote for an autosomal matic. Thus, the terms dominant and recessive as applied to auto-
gene mutation, a female heterozygous for an X-linked gene mu- somal disorders are not strictly applicable to X-linked diseases.
tation does not have a uniform population of cells, each of which In female carriers of some X-linked conditions, such as
expresses both the normal and abnormal gene. Instead, the so- X-linked SCID due to defects in the IL-2Rγ receptor (see Chap-
matic tissues of a female are made of a mixture of cells, some of ter 9) or X-linked agammaglobulinemia (XLA) due to defects in
which have an active X chromosome carrying the normal gene, the Btk kinase (see Chapter 21), the expected random X inacti-
while the rest have an active X carrying the abnormal gene. The vation in the lymphocyte population targeted by the gene defect
relative proportion of cells with one or the other X chromosome is not seen (Puck, 1993). In these situations, a female carrier of
active in any one tissue averages 50%, but may differ substan- X-linked SCID (or of XLA) will have no lymphocytes (or in the
tially depending on chance and the number of precursor cells for case of XLA no B cells) whose active X chromosome carries the
that tissue that were present in the embryo when X inactivation mutation because the fraction of the lymphocyte precursors that
took place. The fraction of cells in a tissue that have an active X have inactivated the X chromosome carrying the normal version
chromosome carrying the normal gene is usually sufficient for of the gene cannot develop and differentiate normally. As a re-
normal function of the tissue, so female heterozygotes for X-linked sult, the target lymphocyte population for each disease will show
disorders are usually silent carriers. If, however, the cells that marked “skewing” of X-inactivation. The abnormal X-inactiva-
tion pattern seen in X-linked immunodeficiencies is discussed in
greater detail in the chapters related to specific diseases and in
Chapter 44.
A typical X-linked inheritance pattern (Fig. 2.4) is character-
ized by multiple affected male siblings and cousins as well as af-
fected males in additional generations, all affected members of
the kindred being related through unaffected female relatives.
However, a lack of family history does not rule out an X-linked
inheritance mechanism for immune deficiency. As with autosomal
dominant disorders, a spontaneous new mutation in an X-linked
gene can cause the disease to appear in the family, either directly
in a male, or by the creation of a silent female carrier who passes
the mutation on to her male children. One-third of the cases of
X-linked diseases severe enough to prevent reproduction by af-
fected males are expected to be the first manifestation in their
pedigree of a new mutation (Haldane, 1935). Because males do-
nate a Y chromosome and not an X chromosome to their sons,
documenting male-to-male transmission of any trait in any pedi-
gree rules out X-linked inheritance.

Heterogeneity
Genetic heterogeneity is a broad term used to describe departures
from the simple models of “one gene—one enzyme” or “one
mutation—one disease.” Diseases can show allelic heterogeneity,
in which different mutations in the same gene cause disease, as is
Figure 2.5. Idiogram of human chromosome X, illustrating the major
Giemsa bands and conventional cytogenetic nomenclature, including the rule in single-gene immunodeficiency diseases. Locus hetero-
p (short) arm and q (long) arm, integers denoting major bands increasing geneity occurs in diseases such as SCID in which a similar phe-
from centromere to telomere, and additional digits to the right of the notype of opportunistic infections from of lack of cellular and
decimal point denoting sub-bands. The loci on the X chromosome of humoral immunity can arise from mutations in a number of dif-
known human immune disease genes are indicated. ferent genes; the diseases caused by mutations at these different
20 Overview

loci are termed genocopies. In contrast, a phenocopy is an ac- Aneuploidy, or abnormal chromosome number, is associated
quired, not a genetic, disease that resembles genetic forms of the with immune defects. Trisomy 21, or Down syndrome, the most
disease. common genetic cause of human mental retardation, is accompa-
Still more complicated models of inheritance appear to be op- nied by depressed in vitro immune responses and by increased
erating in disorders such as common variable immune deficiency incidence of autoimmunity and infections, the leading cause of
and IgA deficiency (see Chapter 23) or atopic disease. In these dis- death in Down syndrome (Epstein, 2001).
orders one can observe a clearly increased incidence within fami- At the subchromosomal level, contiguous gene deletion syn-
lies; however, an obvious Mendelian pattern of inheritance is not dromes are collections of clinical manifestations resulting from
seen. A genetic contribution to such diseases is suspected when consistently observed chromosomal deletions spanning multiple
there is greater concordance of the disease in monozygotic (identi- neighboring genes. An example is the chromosome 11p13 dele-
cal) twins than in dizygotic (fraternal) twins and when there is an tion syndrome associated with Wilms tumor, aniridia, genitouri-
increased risk for the disease in relatives of affected patients com- nary anomalies, and mental retardation (Haber, 2001; Schaffer
pared to that in the population at large. The risk of a second af- et al., 2001). Larger deletions produce the complete phenotype,
fected individual in a family is greater the closer the blood while smaller disruptions involving single genes within the re-
relationship with the proband. Such complex inheritance patterns, gion produce limited phenotypes, such as isolated aniridia. A
well described in asthma and insulin-dependent diabetes mellitus, contiguous gene deletion syndrome in the context of an immun-
are the result of interactions between genes at different loci com- odeficiency has been postulated, but not proven, in DiGeorge
bined with unidentified, but substantial environmental effects. syndrome, which is associated with deletions of chromosome
22q11 (see Chapter 33; Schaffer et al., 2001).
Rare or unique chromosomal abnormalities are occasionally
How to Identify Disease Gene Loci
found in the context of primary genetic disorders. Coexistence
of a chromosomal translocation, duplication, or deletion and an
Abnormal Protein Products
abnormal phenotype in a patient is very unlikely to be a coinci-
The first disease genes to be recognized as mutated in immune dis- dence; rather, the cytogenetic lesion provides direct evidence for
orders were identified by defining abnormalities in their protein the genetic localization of a disease. One of the best examples
products. Adenosine deaminase deficiency was originally identi- of chromosomal abnormality leading to gene identification is
fied as a purine metabolic defect, and subsequently the absence of the contiguous gene deletion syndrome produced by interstitial
ADA enzyme activity was noted in patients who lacked lympho- deletion of chromosome Xp21 in male patients suffering from
cytes and had immune defects (see Chapter 12; Giblett et al., multiple disorders including chronic granulomatous disease as
1972). This approach was fruitful in ADA-deficient SCID because well as Duchenne muscular dystrophy, retinitis pigmentosa, and
the enzyme encoded by the disease gene turned out to be a “house- McLeod hemolytic anemia (see Chapter 37; Schaffer et al.,
keeping” gene, expressed in all normal cells. It was subsequently 2001).
appreciated that the amount of ADA protein normally found in
lymphocytes is far greater than that in other tissues and that T cells
Disease Gene Localization
are exquisitely sensitive to elevated levels of its substrates, includ-
by Linkage Mapping
ing deoxyadenosine. These facts help to explain why ADA defi-
ciency is much more harmful to lymphocytes than to other cell
types, although effects on organs such as the liver and central ner- DNA polymorphisms
vous system are recognized. The general method of first identifying Each child inherits one chromosome of each pair of homologous
protein abnormalities in immune disorders and then documenting chromosomes from one parent and the other chromosome of the
gene lesions has been less successful for disease genes that have re- homologous pair from the other parent. The parent of origin of
stricted tissue expression or are only active in an early stage of dif- each chromosome in a pair can be identified by tracing the inher-
ferentiation of the target cell type. For these, positional cloning and itance of DNA polymorphisms, small differences in DNA se-
testing for mutations in candidate genes have been essential. quence between chromosomes. Polymorphic alleles for linkage
analysis were originally detected by different lengths of the DNA
segments seen on Southern blots of DNA digested with various
Cytogenetic Abnormalities
restriction endonucleases (restriction fragment length polymor-
When clinical disorders are associated with abnormalities in the phisms, or RFLPs) (Drayna and White, 1985). By 1990, RFLPs
number or structure of an individual’s chromosome complement, were largely replaced by short tandem repeat polymorphisms
cytogenetic techniques can lead to the identification of disease (STRPs) composed of stretches of simple dinucleotide, trinu-
genes. Metaphase chromosomes from dividing cells can be stained cleotide, or tetranucleotide, repeats of variable length, such as
with Giemsa to reveal segmental banding patterns that uniquely CACACACA . . . . CA. The number of repeats in an STRP can
characterize each human chromosome (Fig. 2.1). Cytogenetic vary tremendously, with as many as a dozen alleles or more found
analysis involves comparison of each chromosome to the stan- in populations of healthy subjects. STRPs occur frequently in the
dard karyotype idiogram, as illustrated for the X chromosome in genome and can be assayed by the polymerase chain reaction (Litt
Figure 2.1. Hybridization of labeled DNA probes to denatured and Luty, 1989; Weber and May, 1989). More recently, single
chromosomes, known as fluorescent in situ hybridization, or FISH nucleotide polymorphisms (SNPs) have begun to replace STRPs
(Color Plate 2.1), can pinpoint much smaller regions of the genome as useful polymorphisms (Sachidanandam et al., 2001; Holden,
to indicate the chromosomal location of a disease-associated mi- 2002). Although SNPs are comprised of only two alleles and,
crodeletion, duplication, or rearrangement. The example in Plate therefore, are less informative than STRPs, they can be analyzed
2.1 shows hybridization of a fluorescent labeled cosmid containing much more inexpensively than STRPs by high-throughput tech-
the Fas-associated death domain (FADD) gene to identify its local- nology. Because SNPs are far more frequent, occurring approxi-
ization to human chromosome 11q13.3 (Kim et al., 1996). mately every 1000 base pairs, SNP variants are dense enough to
 Medical Genetics in the Study of Immune Disorders 21

be used for association studies (see below). For more informa- resulting gametes will have a chromosome with a new (recombi-
tion on genetic marker loci, see Chapter 44. nant) combination of alleles, i.e., either alleles A and b or a and B.
From a knowledge of the genotypes of parents and their offspring,
Meiotic crossing-over one can count the number of offspring resulting from a gamete
In the absence of abnormal cytogenetic findings to point to carrying a crossover between locus 1 and locus 2 and determine
the chromosomal locus for a genetic disorder, mapping of a dis- the observed recombination frequency with which crossing-over
ease gene usually relies on linkage analysis in kindreds in which events happen between the two loci during gametogenesis.
the disorder affects multiple individuals. Gene mapping by link- If crossing-over occurs approximately uniformly along a chro-
age analysis is made possible by the normal phenomenon of mei- mosome, then the chance of a crossing-over event should reflect
otic recombination, or crossing-over during gametogenesis. how far apart the two loci are on that chromosome. The further
During the first meiotic division, each pair of homologous chro- apart the loci are physically, the greater the chance that at least
mosomes lines up randomly on the spindle and then separates in one crossover will occur between them; the closer they are to
the course of the first reduction division of meiosis I. This indepen- each other, the smaller the chance of crossing over. It is straight-
dent assortment of chromosomes during meiosis I is responsible forward to show that if two loci are so far apart that at least one
for randomly distributing one member of each pair of homologous crossover will always occur in the chromosomal interval between
chromosomes into each gamete. It is also in meiosis I that homolo- locus 1 and 2 during gamete formation, then 50% of all the off-
gous segments of two chromatids form a pair of homologous chro- spring will have the nonrecombinant and 50% the recombinant
mosomes that interchange their genetic material by crossing over genotype (Nussbaum et al., 2006). At the other extreme, when
at points of contact, known as chiasmata (Fig. 2.6). On average, two loci are so close together that crossovers almost never occur,
between two and four chiasmata develop between every pair of the observed recombination frequency will approach zero. Be-
homologous chromosomes during each meiosis. tween these two extremes are linked loci on a chromosome. These
Suppose two polymorphic loci are situated at locus 1 and lo- loci have less than 50% recombination in offspring since recom-
cus 2 on the same chromosome, as shown in Figure 2.6, and binants can arise only through a relatively rare crossing-over
there are polymorphic alleles A and a at locus 1 and alleles B and event that just happens to fall within the short segment of chro-
b at locus 2. Also suppose that a parent is heterozygous at both mosome separating them. For such loci, the frequency of recom-
loci (genotype Aa Bb), and, in addition, allele A at locus 1 hap- binant offspring will be somewhere between 0% and 50%. Thus,
pens to be on the same chromosome (same DNA molecule) as in principle one should be able to correlate recombination fre-
allele B at locus 2, while alleles a and b are both on the other quency with the actual distance between two loci. This is the case
chromosome. If no crossing-over occurs in the interval between when two loci are reasonably close, with a recombination fre-
locus 1 and locus 2 during meiosis, each gamete will receive ei- quency less than 10%; recombination frequency then translates
ther the chromosome containing alleles A and B or the one carry- directly into a theoretical genetic distance, measured in units
ing alleles a and b (nonrecombinant). If, however, a crossing-over called centiMorgans (cM), where 1% recombination frequency is
event between the two loci in the Aa/Bb individual occurs, the equal to 1 cM. This relationship does not hold when loci are
loosely linked (recombination frequencies >10%–20%) because
of the chance that two independent crossovers, rather than just
one, will occur between the two loci. A double crossover will not
be detected as a recombination between the two markers and,
thus, the measured recombination frequency will always be less
than the genetic distance in cM.
In physical terms, the average recombination rate across the
entire genome is 1.2 cM per megabase (Mb) of DNA, which means
that 1 cM of genetic distance represents approximately 830,000
base pairs of DNA (Kong et al., 2002). The correlation between
genetic distance and molecular distance, however, can vary with
the gender of the individual in whom the meiosis is occurring and
the region of the chromosome being examined. Overall, across all
22 autosomes, the recombination rate in males is 0.9 cM per Mb
whereas it is 1.5 cM per Mb in females, presumably because of
biologic differences in meiosis I in female vs. male gameto-
genesis. As one looks at smaller and smaller segments of DNA,
the average recombination frequency per DNA segment length
becomes increasingly inhomogeneous. For example, telomeric re-
gions have threefold higher recombination per unit length of
DNA in males than do centromeric regions. At an even finer scale,
recombination becomes very nonuniform, with some segments of
a few thousand bases showing a 200 times higher recombination
rate than that of neighboring segments of equal length (Jeffreys
et al., 2001; Gabriel et al., 2002).
Model-based linkage analysis
Figure 2.6. Diagram of meiotic crossing-over involving two hypotheti-
cal loci, 1 and 2. Alleles at locus 1 are A and a, alleles at locus 2 are B and Linkage analysis is used to map genes responsible for diseases
b. Recombinant gametes are products of a crossover event between locus 1 inherited in a classical Mendelian pattern (Borecki and Suarez,
and locus 2. 2001). Affected and unaffected members of families in which the
Exploring the Variety of Random
Documents with Different Content
SECRETARY STANTON’S GENEROUS
GIFT.

IN October, 1863, I came up from the hospitals in the front, to attend

a sanitary convention at Muscatine, Iowa.
As I was legally commissioned the sanitary agent of the State by
Governor Samuel J. Kirkwood, having been elected to that position
by the Legislature of Iowa, my presence was greatly desired by the
workers.
The convention was large and representative. But my own heart was
greatly burdened with touching messages from dying soldiers to their
wives and children. In the midst of the convention I boldly announced
my purpose to try to establish a home for soldiers’ orphan children.
The proposition was received with the wildest enthusiasm; and the
convention took action at once, not only indorsing the movement, but
pledging financial support.
There was no precedent to follow, as there was no institution of the
kind in all the world.
I was elected president of “The Orphans’ Home Association,” but
declined, and Governor Stone, the newly elected governor of the
State, was chosen. The ablest men and women of the State were
brought into the organization, and the Home was duly opened in a
rented house.
The house, although large, was soon crowded to overflowing, and
we could get no larger building that would accommodate the
hundreds who were applying for admission.
A committee sent out to search for more commodious quarters
reported new, fine barracks on a piece of confiscated land of thirty
acres, adjoining the town of Davenport.
The barracks were new and well-built, and had cost $46,000.
The leading men of Iowa, as well as the women, were actively
enlisted in the work.
Ex-Governor Kirkwood, and his private secretary, N. H. Brainard,
Governor Stone, Judge Lowe, Judge Coles, Chaplain Ingalls, John
Parvin, and many others whose names were a guaranty of honest
and faithful work, were active.
I was selected to go to Washington and secure these barracks as a
gift from the government, if possible. If I could not obtain them as a
gift, I was authorized to offer $1,000 a year as rent for them. I
protested strongly against being sent on such an important mission;
but I was overruled, and was obliged to accept the duty.
When I reached Washington, October, 1865, I went to the surgeon-
general’s office, and made known my mission, and secured an
official statement that those barracks would not be needed for
hospital purposes. I want to say in this connection that Surgeon-
General J. K. Barnes had always co-operated with me most heartily
in all my work.
I then called on Quartermaster-General Meigs, the man who with
such wonderful executive ability fed and clothed the great armies of
the republic, furnishing quarters and equipments, and paid their
wages with an honesty and fidelity that have never been questioned.
I had often met him before; and no one who ever saw him could
forget his honest, rugged, but kindly face.
When I made known my mission, he looked surprised and pleased,
and then said,—
“Well, now, that is certainly a good use to put these deserted
barracks to.”
“General,” I said, “all I want you to do, is to say officially to the
government that they will not be needed for military purposes.”
“They were never needed; they ought never to have been built. It
was a waste of money.”
“Then, General, you can certainly say they will not be needed for
military purposes. Please say that officially.”
He took up his pen and wrote out a statement, informing the
government that the new cavalry barracks at Davenport, Ia., would
not be needed for military purposes, “even if hostilities were
resumed.” His statement covered over two pages.
Thus armed, I went to the office of the Secretary of War.
I had become acquainted with Mr. Stanton under the most favorable
circumstances.
The governor of Iowa had commended me to him, and early in 1862
obtained for me a general order for transportation of myself and
supplies and rations. And later, when I called on him personally, I
was the bearer of letters of introduction and commendation from
some of his most influential and trusted friends.
Afterwards he always seemed glad to see me, and graciously
granted all my requests.
He was prompt and clear in all his business methods, and was by far
the best listener I have ever met. When I talked to him there was no
need of repeating; he apprehended my meaning. When he talked,
there was no room to misunderstand him. There was no fuss and
bluster, or pretence, or attempt to show off himself or his authority;
and that pleased me. I went, therefore, to his office with great hope
and courage. When I asked to see the Secretary of War, a young,
jolly-looking officer came forward and asked,—
“What can I do for you, madam?”
“I wish to see Mr. Stanton.”
“Mr. Stanton is in Boston. I am Major Eccles, acting Secretary of
War, and will attend to any business you may have to transact.”
I informed him as to my mission. He laughed heartily.
“That, madam, is a little beyond my prerogative. I don’t feel
authorized to give away the property of the government.”
I put myself at once in telegraphic communication with Mr. Stanton.
He asked some questions as to the legal status of the institution, and
that was all I heard that day.
The next morning I took another requisition to the War Department. It
was for hospital supplies. I distinctly remember the first few items,
1,800 blankets; 2,500 sheets; 3,000 pillow-cases; 1,500 pillows, and
so on, till everything I could remember that could be of use to the
Home were enumerated.
When I handed the document to Major Eccles, I said,—
“Here is a small requisition I should like to have go in with the
application for the property.”
“This is a small requisition,” and he laughed heartily as he read the
list aloud.
“Yes, sir,” I said with great gravity. “This is a small requisition; but
with the help of the generous people of Iowa, I hope we shall be able
to get along with that.”
“Now seriously, on what grounds have you a right to ask these
supplies from the government?”
“Well, sir, I call your attention to the fact, that at the beginning of the
war the government had very few hospital supplies. The loyal people
of the North helped to fit them up. The loyal State of Iowa sent nearly
$200,000 worth of supplies into the military hospitals. Now, all I ask
is that you give us back a few of the supplies that we gave you, as
you no longer need them.”
“You are certainly entitled to them. I will do what I can to get this
through.”
The Iowa delegation at Washington, and the officers in the War
Department, including Major Eccles, became greatly interested, and
anxious that Secretary Stanton’s answer should be favorable.
When the answer came it was:—
“Will you accept the property subject to the approval of Congress?”
I flashed back my answer as quickly as possible:—
“Yes; and will get the bill through without annoyance to you.”
As I was obliged to leave the War Department before an answer
came, Major Eccles drove up to the house of my friend, where I was
stopping, with the telegraphic order, turning over the property to the
Association. The gift of the barracks and the hospital supplies
aggregated $52,000.
I was lifted to the clouds, figuratively speaking, and rushed to the
telegraph-office, and sent off despatches to the newspapers in Iowa.
The next morning all the leading papers in Iowa appeared with great
head-lines announcing the magnificent gift.
Before Congress met we had bought out the heirs of the confiscated
property, remodelled and plastered the buildings, and had nearly five
hundred soldiers’ orphan children comfortably housed there.
Hon. Hiram Price, a member of Congress from the Davenport
District, took charge of our bill, and carried it through Congress
without annoyance to Mr. Stanton.
The fact that we had possession, and were housing and supporting
so many soldiers’ orphan children in these barracks, made
opposition almost impossible.
With this valuable property in our possession, it was an easy task to
induce the State Legislature to take this burden off our hands and
make it a State institution. The frame barracks have been replaced
by substantial brick buildings; but the Home is still conducted on the
cottage plan, and is one of the finest institutions of the State.
Edwin M. Stanton’s generous action in giving this timely help to a
weak society secured the success of a worthy institution, that has
educated and sent out thousands of children to be good and useful
citizens.
Mr. Stanton was one of the strong, true, honest men who made Mr.
Lincoln’s administration a success. He was intensely loyal, and
intolerant to treason and self-seeking, and he made traitors tremble
on both sides of the line. He was, more than any other man, the
balance-wheel in the complicated machinery of the government
which held and regulated its internal workings.
He was a clear and close thinker, a keen and sagacious discerner of
human motives, a tireless worker, and was too open and frank to
conceal his opinions of men and things.
Too unselfish to enrich himself, he toiled on, literally killing himself at
work, and dying poor. When passion and prejudice have passed
away he will receive his full meed of praise.
 THE SPECIAL-DIET KITCHEN WORK.

NO part of the army service was so defective, during the first two
years of the war, as the cooking department in the United States
government hospitals.
Few of the men employed as cooks in these hospitals were trained
or skilled; most of them had obtained their knowledge of cookery
after being assigned to duty, under most unfavorable circumstances,
and without the proper facilities for doing their work.
One general kitchen provided the food for all—the sick, the
wounded, and the dying, as well as the nurses and convalescents.
Where there were women nurses in a hospital, and they could get a
little stove of their own, special dishes were prepared for the worst
patients; but there was no general system of providing dainty and
suitable diet for the thousands in need of delicate food in home-like
preparation.
The supplies coming from the generous people of the North
occasioned great anxiety.
The surgeons forbade their distribution at the bedside of the patients,
on the ground that something might be given which would endanger
their lives or retard their recovery, and ordered them turned over to
the commissary. Often supplies thus turned over failed to reach the
sick or wounded.
It was under these trying circumstances that the plan of a system of
special-diet kitchens came to me,—clearly and definitely, as a flash
from the skies,—like a divine inspiration.
It was in December, 1863, that the thought came to me, and I
hastened at once to put the plan into execution.
Everybody seemed to accept the plan with enthusiasm; and the
Sanitary and Christian Commission, and the officers and surgeons of
the army, all hastened to co-operate with me in inaugurating and
accomplishing this great reform.
The plan in itself was very simple and practical, and was entirely
satisfactory to all parties.
1. The food for those needing special diet was prescribed by the
ward surgeons. A bill of fare was provided, with the name of the
patient and the number of his bed, for every patient put on special
diet; and on this bill the surgeon prescribed his diet by making a
mark opposite the articles the patient was allowed. This plan gave
the sick or wounded man a chance to express his own wants in
regard to food, which was a great advantage.
2. These bills of fare were consolidated by the ward-master, and a
copy sent to the superintendent of the special-diet kitchen, and the
bills were returned to their places again. So with these consolidated
lists before them, the managers of the special-diet kitchen knew just
what to cook, and just the quantity.
3. The food thus ordered was prepared in the special-diet kitchen,
which, although under separate management, was a part of the
hospital, and as completely under the control of the authorities as
any other part of the hospital.
The kitchens were fitted up with ranges and other suitable
conveniences, and were under the management of suitable ladies
employed by the surgeons in charge. A storeroom conveniently near
or adjoining was provided, where the commuted rations of soldiers
put on special diet were stored, also the supplies furnished by the
Sanitary and Christian Commissions; and the woman in charge of
the special-diet kitchen carried the keys.
4. These dietary nurses were not cooks; they only superintended the
work. Many of those who worked in these kitchens were soldiers
who were somewhat disabled, or convalescent soldiers who were
not able to join their regiments.
In large hospitals, where one thousand or fifteen hundred were
furnished meals three times a day, the work was divided up, and
each man had his part of the work, and soon became an expert in it.
There were in the large kitchens from twenty-five to thirty men
required to do the work.
The food thus systematically prepared under the watchful eyes of
women competent to govern such a force and direct the work, was
brought to the bedside of the patients in home-like preparation.
No mistake would likely be made in the distribution, as each patient
had at the head of his bed the list of articles of food prescribed by
the surgeon of his ward.
The first kitchen was opened at Cumberland Hospital, Nashville,
Tenn.
The Christian Commission of Pittsburg, Pa., sent me the lumber to
build a kitchen, storeroom, and a ladies’ room, and two of the largest
ranges in the market.
Mary E. Moorhead, a wealthy lady of that city, daughter of Hon. J. K.
Moorhead, at that time a member of Congress, and one of
Pittsburg’s most honored citizens, and Hannah Shaw, who has since
distinguished herself in missionary work in China, took charge of that
kitchen. Miss Moorhead has since the close of the war devoted
herself to benevolent work.
The change wrought in that hospital was so marvellous that all the
leading surgeons from Louisville to Chattanooga were anxious for
the establishment of special-diet kitchens in connection with their
hospitals. Many of them could not believe the wonderful stories
circulated as to the great reform wrought in Cumberland Hospital,
and, like the Queen of Sheba, came long distances to see for
themselves as to the truth of the matter, and, like her, confessed that
“the half had not been told them.”
I was most generously sustained in this work by the Christian
Commission, who turned all their supplies into these kitchens, and
paid all the expenses of this service. I was chosen superintendent of
the special-diet kitchen work, which rapidly extended all along the
lines from Vicksburg to Petersburg.
The surgeons accepting this help, agreed to employ the women
selected by me, and allow them to have charge of the supplies
furnished for use in the special-diet kitchens, from the government
and the Sanitary and Christian Commissions. The surgeons had
charge of the kitchen, appointed these women, and directed their
work, as in all parts of their hospitals.
There was no opposition to this work. Mr. Lincoln, Secretary Stanton,
Surgeon-General Barnes, and Assistant-Surgeon-General Wood,
gave me their indorsement and all the aid I needed. It soon became
an admitted fact that thousands of lives were being saved by this
supply of better food, which many of them needed more than they
did medicine.
Surgeon-General Barnes became so enthusiastic over the plan that
he appointed a commission of United States army surgeons to
consider it, with a view of adopting it and ingrafting it upon the United
States general hospital system.
I was invited by the surgeon-general to meet with them. The
committee received me most graciously at their regular sittings in
Washington, D. C., and listened with great respect to my
explanations; and after carefully considering my plans, adopted them
as a part of the regular United States hospital system.
To give some idea of the magnitude of the work, out of over one
hundred special-diet kitchens established by me, I give the amount
of food in rations issued from sixteen special-diet kitchens, a record
of which I happen to have now on hand for February, 1865.
rations.
Tea 100,350
Coffee 54,818
Cocoa 4,770
Milk, Cold 12,194
Milk, boiled 9,860
Milk, Thickened 7,517
Bread and Milk, Boiled 2,689
Beef Tea 7,548
Beef Essence 1,699
Bread and Butter 133,938
Toast, Buttered 28,539
Toast, Dry 23,809
Toast, Milk 33,611
Crackers 18,999
Corn Bread 15,714
Biscuit 5,458
Warm Cakes 2,629
Rice 9,239
Barley 492
Farina 8,424
Gruel 1,589
Corn Starch 17,150
Mush 10,831
Soup, Chicken 8,472
Soup, Mutton 856
Soup, Beef 10,716
Soup, Barley 599
Soup, Oyster 10,193
Soup, Potato 2,301
Soup, Vegetable 4,885
Beef Steak 27,623
Roast Beef 36,599
Ham 3,585
Chicken 11,389
Turkey (only occasionally) 809
Mutton 2,357
Veal 1,510
Pork 2,208
Hash 7,925
Oysters 5,086
Fish 5,721
Eggs 15,538
Potatoes 47,725
Turnips 7,785
Carrots 1,070
Onions 12,356
Beets 271
Cabbage 15,059
Krout 1,296
Beans 494
Parsnips 1,291
Tomatoes 7,312
Puddings 34,249
Pies 5,113
Cakes 3,485
Tapioca 2,772
Sago 60
Blanc-Mange 807
Custard 1,616
Jellies 1,763
Canned Fruit 12,816
Stewed Fruit 29,266
Apple Sauce 7,618
Apples, Baked 11,774
Pickles 20,343
Lemons 127
Cheese 825
Cordials, etc 1,940
————
 Total, 899,472
This was the regular bill of fare in all the special-diet kitchens. If any
one of these articles could not be obtained, they were marked off.
Turkey was only on the list occasionally. It will be seen by the great
variety that the appetites of the patients were consulted. Nothing,
however, was issued without it being ordered by the surgeon in
attendance upon the patient.
Some of the articles furnished on the above list may seem unfit for
sick men; but when we take into consideration that there were many
wounded men who were allowed by the surgeons to eat anything
they might choose, and others who were homesick, or hopelessly ill,
or dying, who in the loneliness of suffering remembered and craved
something because a kind mother’s hand had once prepared such
dainties for them, it is no longer a matter of wonder.
And since the loved ones at home could not cheer them with their
presence and love in their dark hours of suffering, it was a delightful
task for these noble women to substitute home food and words of
cheer.
It is the verdict of history that this system of special-diet kitchens
saved thousands of lives. During the last eighteen months of the war,
over two million rations were issued monthly from this long line of
special-diet kitchens, established, many of them, almost under the
guns.
 THE AMERICAN REPUBLIC—ITS
GLORIES AND ITS DANGERS.

THE remarkable growth of the American Republic is without a

parallel in the history of the world.
A hundred years ago she was a feeble nation—in her infancy, and
scarcely recognized by the other nations of the earth. Now she
stands foremost among the governments of the world, and leads the
nations in almost everything.
Her territory is extensive and contiguous, lying between two great
oceans, and bounded on the north and south by navigable lakes and
seas.
Her resources are almost boundless. She gluts the markets of the
world with her silver and gold. Her iron and copper ores are rich and
abundant, nearly all the metals needed for the use of her people may
be had for the digging, and she may bedeck her children with the
jewels gathered from her own fields.
She can produce an abundance of cotton, wool, flax, hemp, and silk.
She is already the chief competitor in the cotton markets of Asia, and
from her own looms is clothing her people in muslins and fine linen,
and her daughters in royal purple from her silk factories. Her food
supply is immense. Her grain-fields are broad and rich enough to
supply bread to the millions of her own people, and to meet the
needs of the needy nations of the earth. Her meat supply is so large
that she is glad to share it with all the world. Her fruit yield is ample,
sufficient in variety and abundance to meet the needs of all. Only a
few luxuries are denied her. She could shut herself in, and live
luxuriously on her own products. There is not one thing that comes
from abroad that her people could not live comfortably without. Tea,
coffee, spices, and tropical fruits are not necessary to human life.
Her woods are abundant and fine, equal to any reasonable demand.
Her furniture goes to the ends of the earth.
Her building material is abundant and of superior quality. She has
granite and marble in variety, nearly all kinds of valuable building-
stones, and clays of almost every description. Her potteries are now
doing credible work, and her china and glass wares are attracting
attention in other lands. The new process by which glass china is
produced is a marvellous success.
Her people are intelligent and enterprising. The rich resources of the
country have stimulated their activities and awakened their inventive
genius till they are the leaders in the work of the world, and the most
thrifty and enterprising nation on the face of the globe.
They have tunnelled the mountains; bridged the rivers; created
water-ways; made the wilderness to bloom; and chained steam and
electricity as motive powers to their chariot-wheels, to do their
bidding on the land and under the sea.
A system of government has been established superior to any other
known before among men; and a system of free schools that has no
parallel on the face of the earth has made the people intelligent and
efficient for the practical work of life, far beyond other nations, taken
as a mass. And yet with all these blessings, dangers threaten her.
One of the dangers that threaten this glorious Republic is the foreign
emigration. Attracted by her rich resources and the marvellous
stories of her wealth, the people of other nations are coming to share
our blessings. The danger is not in the number who come, but in the
character of many of these new-comers.
They come to a new nation with old habits, and old prejudices, and
another language. They are a misfit. They care nothing for the
American Republic and her free institutions, only as they will add to
their physical comfort and personal aggrandizement. They do not
assimilate or become Americanized. Many of them are ignorant and
brutish. They huddle together; they are as much foreigners as they
were in Hungary or Sicily. They remain foreigners, and they have
nothing in common with us except their physical needs.
Among them are the vicious and the idle. Our thoroughfares are
filled with tramps and beggars. The prisons of our cities are crowded
with foreign criminals and paupers. Almost two-thirds of all the
criminals and paupers in our large cities are foreign born. Criminals
flying from justice; paupers who, from infirmities of body and mind, or
from idle and dissolute habits, must be supported,—find a refuge
here.
Statesmen may well question as to how long this Republic can take
into her bosom, and accord all the rights of citizenship to, the
criminals and paupers of the world, without danger.
But there is danger from our own people. The accumulation of great
wealth, without a corresponding increase of brains and culture, is
giving us an undesirable aristocracy. They ape the old, effete
aristocracies of the Old World.
They discount American institutions, and “adore a title.” They try to
rule business, politics, and social life. But this evil will be overcome.
In this country, where there are no entailed estates, death equalizes
wealth and power every few years.
 MEMORIAL DAY.

Bow low, fair clouds, and kiss the earth,

Where Human Freedom had her birth,
Where heroes struggled in the fight,
And patriots died for human right.
Bow low, and rainbow glories shed
Above a nation’s gallant dead;
Then bear the news o’er land and sea,
Earth’s fettered millions may be free.

Fly low, bright birds with painted wings,

And join the song a nation sings,
A glad, and sacred jubilee,
For God has set his people free.
Sing of the flag with starry field,
Sing of the eagle and the shield,
Sing of the victories of Peace,
Sing of the time when wars shall cease.

Bloom on, sweet flowers, thy perfume shed

Above each soldier’s lowly bed;
Kind nature’s fairest tribute bring,
And clothe each mound with flowers of spring.
Look up, with loving, dewy eyes,
Into the blue recording skies,
And pledge in red, and white, and blue,
That May flowers ever will be true.

Let all the people gather near,

And bow themselves with reverent fear;
For God with mighty, outstretched hand
Has graciously redeemed our land.
Come, Peace, and spread thy sheltering wing;
Come, Love, thy sweetest tribute bring;
Come, all, and join a sacred lay
To celebrate Memorial Day.
 TRANSCRIBER’S NOTES:
Obvious typographical errors have been corrected.
Inconsistencies in hyphenation have been
standardized.
Archaic or variant spelling has been retained.
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