Primary immunodeficiency diseases : a molecular and genetic approach

746 Pages·2007·16.375 MB·English

by  Hans D Ochs, C I Edvard Smith, Jennifer Puck

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
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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.
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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